Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6])([CH3:4])[CH3:3].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][C:24](O)=[O:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.O1CCCC1CCO>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][C:24]([NH:1][C:2]([CH3:4])([CH3:3])[CH:5]([OH:6])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: CC(C)(N)C(O)c1ccccc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: OCCC1CCCO1
Product: COc1ccc(CC(=O)NC(C)(C)C(O)c2ccccc2)cc1OC
Reaction time: 20 h
Yield: 82 %

Procedure:
A solution of 8.3 g. (0.05 mole) of α-(1-amino-1-methylethyl)benzenemethanol, 9.8 g. (0.05 mole) of 3,4-dimethoxyphenylacetic acid and 13.6 g. (0.055 mole) of EEDQ (Aldrich Chem. Co.) in 300 ml. of tetrahydrofuran-ethanol is refluxed for 45 minutes and then allowed to stand for 20 hours at 25° C. The solution is evaporated in vacuo. The residue is taken up with 250 ml. of ethyl acetate, washed with dilute HCl, followed by washing with aqueous NaHCO3. Subsequently, the extract is washed with aqueous NaCl, dried (Na2SO4) and evaporated to dryness in vacuo. Crystallization of the residue from ether gives 14.0 g. (82% yield) of pure 2-(3,4-dimethoxyphenyl)-N-(β-hydroxy-α,α-dimethylphenethyl)acetamide, m.p. 123°-124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.CC(C1C=CC(Cl)=CC=1)=O.[Cl-].[In+3].[Cl-].[Cl-].[CH3:31][S:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:42]=1[NH:41][CH:40]=[CH:39]2>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:39]2[C:38]3[C:42](=[C:34]([CH2:33][S:32][CH3:31])[CH:35]=[CH:36][CH:37]=3)[NH:41][CH:40]=2)([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CCOC(=O)CC(C)(O)c1ccc(Cl)cc1
Agent: CC(=O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [In+3]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(C)(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12
Temperature: 80 °C
Reaction time: 5 h

Procedure:
3.42 g (14.10 mmol) of ethyl 3-(4-chlorophenyl)-3-hydroxybutanoate (preparation in analogy to the synthesis of Example 88A starting from 4-chloroacetophenone and ethyl acetate) and 3.12 g (14.10 mmol) of indium(III) chloride were added to 2.50 g (14.10 mmol) of the compound from Example 8A in 100 ml of toluene. The reaction mixture was stirred at 80° C. for 5 h. After cooling to RT, the reaction solution was mixed with water and ethyl acetate, and the solid was filtered off. The phases of the filtrate were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the crude product by flash chromatography on silica gel (mobile phase: dichloromethane/methanol 95/5) and then by preparative HPLC (mobile phase: acetonitrile/water gradient) resulted in 0.98 g (17% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[C:4]([C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13])=O.[OH-].[K+]>C(O)COCCO>[Cl:18][C:15]1[CH:14]=[C:3]([CH2:4][C:6]2[C:7]([F:13])=[CH:8][CH:9]=[CH:10][C:11]=2[F:12])[C:2](=[CH:17][CH:16]=1)[NH2:1]
Reactant: Nc1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: Nc1ccc(Cl)cc1Cc1c(F)cccc1F

Procedure:
In the manner given in Preparation 11, 2-amino-5-chloro-2',6'-difluorobenzophenone is refluxed with potassium hydroxide in diethylene glycol to give 4-chloro-α-(2,6-difluorophenyl)-0-toluidene.
Reaction SMILES: C(OP([CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1)(OCC)=O)C.[Li+].CC([N-]C(C)C)C.[CH:42]([CH:44]1[CH2:49][CH2:48][N:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:46][CH2:45]1)=O>C1COCC1>[C:28]1([C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:13]2[CH:14]=[C:10]([CH:9]=[CH:42][CH:44]3[CH2:49][CH2:48][N:47]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[CH2:46][CH2:45]3)[N:11]=[CH:12]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOP(=O)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OCC
Reactant: O=CC1CCN(c2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C(=CC1CCN(c2ccccc2)CC1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
The product from Step D is dissolved in THF and cooled to -78° C. under nitrogen. A solution of LDA in THF is added dropwise. The reaction was stirred at -78° C. for 1 h, then a solution of 4-formyl-1-phenylpiperidine from Step A is added, and the reaction warmed to room temperature overnight. The reaction is quenched with ammonium chloride solution, and extracted with ethyl acetate. The title compound is obtained after chromatography on silica gel.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].II.[I:14](O)(=O)(=O)=O.C(OCC)(=O)C>C(O)C.O>[OH:1][C:2]1[C:9]([I:14])=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C=O)c(O)c1I
Temperature: 68 °C
Yield: 24.6 %

