Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:18](C)=[C:17]2[N:8]([C:9](=[O:20])[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1)=O)C.[OH-].[K+]>>[OH:3][CH2:4][C:6]1[CH:18]=[C:17]2[N:8]([C:9](=[O:20])[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1
Reactant: CCOC(=O)c1nn2c(=O)[nH]c3ccccc3c2c1C
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH]c2ccccc2c2cc(CO)nn12

Procedure:
Following the procedure of Example 25, but substituting 2-[(acetoxy)methyl]pyrazolo[1,5-c]quinazoline-5(6H)-one for 1-methylpyrazolo[1,5-c]quinazoline-5(6H)-one-2-carboxylic acid ethyl ester in Example 25 and using a mole ratio of 2 to 1 for the quantity of potassium hydroxide to ester, the title compound is obtained.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[CH:10]=1)[NH2:4].[C:14](Cl)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.Cl.N>>[N:13]1[CH:12]=[CH:11][N:9]2[CH:10]=[C:5]([C:3]3[N:4]=[C:14]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[O:1][N:2]=3)[CH:6]=[CH:7][C:8]=12
Reactant: O=C(Cl)c1cccnc1
Reactant: NC(=NO)c1ccc2nccn2c1
Agent: Cl
Agent: N
Product: c1cncc(-c2nc(-c3ccc4nccn4c3)no2)c1

Procedure:
The title compound was prepared according to Method D using N′-hydroxyimidazo[1,2-a]pyridine-6-carboximidamide (Bionet) and nicotinoyl chloride, hydrochloric Acid (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.62-7.91 (m, 4H), 8.20 (s, 1H), 8.56 (dt, J=8.1, 1.9 Hz, 1H), 8.92 (dd, J=4.7, 1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 264 (M+H)+.
Reaction SMILES: C[Li].Br[C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Br:11])[C:9]=1[OH:10].C([Li])CCC.[C:17](=[O:19])=[O:18].Cl>CCOCC.C1COCC1.CCCCCC>[Br:11][C:8]1[C:9]([OH:10])=[C:4]([C:17]([OH:19])=[O:18])[CH:5]=[N:6][CH:7]=1
Reactant: O=C=O
Reactant: Oc1c(Br)cncc1Br
Agent: Cl
Agent: [Li]C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1cncc(Br)c1O
Reaction time: 0.5 h

Procedure:
A solution of methyllithium in ether (1 M, 4.8 ml) was added to a solution of 3,5-dibromopyridin-4-ol (1200 mg) in THF (10 ml) at −78° C., and the mixture was stirred for 30 minutes. A solution of n-butyllithium in hexane (1.65 M, 6.0 ml) was added at −78° C., and the mixture was stirred for one hour. Dry ice was added at −78° C. and the mixture was stirred at 0° C. for 20 minutes, followed by addition of a 4 N aqueous hydrochloric acid solution. The precipitated solid was collected by filtration and washed with water to give a mixture of the title compound and 3,5-dibromopyridin-4-ol.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.FC(F)(F)C(O)=O.[NH2:21][C@H:22]1[CH2:26][CH2:25][C@@H:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:21][C@H:22]2[CH2:26][CH2:25][C@@H:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: CCOC(=O)[C@@H]1CC[C@H](N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)C1
Temperature: 90 °C
Reaction time: 1.67 h
Yield: 53.2 %

Procedure:
To a stirred mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.18 g, 0.84 mmol) and ethyl (1R,3S)-3-aminocyclopentanecarboxylate trifluoroacetate (0.25 g, 0.92 mmol) in isopropyl alcohol (2.3 mL) was added N,N-diisopropylethylamine (0.73 mL, 4.2 mmol). The resulting mixture was stirred at 90° C. for 100 min, and then the solvent was evaporated. The crude residue was purified on silica gel, eluted with 10-60% EtOAc in hexanes to give 0.15 g (55%) of the desired product. LCMS calculated for C15H18N3O4S (M+H)+: m/z=336.1. Found: 336.0.
Reaction SMILES: [C:1]([N:4]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[C:5](=[O:28])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:8]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:7]=1)(=[O:3])[CH3:2].[CH3:36][I:37]>>[I-:37].[C:1]([N:4]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N+:31]=1[CH3:36])[C:5](=[O:28])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:8]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(C)=O)cc1OCCCCCCC
Product: CCCCCCCOc1ccc(C(=O)N(Cc2cccc[n+]2C)C(C)=O)cc1OCCCCCCC
Product: [I-]
Temperature: 105 °C
Yield: 95.8 %

