Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:49])[CH2:17][N:18]2[C:23](=[O:24])[C:22]3[CH:25]=[C:26]([CH2:28][C:29]([F:32])([F:31])[F:30])[S:27][C:21]=3[N:20]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=4)=[CH:36][CH:35]=3)[C:19]2=[O:48])=[CH:12][CH:11]=1.II>C(Cl)(Cl)Cl.C(Cl)Cl.CS(C)=O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:49])[CH2:17][N:18]2[C:23](=[O:24])[C:22]3[CH:25]=[C:26]([CH2:28][C:29]([F:31])([F:32])[F:30])[S:27][C:21]=3[N:20]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[C:46]4[NH:3][C:4](=[O:7])[O:5][N:47]=4)=[CH:36][CH:35]=3)[C:19]2=[O:48])=[CH:12][CH:11]=1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CC(=O)c3ccc(F)cc3)c(=O)c3cc(CC(F)(F)F)sc32)cc1
Agent: II
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(Cn1c(=O)c2cc(CC(F)(F)F)sc2n(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c1=O)c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 13.6 %

Procedure:
A mixture of hydroxylammonium chloride (0.97 g), sodium hydrogencarbonate (1.4 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[3-[2-(4-fluorophenyl)-2-oxoethyl]-2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.8 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride (15 mL), N,N′-carbonyldiimidazole (0.23 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methylene chloride (50 mL), iodine acid (0.34 g) was added, and the mixture was stirred at 35° C. for 16 hr. The reaction mixture was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as a colorless amorphous solid (0.12 g, 14%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([OH:27])=O)#[N:21].[NH:31]1C=N[N:33]=[N:32]1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH:16][C:25]([C:24]1[CH:23]=[C:22]([C:20]2[NH:21][N:33]=[N:32][N:31]=2)[CH:30]=[CH:29][CH:28]=1)=[O:27]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: Nc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: c1nnn[nH]1
Product: O=C(Nc1cccc(OCc2ccc3ccccc3n2)c1)c1cccc(-c2nnn[nH]2)c1

Procedure:
When the procedure of Example 64 is followed and 3-(2-quinolinylmethyloxy)aniline is used in place of 3-amino-benzonitrile and 3-cyanobenzoic acid is used in place of 3-(2-quinolinylmethyloxy) benzoic acid, then the product prepared is 5-(3-(2-quinolinylmethyloxy)anilinocarbonyl)phenyl)tetrazole.
Reaction SMILES: [C:1]1([P:7](=O)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:24])=O.[C]=O.C(=O)=O>ClC1C=CC=CC=1>[Cl-:24].[Cl-:24].[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C=O
Agent: [C]=O
Solvent: Clc1ccccc1
Product: [Cl-]
Product: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Yield: 200 %

Procedure:
In Example 1, 3.36 g (12 millimoles) of triphenylphosphine oxide and 1.54 g (12 millimoles) of oxalyl chloride were dissolved in 50 ml of monochlorobenzene, and the solution was left standing until the evolution of carbon monoxide and carbon dioxide from the solution was completed. A solution of 12 millimoles of triphenylphosphine dichloride in 50 ml of monochlorobenzene was obtained. That is, the conversion of triphenylphosphine oxide to triphenylphosphine dichloride was effected stoichiometrically.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)[O:14][CH:13]([CH2:15][CH:16]([CH3:18])C)[CH2:12][O:11]2)=[CH:4][CH:3]=1.ClC1C=C[C:29]([CH2:32][CH2:33][C:34](=[O:41])CN2C=CN=C2)=CC=1.[CH2:42](O)CO>>[CH2:34]([O:41][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2([CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)[O:14][CH:13]([CH2:15][CH2:16][CH2:18][CH3:42])[CH2:12][O:11]2)=[CH:6][CH:7]=1)[CH2:33][CH2:32][CH3:29]
Reactant: O=C(CCc1ccc(Cl)cc1)Cn1ccnc1
Reactant: OCCO
Reactant: CC(C)CC1COC(CCc2ccc(Cl)cc2)(Cn2ccnc2)O1
Product: CCCCOc1ccc(CCC2(Cn3ccnc3)OCC(CCCC)O2)cc1