Procedure:
To a solution of 4.0 g (26.3 mmol) of 2-hydroxyl-4-methoxybenzaldehyde in 30 mL of ethanol was added 1.87 g (7.4 mmol) of iodine, followed by addition of a solution of 6 g (26.3 mmol) of periodic acid in 10 mL of water. The resulting dark yellow solution was heated to 68° C. for two h. After cooling to room temperature, the reaction was added to 300 mL of ethyl acetate. The resulting organic solution was washed with saturated aqueous solution of sodium sulfite, washed with brine and dried over anhydrous magnesium sulfate. After removing the volatiles, the crude products were purified by silica chromatography to afford 1.8 g (49%) of a light yellow solid: 1H NMR(CDCl3/400 MHz,) 12.18(s, 1H), 9.63(s, 1H), 7.53(d, J=8.4 Hz, 1H), 6.56(d, J=8.4 Hz, 1H), 3.99(s, 3H). 13C NMR (CDCl3/400 MHz) 194.2, 165.3, 163.0, 136.3, 116.1, 103.6, 57.2. MS (ESI+) 278.9(M+1, 100).
Reaction SMILES: [C:1]([C:3]1[C:4]([O:16][CH3:17])=[C:5]([O:14][CH3:15])[CH:6]=[C:7]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[CH:8]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(OCC)C>[NH2:2][CH2:1][C:3]1[C:4]([O:16][CH3:17])=[C:5]([O:14][CH3:15])[CH:6]=[C:7]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[CH:8]=1
Reactant: COc1cc(C2OCCO2)cc(C#N)c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C2OCCO2)cc(CN)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(5-cyano-3,4-dimethoxyphenyl)-1,3-dioxolane (50) (FIG. 22) (0.555 g, 2.23 mmole) was predissolved in 2 ml dry THF and 10 ml anhydrous diethyl ether. To this solution under an argon atmosphere at room temperature was added 2.23 ml of 1.0M lithium aluminum hydride in diethyl ether solution. The reaction was then stirred at room temperature for 4 hours. The reaction was then cooled to 0° C. and the excess hydride destroyed with H2O. The reaction mixture was subsequently quenched with 10% NaOH and extracted with diethyl ether. The organic layer was dried over MgSO4, and concentrated to an oil in vacuo.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([C:6]1[CH:7]=[CH:8][C:9]([F:33])=[C:10]([C:12]2[CH:13]=[N:14][C:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=4)[C:20]([CH:31]=[O:32])=[CH:19]3)=[N:16][CH:17]=2)[CH:11]=1)[CH3:5]>C1COCC1>[CH2:4]([C:6]1[CH:7]=[CH:8][C:9]([F:33])=[C:10]([C:12]2[CH:17]=[N:16][C:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=4)[C:20]([CH:31]([OH:32])[CH3:1])=[CH:19]3)=[N:14][CH:13]=2)[CH:11]=1)[CH3:5]
Reactant: C[Mg]Br
Reactant: CCc1ccc(F)c(-c2cnc(-n3cc(C=O)c4ccc(C(=O)OC)cc43)nc2)c1
Solvent: C1CCOC1
Product: CCc1ccc(F)c(-c2cnc(-n3cc(C(C)O)c4ccc(C(=O)OC)cc43)nc2)c1
Reaction time: 6 h