Procedure:
A mixture of 1.0 g of product from Example 112 and 14.7 g of methyl iodide is heated in a sealed tube at 105° C. from 171/4 hours. The reaction is concentrated in vacuo to give 1.24 g of the desired product as yellow crystals.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].[CH3:11][CH:12]([CH3:15])[C:13]#[CH:14]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[CH:14]=[C:13]([CH:12]([CH3:15])[CH3:11])[O:10][C:3]=2[CH:4]=1
Reactant: COc1ccc(I)c(O)c1
Reactant: C#CC(C)C
Product: COc1ccc2cc(C(C)C)oc2c1
Yield: 38 %

Procedure:
Example 15(a) was prepared from 2-iodo-5-methoxyphenol (896 mg, 3.6 mmole) and 3-methyl-1-butyne in a manner as previously described for example 12a to give 265 mg (38%) of an amber oil. 1H NMR (CDCl3) δ7.33 (1H, d, J=8.6 Hz), 6.97 (1H, d, J=2.2 Hz), 6.80 (1H, dd, J=2.2, 8.6 Hz), 6.26 (1H, s), 3.83 (3H, s), 3.07-3.01 (1H, m), 1.31 (6H, d, J=7.1 Hz).
Reaction SMILES: CC(C[AlH]CC(C)C)C.C(C[CH2:14][CH:15]1[CH:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:19][C:18](=[O:28])[NH:17][CH2:16]1)(O)=O.C[OH:30]>O1CCCC1.C1(C)C=CC=CC=1>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:20]2[CH2:19][C:18](=[O:28])[NH:17][CH2:16][CH:15]2[CH2:14][OH:30])=[CH:22][CH:23]=1
Reactant: CO
Reactant: O=C(O)CCC1CNC(=O)CC1c1ccc(F)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1CC(c2ccc(F)cc2)C(CO)CN1
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 67 %

Procedure:
DIBAL-H (15.1 ml, 0.0225 mol) was added at a rate of 50 ml/hour, by means of a syringe pump, to a solution of 3-carboxyethyl-4-(4-fluorophenyl)-piperidine-6-one (1.99 g, 0.0075 mol) in tetrahydrofuran (15 ml) at −70° C. under an argon atmosphere keeping the temperature below 0° C. The mixture was allowed to warm to 23° C. and stirred for 45 minutes, then a solution of methanol (0.9 ml) in toluene (7.5 ml) was added to destroy the excess DIBAL-H, followed by 30% potassium carbonate solution (8.5 ml), all below 30° C. The organic phase was separated, dried with anhydrous sodium sulphate, filtered, and evaporated to afford the title compound (1.54 g) as a slightly colored oil, which was crystallized by trituration with ether. Yield 67%.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=2)[O:10]C(C)C(O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:19]>C(O)C.[Hg]>[CH:1]1([C:7]2[CH:18]=[CH:17][C:16]([CH:8]([CH3:7])[C:9]([OH:10])=[O:19])=[C:9]([OH:10])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O
Reactant: CC(Oc1cccc(C2CCCCC2)c1)C(=O)O
Agent: [Hg]
Solvent: CCO
Product: CC(C(=O)O)c1ccc(C2CCCCC2)cc1O

Procedure:
2 g of 2-(3-cyclohexyl-phenoxy)propionic acid in 180 cc of 95% ethanol are irradiated with a 150 Watt mercury high pressure burner for 2 hours in an atmosphere of argon and while cooling with water. The solution is concentrated by evaporation and the residue is chromatographed on 150 g of silica gel. By-products are first eluted with ethyl acetate/hexane (1:1). Elution with ethyl acetate finally yields pure 2-(4-cyclohexyl-2-hydroxyphenyl)propionic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[CH:3]=1.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][OH:18].[OH-].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)[O:18][CH2:17][CH2:16][N:15]([CH3:19])[CH3:14]
Reactant: O=[N+]([O-])c1cc(Br)cc([N+](=O)[O-])c1
Reactant: CN(C)CCO
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCOc1cc(Br)cc([N+](=O)[O-])c1
Reaction time: 20 h
Yield: 56.4 %