Procedure:
Substituting 4-methylpentane-1,2-diol for ethylene glycol in part (a) of this example there is prepared 1-[[2-(2-(4-chlorophenyl)ethyl)-4-(2-methylpropyl)-1,3-dioxolan-2-yl]methyl]imidazole. By substituting the appropriate ketones for 1-[4-(4-chlorophenyl)butan-2-on-1-yl]imidazole and substituting 4-methylpentane-1,2-diol for ethylene glycol in part (a) of this example the following compounds are prepared:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-])=O)[CH:4]=1)[CH3:2].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)C.O>[NH2:10][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: CCc1ccc(O)c([N+](=O)[O-])c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1ccc(O)c(N)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 18.8 %

Procedure:
To a mixture of 4-ethyl-2-nitrophenol (5.5 g, 0.032 mol) in ethanol (180 mL) and water (90 mL) was added sodium thiosulfate (23 g, 0.131 mol) at room temperature. The heterogeneous mixture was stirred at 80° C. under an atmosphere of nitrogen for 16 hour. The reaction mixture was cooled to room temperature, and ethanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (3×100 mL), and the organic layer was washed with brine and dried under sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography on silica using 0%-25% methanol/dichloromethane as a mobile phase (×2). The solvent was removed under reduced pressure to give 2-amino-4-ethylphenol (0.89 g, 0.006 mol). 1H NMR (DMSO-d6, 400 MHz) δ 8.61 (br, 2H), 6.47 (d, 1H), 6.37 (s, 1H), 6.18 (d, 1H), 2.17 (q, 2H), 1.08 (t, 3H). MS: MH−: 137
Reaction SMILES: [CH2:1]([C:3]1[C:11](I)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([F:20])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:11]2[C:3]([CH2:1][CH3:2])=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: CCc1nn2ccccc2c1I
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1nn2ccccc2c1-c1cc(F)cc(F)c1
Temperature: 100 °C
Yield: 79.4 %

Procedure:
2-Ethyl-3-iodopyrazolo[1,5-a]pyridine (0.5 g, 2.0 mmol) and (3,5-difluorophenyl)boronic acid (0.35 g, 2.2 mmol) [Aldrich 471925] were stirred in dioxane (12 mL). A solution of potassium carbonate (0.29 g, 2.1 mmol) in water (2.8 mL) was added. Tetrakis-(triphenylphosphine)palladium(0) (0.13 g, 0.1 mmol) was added and the mixture was heated at 100° C. for 16 h. After cooling, the mixture was diluted with ethyl acetate and washed with water and brine. The extracts were dried over magnesium sulfate, filtered, concentrated and purified on silica gel with ethyl acetate in hexanes (0-10%) to give the desired compound (0.41 g, 80%). LCMS for C15H13F2N2 (M+H)+: m/z=259.2. 1H NMR (300 MHz, DMSO-d6): δ 8.67 (m, 1 H), 7.64 (m, 1 H), 7.25 (m, 1 H), 7.18 (m, 3 H), 6.90 (m, 1 H), 2.89 (m, 2 H), 1.22 (m, 3 H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[H][H].Br[CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([CH2:22][CH2:23][CH3:24])[NH:16][C:15]2=[O:25]>CN(C=O)C.CCOC(C)=O>[N:1]1([CH2:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][CH2:23][CH3:24])[NH:16][C:15]3=[O:25])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCc1nc2ccc(CBr)cc2c(=O)[nH]1
Reactant: c1c[nH]cn1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc2ccc(Cn3ccnc3)cc2c(=O)[nH]1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a solution of 0.20 g (3 mmol) of imidazole in 3 mL of dry DMF was added 79 mg of 80% NaH (3.3 mmol). After hydrogen evolution had ceased a solution of 0.28 g (1 mmol) of 6-bromomethyl-2-propylquinazolin-4(3H)-one was added in 1 mL of DMF. The reaction mixture was heated at 60° C. for 6 hours and was then stirred at room temperature for a further 2 days. The mixture was diluted with 25 mL of EtOAc and washed with saturated NaHCO3 (1×5 mL), water (1×5 mL) and brine (1×5 mL) and was dried over MgSO4. The solution was filtered and concentrated in vacuo and the residue was purified by flash chromatography over silica gel eluting with 7% MeOH/CH2Cl2 to provide the title compound.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:17]=[N:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=NN=1>C1(C)C=CC=CC=1>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:1][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Cl:9])=[N:17][N:18]=1
Reactant: Clc1ccccc1-c1nnc(-c2ccccc2Cl)nn1
Reactant: C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: Clc1ccccc1C1=NN=C(c2ccccc2Cl)C(c2ccccc2)C1