Procedure:
Methylmagnesium bromide (3 M in ether, 0.45 mL, 1.33 mmol) was added at 0° C. to a solution of 331c) (0.36 g, 0.89 mmol) in THF (70 mL) and the resulting mixture was stirred at this temperature for 6 h. The mixture was quenched with ammonium chloride solution (20 mL) and extracted with ethyl acetate (2×50 mL). The organic phase was washed with brine, dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography [silica; dichloromethane with 0-1.5% methanol]. Light yellow solid. Yield: 0.22 g (59% of theory)
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][CH2:10][C@H:11]([CH3:45])[O:12][C:13]1[CH:14]=[C:15]([CH:31]=[C:32]([O:34][C:35]2[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][CH:36]=2)[CH:33]=1)[C:16]([NH:18][C:19]1[CH:23]=[CH:22][N:21](C(OC(C)(C)C)=O)[N:20]=1)=[O:17]>C(Cl)Cl>[CH3:8][O:9][CH2:10][C@H:11]([CH3:45])[O:12][C:13]1[CH:14]=[C:15]([CH:31]=[C:32]([O:34][C:35]2[CH:36]=[CH:37][C:38]([S:41]([CH3:44])(=[O:42])=[O:43])=[CH:39][CH:40]=2)[CH:33]=1)[C:16]([NH:18][C:19]1[CH:23]=[CH:22][NH:21][N:20]=1)=[O:17]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2cc[nH]n2)c1
Reaction time: 3 h
Yield: 98.6 %

Procedure:
TFA (0.5 mL) was added to a solution of tert-butyl 3-({3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]benzoyl}amino)-1H-pyrazole-1-carboxylate (180 mg, 0.330 mmol) in dry DCM (3 mL) and the reaction was stirred under argon for 3 h. A further portion of TFA (0.2 mL) was then added and the reaction was stirred for 30 min before all the solvent was removed in vacuo. The residue was taken up in ethyl acetate (30 mL) and saturated aqueous sodium hydrogencarbonate (15 mL) and the residue was evaporated then re-evaporated with DCM/hexanes to produce the title compound as a colourless foam (145 mg, 100%).
Reaction SMILES: CC(C)([O-])C.[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]=O.[C:13](OCC)(=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].CC([O-])=O.[Na+].C([O-])([O-])=O.[K+].[K+]>C(O)(C)(C)C.Cl.CC(OC(C)=O)=O.CCO>[CH2:19]([O:18][C:16]([C:15]1[CH:14]=[C:13]([OH:21])[C:8]2[CH:9]=[CH:10][O:6][C:7]=2[CH:11]=1)=[O:17])[CH3:20]
Reactant: O=Cc1ccco1
Reactant: CCOC(=O)CCC(=O)OCC
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc(O)c2ccoc2c1
Temperature: 25 °C
Yield: 13.6 %

Procedure:
t-Butoxide (1.7 g, 15 mmol) was added to a solution of 2-furaldehyde (2.5 mL, 30.2 mmol) and diethyl succinate (3.2 mL, 19 mmol) in t-butanol (20 mL). The mixture was refluxed for 2 hr, cooled to room temperature and acidified with aqueous HCl (20% v/v) to pH˜2. The mixture was diluted with 5% HCl (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were then extracted with 10% aqueous solution of Na2CO3 (2×100 mL). The aqueous solution was washed with EtOAc and then acidified with 20% HCl to pH˜2. The aqueous layer was finally extracted with EtOAc (3×100 mL), dried over MgSO4 and concentrated to give a brown oil. The crude product was dissolved in Ac2O (10 mL) and added NaOAc (1.6 g, 19 mmol). The mixture was heated to reflux for 5 hr, cooled to room temperature and concentrated. The residue was taken into 1/2 saturated Na2CO3, extracted with EtOAc (2×150 mL), dried over MgSO4 and concentrated to give a brown color solid. The solid was then dissolved in EtOH (10 mL). To the solution was added K2CO3 (2.5 g, 18 mmol). The resulting reaction mixture was heated to reflux overnight and the solvent was removed in vacuo. The brown residue was then treated with H2O (50 mL) and acidified with 6N HCl to pH 6. The solution was then extracted with EtOAc (2×50 mL), and combined organic layers were dried over MgSO4 and concentrated. The crude material was purified by flash column chromatography to give a yellow color solid (532 mg, 9% yield). 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1 H) 7.68 (d, J=2.02 Hz, 1 H) 7.51 (s, 1 H) 6.92-7.00 (m, 1 H) 4.42 (q, J=7.24 Hz, 2 H) 1.42 (t, J=7.20 Hz, 3 H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=CC(OC(=O)C)=[CH:7][C:6]=1[O:15]C(=O)C)(=O)C.[CH2:19]([CH:26]([C:32]([CH3:34])=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.S(=O)(=O)(O)O>>[OH:4][C:5]1[CH:10]=[C:31]2[C:30](=[CH:7][C:6]=1[OH:15])[O:29][C:27](=[O:28])[C:26]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[C:32]2[CH3:34]
Reactant: CC(=O)Oc1ccc(OC(C)=O)c(OC(C)=O)c1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Agent: O=S(=O)(O)O
Product: Cc1c(Cc2ccccc2)c(=O)oc2cc(O)c(O)cc12
Temperature: 0 °C
Reaction time: 16 h