Procedure:
1-Bromo-3,5-dinitrobenzene (1 g, 4.1 mmol), 2-(dimethylamino)ethanol (0.54 g, 6.1 mmol), potassium hydroxide (0.45 g, 8.1 mmol), and water (0.5 mL) in DMF (5 mL) were heated at 80° C. After 20 hours, the reaction mixture was diluted with cold water and extracted with dichloromethane (2×100 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (stepwise gradient, 2% ethyl acetate in hexanes to ethyl acetate) to give 2-(3-bromo-5-nitrophenoxy)-N,N-dimethylethanamine (669 mg, 57.2% yield) as a brown oil. HPLC: Rt=1.04 min. (PHENOMENEX® Luna 5 micron C18 4.6×30 mm, 10-90% aqueous methanol containing 0.1% TFA, 2 min. gradient, flow rate=5 mL/min., detection at 254 nm). MS (ES): m/z=290.93 [M+H]+.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11](=[O:30])[C:12](=[CH:20][C:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[NH:23][CH:22]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C1COCC1>[CH3:9][O:10][C:11](=[O:30])[CH:12]([CH:20]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[NH:23][CH:22]=1)[C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14]
Reactant: COC(=O)C(=Cc1c[nH]c2cccnc12)C(=O)OC(C)(C)C
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC(C)(C)C)C(c1ccccc1)c1c[nH]c2cccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a RT solution of PhMgBr (1 M in THF, 6.5 mL) in THF (10 mL) was added a solution of 2-(1H-pyrrolo[3,2-b]pyridin-3-yl-methylene)-malonic acid tert-butyl ester methyl ester in THF (15 mL) dropwise. After stirring the mixture for 1 hour at RT, the reaction was quenched by addition of water. The diluted mixture was neutralized by addition of HCl (I M) to pH 7 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording 2-[Phenyl-(1H-pyrrolo[3,2-b]pyridin-3-yl)-methyl]-malonic acid tert-butyl ester methyl ester (680 mg, 69% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[N+:38](=[CH2:40])=[N-:39]>C1COCC1.CCOCC>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:10](=[O:12])[CH:40]=[N+:38]=[N-:39])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: C=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)C=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 82.3 %

Procedure:
To a 0° C. solution of 2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid (1.20 g, 4.0 mmol) in THF (20 mL) is added dropwise triethylamine (0.61 mL, 4.4 mmol) followed by iso-butyl chloroformate (0.57 mL, 4.4 mmol). The reaction mixture is stirred at 0° C. for 20 minutes and filtered. The filtrate is treated with an ether solution of diazomethane (˜16 mmol) at 0° C. The reaction mixture is stirred at room temperature for 3 hours then concentrated in vacuo. The resulting residue is dissolved in EtOAc and washed successively with water and brine, dried (Na2SO4), filtered and concentrated. The residue is purified over silica (hexane/EtOAc 2:1) to afford 1.1 g (82% yield) of the desired product as a slightly yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.16 (d, J=8.7 Hz, 2H), 7.39 (d, J=8.7 Hz, 2H), 5.39 (s, 1H), 5.16 (d, J=6.3 Hz, 1H), 4.49 (s, 1H), 3.25 (dd, J=13.8 and 6.6, 1H), 3.06 (dd, J=13.5 and 6.9 Hz, 1H), 1.41 (s, 9H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.[Cl:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.O1CCCC1>[Cl:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: OCCCCCCCCCl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(-c2ccc(OCCCCCCCCCl)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.1 %