Procedure:
To styrene (2.34 ml) was added 3,6-bis(2-chlorophenyl)-1,2,4,5-tetrazine (2.6 g) in toluene (20 ml). The mixture was heated to reflux for 3 hours, and was then cooled. The solid which separated was filtered off and dried to yield 2.6 g of the desired product, mp 151°-153° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([O:19][CH2:20][C@@H:21]([CH2:32][OH:33])[O:22][CH2:23][P:24]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])=[O:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:33][CH2:32][C@@H:21]([O:22][CH2:23][P:24]([CH:26]([CH3:28])[CH3:27])([CH:29]([CH3:30])[CH3:31])=[O:25])[CH2:20][O:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC(C)P(=O)(CO[C@H](CO)COCc1ccccc1)C(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](COCc2ccccc2)OCP(=O)(C(C)C)C(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
p-Tolylsulfonyl chloride (38.8 g, 204 mmol) was added to a solution of compound 6 (31 g) in dry pyridine (200 mL) cooled to 0° C. After 1 h stirring at 0° C. the mixture was stirred at room temperature (rt) for additional 24 h and evaporated in vacuo. The syrupy residue was chromatographed on a column of silica gel (1000 mL) in system toluene-ethyl acetate (5:1). After removal of rests of p-tolylsulfonyl chloride (RF 0.9) the compound 7 was eluted with system toluene-ethyl acetate (1:2), (RF 0.5). Product containing fractions were evaporated to give 18.7 g (77%) of 7 as a colorless syrup.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][CH:16]([NH:18][CH3:19])[CH:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[C:28]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([OH:39])=O)=[CH:32][CH:31]=1)#[N:29]>>[C:28]([C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]([N:18]([CH:16]2[CH:15]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14][N:13]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:12])[CH2:17]2)[CH3:19])=[O:39])=[CH:34][CH:35]=1)#[N:29]
Reactant: CNC1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: N#Cc1ccc(CC(=O)O)cc1
Product: CN(C(=O)Cc1ccc(C#N)cc1)C1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound 2-(4-Cyano-phenyl)-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide was prepared from (1-cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 4-cyanophenylacetic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a yellow oil. MS m/e: 553.2 [M]+.
Reaction SMILES: [OH:1][C@H:2]([C@@H:13]([NH:21][C:22](=[O:41])[C@H:23]([CH2:37][C:38](=[O:40])[NH2:39])[NH:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][N:4]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[NH2:5].[CH2:42]([N:49]=[C:50]=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(Cl)Cl.CO>C1COCC1>[OH:1][C@H:2]([C@@H:13]([NH:21][C:22](=[O:41])[C@H:23]([CH2:37][C:38](=[O:40])[NH2:39])[NH:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][N:4]([CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[NH:5][C:50]([NH:49][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:51]
Reactant: O=C=NCc1ccccc1
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)CC1CCCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(CC1CCCCC1)NC(=O)NCc1ccccc1

Procedure:
Analogously to Example 103, 100 mg (0.178 mmol) of 1-[2(S)-hydroxy-3(S)-(N-(quinoline-2-carbonyl)-(L)-asparaginyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]hydrazine (Example 71E) i) in 0.7 ml of THF are reacted with 21 μl (0.169 mmol) of benzyl isocyanate. Column chromatography (SiO2, methylene chloride/methanol 15:1) and digestion from DIPE yields the title compound: TLC Rf (A')=0.12; tRet (V)=15.5 min; FAB-MS (M+H)+ =694.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][CH:16]=[CH:15][CH2:14]1.IC>C1COCC1>[CH3:1][C:13]1([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][CH:16]=[CH:15][CH2:14]1
Reactant: CC(C)NC(C)C
Reactant: O=C(O)C1CC=CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C(=O)O)CC=CCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
N-isopropylpropan-2-amine (50.1 g, 69.5 mL, 495.5 mmol) was dissolved in 50 mL of THF. To the solution was added n-butyllithium (174.4 mL of 2.5 M solution in hexanes, 436.0 mmol) at −78° C. The resulting solution was stirred for 30 minutes at −78° C. To the reaction was then added cyclohex-3-ene-1-carboxylic acid (25.0 g, 198.2 mmol) and the reaction was allowed to warm to 60° C. for 2 hrs. The reaction was cooled to room temp and iodomethane (29.5 g, 13.0 mL, 208.1 mmol) was added and the reaction was allowed to stir overnight and then quenched with 1 N HCl until the pH<4. The crude product was extracted into CH2Cl2 and water. The organic phase was concentrated in vacuo to a yellow oil (27 g) and used without further purification.
Reaction SMILES: [FH:1].[CH3:2][N:3]=[C:4]=[O:5].[C:6]([C:10]1[CH:15]=[CH:14][C:13]([S:16]Cl)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>O.C1(C)C=CC=CC=1>[CH3:2][N:3]([S:16][C:13]1[CH:14]=[CH:15][C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:11][CH:12]=1)[C:4]([F:1])=[O:5]
Reactant: CC(C)(C)c1ccc(SCl)cc1
Reactant: CN=C=O
Reactant: F
Agent: *CC(*)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CN(Sc1ccc(C(C)(C)C)cc1)C(=O)F
Temperature: -10 °C
Yield: 61 %