Procedure:
1,2,4-triacetoxybenzene (6.3 g, 25 mmol) and ethyl 2-benzylacetoacetate (5.5 g, 25 mmol) were heated together as described in Example 1. 75% sulphuric acid (35 ml) was added to the stirred solution and stirring continued for 16 hours. The dark coloured suspension was poured into ice/water (350 ml) with good stirring and the grey suspension filtered and the residue washed with abundant water. The residual solid was air dried and recrystallised from hot ethanol with subsequent addition of a little water to aid crystallization. The esculetin derivative formed small white needles (5.5 g, 75.3%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:14]Br.N1C=CC=CC=1.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:14][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1ccc2ncc(Br)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a suspension of quinoline-6-carboxylic acid (2.77 g, 16.0 mmol) in CCl4 (20 ml) in a flask wrapped with Al foil was added bromine (987 uL, 19.2 mmol) dropwise. The resulting mixture was stirred at rt for 30 min, then heated under reflux for 30 min. A solution of pyridine (1.55 mL, 19.2 mmol) in CCl4 (4 mL) was added dropwise at refluxing temperature. Then the reaction mixture was heated under reflux for 4 h. The reaction mixture was treated with 3 N NaOH until all the precipitates were dissolved. The aqueous layer was separated and washed with DCM once more, then acidified with 3 N HCl. The resulting orange precipitates were filtered, and washed with H2O, and a small amount of MeOH to afford the titled compound as an off-white solid (3.36 g).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[CH:10]=[CH:9][C:8]=2[NH:18][C:19]([C:21]2[N:22]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CCN(CC)CC.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[C:26]([C:24]1[N:25]=[C:21]([C:19]([NH:18][C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH2:14][O:15][S:44]([CH3:43])(=[O:46])=[O:45])[CH2:16][O:17][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:12][C:7]=2[C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[O:20])[N:22]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[CH:23]=1)#[N:27]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(CO)CO)cc1C1=CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(COS(C)(=O)=O)COS(C)(=O)=O)cc1C1=CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(2-hydroxy-1-hydroxymethyl-ethyl)-phenyl]-amide (0.600 g, 1.21 mmol, as prepared in the previous step) in CH2Cl2 (25 mL) was cooled to 0° C. and was treated with Et3N (421 μL, 3.02 mmol) and methanesulfonyl chloride (190 μL, 2.42 mmol). The mixture was stirred at 0° C. for 2 h, diluted with CH2Cl2, and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo. Silica gel chromatography of the residue with 25-50% EtOAc-hexane afforded the title compound (0.551 g, 70%) as a white solid. Mass spectrum (APCI, m/z): Calcd. for C28H40N4O8S2Si, 653.2 (M+H). found 652.8.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.CC1N=C(C)OC=1.[C:14]([C:17]1[O:21][C:20]([CH3:22])=[N:19][C:18]=1[CH3:23])(=[O:16])[CH3:15]>>[CH3:22][C:20]1[O:21][C:17]([C:14]([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)([OH:16])[CH3:15])=[C:18]([CH3:23])[N:19]=1
Reactant: Brc1ccsc1
Reactant: CC(=O)c1oc(C)nc1C
Agent: Cc1coc(C)n1
Product: Cc1nc(C)c(C(C)(O)c2ccsc2)o1