Procedure:
To 1200 ml of toluene at (-40°)-(20° C.) in a one-gallon polypropylene bottle containing a stirrer, was added with stirring 37.4 grams (1.87 moles) of liquid hydrogen fluoride. The reaction mixture was raised to -10° C. and 107 grams (1.87 moles) of methyl isocyanate was added with stirring and cooling. The reaction mixture was stirred for one hour at 0° C. after the methyl isocyanate addition. To this mixture was then added 375 grams (1.87 moles) of 4-(tert-butyl)phenylsulfenyl chloride at 0° C. over a two minute period. After the 4-(tert-butyl)phenylsulfenyl chloride addition, 189 grams (1.87 moles) of triethylamine was added slowly, with cooling and stirring. The reaction mixture was then warmed to 25° C. and stirred overnight when it was added to 1000 ml of water. The toluene layer was washed four times with water and dried with magnesium sulfate after which it was distilled through a one-foot packed column to give 275 grams of N-methyl-N-[4-(tert-butyl)phenylthio]carbamoyl fluoride, b.p. 122°/1.0 mm (yield 61%). The nmr spectrum agreed with the proposed structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][CH:16]=1)[CH3:13].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>CN(C)C=O>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[NH:11][C:22](=[O:23])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:12][CH3:13])=[CH:16][CH:17]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: CCOc1ccc(CC(=O)O)cc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CN(C)C=O
Product: CCOc1ccc(CC(=O)Nc2cc([N+](=O)[O-])ccc2N)cc1
Temperature: 100 °C
Yield: 63.6 %

Procedure:
4-Nitro-benzene-1,2-diamine 40 (1.00 g, 6.53 mmol) was dissolved in anhydrous dimethylformamide (20 mL) in a small, argon purged flask fitted with an condenser and magnetic stirbar. (4-Ethoxy-phenyl)-acetic acid 5 (1.53 g, 8.49 mmol) followed by 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (2.099 g, 8.49 mmol) are added quickly as solids and resulting solution heated in an oil bath at 100° C. for 17 hours. After cooling to room temperature the solution was diluted with ice cold H2O (25 mL) resulting in the formation of a yellow precipitate that was collected on a sintered glass funnel and washed with H2O. The solid was slurried in boiling ethanol, filtered and dried to yield solid 41 N-(2-Amino-5-nitro-phenyl)-2-(4-ethoxy-phenyl)-acetamide Yield: 1.31 grams (67.5%). 1H NMR (DMSO) δ: 1.31 (t, 3H, J=6.9), 3.61 (s, 2H), 4.00 (q, 2H, J=6.9), 6.50 (br s, 2H, exchange w. D2O), 6.75 (d, 1H, J=9.0), 6.87 (d, 2H, J=8.4), 7.25 (d, 2H, J=8.7), 7.84 (dd, 1H, J=9.0, 2.7), 8.20 (d, 1H, J=2.7), 9.37 (br s, 1H, exchange w. D2O); MS (APCI+): 316 (MH+, 10%), 298 (MH+-H2O, 100%).
Reaction SMILES: [CH2:1]([C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([O:19][CH2:20][CH3:21])C.[CH3:22]CCCCC>C1(C)C=CC=CC=1>[CH2:1]([C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:22]/[C:20](=[O:19])[CH3:21])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC
Reactant: CCCCCCCCc1ccc(C=O)cc1
Reactant: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCCCc1ccc(/C=C/C(C)=O)cc1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
Triphenylphosporanylidene-2-propanone (2.9q, 0.o092 moles) and para-octylbenzaldehyde (2.0g, 0.0092 moles) in toluene (50ml) was heated to reflux for 2 hrs. and then stirred at room temperature for 64 hrs. The solution was poured into a solution of ethyl ether (100 ml) and hexane (100 ml). The white solid was removed by filtration and the filtrate concentrated by rotary evaporator to an oil. The title product was purified by silica gel chromatography. The structure assignment was supported by NMR, infrared spectra and elemental analysis (258.4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][N:13]([C:15](=[O:24])[C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=3)[CH2:12][CH2:11][N:10]2[C:25](=[O:42])[CH2:26][NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:30][CH:29]2[CH3:41])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:44]C(N1CCN(C(=O)C2C=C(C)C=C(C)C=2)CC1C1C=CC(Cl)=C(Cl)C=1)=O.C(N1C2CCC1CC(=O)C2)C1C=CC=CC=1.[BH3-]C#N.[Na+]>O>[NH3:10].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][N:13]([C:15](=[O:24])[C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=3)[CH2:12][CH2:11][N:10]2[C:25](=[O:42])[CH2:26][NH:27][CH:28]2[CH2:44][CH:30]3[N:31]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:32]([CH2:41][CH2:29]3)[CH2:33]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CNC3CCN(Cc4ccccc4)CC3C)C(c3ccc(Cl)c(Cl)c3)C2)c1
Reactant: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CBr)C(c3ccc(Cl)c(Cl)c3)C2)c1
Agent: O=C1CC2CCC(C1)N2Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CNC3CC4CCC(C3)N4Cc3ccccc3)C(c3ccc(Cl)c(Cl)c3)C2)c1
Product: N
Reaction time: 1 h