Procedure:
Starting with 3-bromothiophene and 5-acetyl-2,4-dimethyloxazole dimethyloxazole and following the general method of Example 4 the title compound was prepared. M.p. 132°-133° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]1[CH2:14][CH2:13][CH2:12]1.[H-].[Na+].[CH3:17]I>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:17])[N:6]=[C:5]2[CH:11]1[CH2:14][CH2:13][CH2:12]1
Reactant: Brc1ccc2[nH]nc(C3CCC3)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: Cn1nc(C2CCC2)c2cc(Br)ccc21
Yield: 70.3 %

Procedure:
The title compound was prepared by the method outlined for Preparative Example 59 using the 5-bromo-3-cyclobutyl-1H-indazole intermediate (427 mg, 1.70 mmol), NaH (97.5 mg, 2.25 mmol), and methyl iodide (294 mg, 2.06 mmol) to afford titled compound as a colorless oil (317 mg, 71%). 1H NMR (CDCl3) 7.82 (s, 1H), 7.41 (d, J=8.8, 1H), 7.21 (d, J=8.8, 1H), 3.90 (s, 3H), 3.88 (pent, J=9.2, 1H), 2.51-2.43 (m, 4H), 2.18-2.13 (m, 1H), 2.01 (m, 1H). LC/MS (Method B) 4.05 min, [M+1]+ 265/267.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:31])[C@@H:6]([O:11][C@H:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].[I-:32].[NH+]1C=CC=C[CH:34]=1>C(OCC)C>[I-:32].[C:1]([CH2:3][NH:4][C:5]([C@@H:6]([O:11][C@H:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N+:21]([CH3:34])[CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:31])#[N:2]
Reactant: c1cc[nH+]cc1
Reactant: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(-c2cccnc2)cc1)C(=O)NCC#N
Agent: [I-]
Solvent: CCOCC
Product: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(-c2ccc[n+](C)c2)cc1)C(=O)NCC#N

Procedure:
Using the same procedure as described for example 36 step 3 (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4-pyridin-3-ylphenyl)methyl]oxy}pentanamide (150 mg, 0.36 mmol) was converted to its pyridinium iodide salt. The salt was swished with diethyl ether (20 mL) for 18 h and the title compound was filtered off as an amorphous solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[CH:10][C:11]2[CH:27]=[CH:26][C:14]([C:15]([N:17]([CH3:25])[O:18]C3CCCCO3)=[O:16])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO.CCOCC>[OH:18][N:17]([CH3:25])[C:15](=[O:16])[C:14]1[CH:13]=[CH:12][C:11]([CH:10]=[CH:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:27][CH:26]=1
Reactant: CN(OC1CCCCO1)C(=O)c1ccc(C=CCCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: CCOCC
Product: CN(O)C(=O)c1ccc(C=CCCc2ccccc2)cc1
Temperature: 55 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4-(4-phenyl-1-butenyl)-N-methyl-N-(tetrahydropyran-2-yloxy)benzamide (prepared in Example 1 Part E) (500 mg, 1.37 mmol) in 12 ml of CH3OH under argon was added pyridinium 4-toluenesulfonate (344 mg, 1.0 eq.). The mixture was heated to 55° C. and stirred for 2.5 hours. The solution was diluted with ether and washed with 1/2 saturate sodium chloride (20 ml) and brine (10 ml). The organic layer was dried over anhydrous MgSO4 and reduced to yield a light yellow oil which was flash chromatographed on Merck silica gel, eluting with (7:3) Hex:EtOAc. Product containing fractions were concentrated in vacuo to yield title product, 426 mg (85%) as a golden oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]([N:30]1[CH2:35][C@H:34]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][C:41]3[O:46][CH2:45][CH2:44][N:43]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:42]=3[CH:52]=2)[C@@H:33]([C:53]2[CH:58]=[CH:57][C:56]([CH2:59][O:60][CH2:61][C@@H:62]([CH3:66])[CH2:63][O:64][CH3:65])=[CH:55][CH:54]=2)[C@H:32]([CH2:67][N:68]=[N+]=[N-])[CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO.O1CCCC1.O.N>[CH2:20]([O:27][C:28]([N:30]1[CH2:35][C@H:34]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][C:41]3[O:46][CH2:45][CH2:44][N:43]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:42]=3[CH:52]=2)[C@@H:33]([C:53]2[CH:58]=[CH:57][C:56]([CH2:59][O:60][CH2:61][C@@H:62]([CH3:66])[CH2:63][O:64][CH3:65])=[CH:55][CH:54]=2)[C@H:32]([CH2:67][NH2:68])[CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](CN=[N+]=[N-])[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](CN)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reaction time: 8 h