Procedure:
By an analogous method to that described in Example 16, the product from Example 16, compound 3 (185 mg, 0.44 mmol) was combined with 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (97 mg, 0.45 mmol) and Ti(O-i Pr)4 (105 mL, 0.50 mmol) and left stirring for 1 h. To the thick reaction mixture was added NaBH3CN (59.5 mg, 0.95 mmol) and the mixture was stirred overnight. To the reaction mixture was added H2O (1 mL) and it was filtered. The filtrate was washed with EtOH, concentrated and purified by silica gel chromatography, eluting with 30:1:0.1 to 15:1:0.1 CH2Cl2 --MeOH--NH3 aq. to give the title product as a white foam. HRMS (FAB, M+H+); m/e calc'd [C35H41Cl2N4O2 ]+ : 619.2607, found 619.2594.
Reaction SMILES: C(OC(=O)[CH:5]([CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)[C:6](OCC)=O)C.[OH-:25].[K+].[CH3:27][OH:28]>O>[C:18]1([CH:15]2[CH2:14][CH2:13][CH:12]([CH2:11][CH2:5][CH2:6][C:27]([OH:28])=[O:25])[CH2:17][CH2:16]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CO
Reactant: [OH-]
Reactant: CCOC(=O)C(CC1CCC(c2ccccc2)CC1)C(=O)OCC
Agent: [K+]
Solvent: O
Product: O=C(O)CCCC1CCC(c2ccccc2)CC1
Temperature: 180 °C

Procedure:
(4-Phenyl-cyclohexylmethyl)-malonic acid diethyl ester (2.79 g, 8.4 mmol, 1.0 equiv) was added to a solution of potassium hydroxide (2.35 g, 41 mmol, 5 equiv) in 20 mL of water and 20 mL of MeOH. The resulting mixture was refluxed for 0.5 h and then evaporated to dryness and then dissolved in 100 mL of water. The solution was washed 3×100 mL with hexane and then brought to pH <1 with concentrated HCl. The product was extracted 3×100 mL EtOAc. The organic layers were combined and concentrated to dryness. The crude product was then heated for 10 min at 180° C. to decarboxylate the diacid and yield the monoacid (0.9 g) which was used without further purification.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.O[C:21]1C=CC(C(OC)=O)=CC=1.C1(CCCO)CC1>>[CH:3]1([CH2:1][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:18][CH:19]=2)[CH2:2][CH2:21]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Agent: OCCCC1CC1
Product: O=C(O)CNC(=O)c1ccc(OCCCC2CC2)cc1
Yield: 51 %

Procedure:
The same reactions as in Example 9 (9a) and (9b) were conducted using methyl 4-hydroxybenzoate (6.09 g, 40.0 mmol) and 3-cyclopropylpropan-1-ol (which is the compound disclosed in Helv. Chim. Acta, (2003), 86, 865-893, 4.41 g, 44.0 mmol) to give 5.74 g of the title compound (white powder, yield: 51%).