Procedure:
7.128 mmol of triphenylphosphine are added to a solution of 5.940 mmol of (3S,4R,5R)-3-azidomethyl-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester in 20 ml of methanol, 20 ml of tetrahydrofuran, 5 ml of water and 3.56 ml of concentrated aqueous ammonia (25%) at room temperature. After overnight stirring, the reaction mixture is partitioned between tert-butyl methyl ether and 5:1 water/saturated aqueous sodium bicarbonate solution. The aqueous layer is extracted with tert-butyl methyl ether—the combined organic layers are washed successively with water and brine, dried with sodium sulfate and evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound as a yellow oil. Rf=0.42 (dichloromethane-methanol-25% ammonia conc. 200:20:1); Rt=4.64 (gradient I).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH2:8].Br[C:10]([CH3:19])([CH:16]([CH3:18])[CH3:17])[C:11]([N:13]=[C:14]=[S:15])=[O:12]>C(Cl)Cl>[CH:16]([C:10]1([CH3:19])[S:15][C:14]([NH:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:13][C:11]1=[O:12])([CH3:18])[CH3:17]
Reactant: CC(C)C(C)(Br)C(=O)N=C=S
Reactant: NCc1ccccn1
Solvent: ClCCl
Product: CC(C)C1(C)SC(NCc2ccccn2)=NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.5 %

Procedure:
Pyridin-2-ylmethanamine (0.22 mL, 2.1 mmol) was added to 2-bromo-2,3-dimethylbutanoyl isothiocyanate (240 mg, 1.1 mmol) at room temperature. The reaction was exothermic, and was stirred at room temperature for 15 min. CH2Cl2 (2 ml) was added, and the resulting precipitate was removed by filtration. The CH2Cl2 solution was concentrated, and the mixture was purified by silica gel column (gradient 1% (10% NH3 in MeOH) to 30% (10% NH3 in MeOH) in CH2Cl2) to give the title compound as an off-white solid (123 mg). Mass Spec.=m/z+ion 264.1 (M+H)
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.Cl[S:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10].CN>ClCCl>[CH3:1][NH:3][S:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CC
Agent: CN
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
2.8 ml (20 mmol) triethylamine was added to and dissolved in a suspension of 4.4 g (20 mmol) of 4-chlorosulfonylbenzoic acid in dichloromethane. To the solution 3.1 ml of 40% aqueous solution of methylamine was added and stirred at room temperature overnight. After the reaction solution was concentrated under vacuum, the residue was dissolved in ethyl acetate-5% sodium hydrogencarbonate aqueous solution. The water layer was washed with ethyl acetate and adjusted to 2-3 pH with citric acid. The organic layer obtained by extracting the water layer with ethyl acetate was washed with distilled water, then with saturated brine, dried over anhydrous magnesium sulfate. This solution was concentrated under vacuum and the residue was crystallized from ethyl acetate-hexane to obtain 2.9 g of 4-methylaminosulfonylbenzoic acid (yield 67%).