Procedure:
A solution of diethyl azodicarboxylate (3.5 g; 20 mmol) and tetrahydrofuran (10 ml) was added dropwise at 0° C. to a solution of 4,4′-dihydroxybiphenyl (7.4 g; 40 mmol), 8-chloro-1-octanol (3.3 g; 20 mmol), triphenylphosphine (5.2 g; 20 mmol) and tetrahydrofuran (120 ml) and stirred at room temperature 72 h. The reaction mixture was added to water (400 ml) and extracted with ethyl acetate (3×150 ml). The combined organic layers were washed with water (2×150 ml), dried over magnesium sulphate and filtered. The solvent was removed in vacuo. The residue (19.2 g) was purified by flash chromatography on a silica gel column using a toluene/ethyl acetate mixture (95:5) as eluent, to give 2.6 g (40%) of 4′-[(8-chlorooctyl)oxy]-4-biphenylol.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][OH:25])[O:21][C:20]3=[O:26])=[CH:15][C:14]=2[F:27])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[C:29]1[CH:33]=[CH:32][O:31][N:30]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Si:1]([O:8][CH:9]1[CH2:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][O:25][C:29]4[CH:33]=[CH:32][O:31][N:30]=4)[O:21][C:20]3=[O:26])=[CH:15][C:14]=2[F:27])[CH2:12]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)C1
Reactant: Oc1ccon1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Reaction time: 18 h

Procedure:
3-(4-(3-t-Butyldimethylsilyloxy-1-azetidinyl)-3-fluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one (WO 96/13502; 2.47 g, 6.25 mmol), 3-hydroxyisoxazole (580 mg, 6.86 mmol), and tributylphosphine (1.58 g, 7.8 mmol) were dissolved by stirring in dry tetrahydrofuran (100 ml) under nitrogen. The mixture was cooled in an ice-bath, and 1,1′-(azodicarbonyl)dipiperidine (1.96 g, 7.8 mmol) added dropwise over 10 minutes. The solution was stirred 18 hours, allowing the temperature to rise to ambient. Reduced azo compound was filtered off, and the solution evaporated to dryness and the residue triturated with ether. The residue was purified by chromatography on a silica flash column, eluting with a gradient from 50 to 75% EtOAc in isohexane. Relevant fractions were combined and evaporated to the product as an oil (1.31 g).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)C=C[C:6]=1[CH:15]([C:22]([CH:24]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)C1C=CC2C(=CC=CC=2)C=1)=[O:23])[C:16]1C=CN=CC=1.O>Cl>[OH:3][N:1]=[C:24]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)[C:22]([C:15]1[CH:6]=[CH:5][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:16]=1)=[O:23]
Reactant: O=N[O-]
Reactant: O=C(C(c1ccncc1)c1ccc2ccccc2c1)C(c1ccncc1)c1ccc2ccccc2c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(C(=NO)c1ccncc1)c1ccc2ccccc2c1
Reaction time: 3 h

Procedure:
NaNO2 (0.35 g, 5 mmol) was added to a suspension of the product of step (b) above, (0.98 g, 4 mmol), in 3N HCl (20 mL), and H2O (20 mL). The slurry was stirred for 3 hours, filtered, washed with water, air dried to give the title compound. MS(ES) m/e 277 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([N:12]2[C@H:17]([C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:15][C@H:14]([C:22]([NH:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:23])[CH2:13]2)[CH:3]=1.C[CH2:32][N:33](C(C)C)C(C)C.CN.C1COCC1>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:33][CH3:32])[N:5]=[C:4]([N:12]2[C@H:17]([C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:15][C@H:14]([C:22]([NH:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:23])[CH2:13]2)[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CS(=O)(=O)c1nc(Cl)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C(F)(F)F)n1
Agent: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C(F)(F)F)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
To cis-1-[6-chloro-2-(methylsulfonyl)-4-pyrimidinyl]-N-cyclohexyl-6-(trifluoromethyl)-3-piperidinecarboxamide (390 mg, 0.832 mmol) in 1,4-dioxane (8 mL) was added Hunig's base (0.29 mL, 1.66 mmol) followed by 2M methylamine in THF (1 mL, 2 mmol), and the reaction mixture was stirred overnight at 60° C. into a sealed tube. The mixture was poured onto water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% Hexanes to 50% EtOAc in Hexanes) afforded the title compound (204 mg) as a white foam. LC-MS (ES) m/z=420, 422 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1F)=[O:3].CN(C)C=O.[C:18](=[S:20])=[S:19].[H-].[Na+]>CO.C1C=CC=CC=1>[SH:19][C:18]1[S:20][C:5]2[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=2[C:2](=[O:3])[CH:1]=1
Reactant: COc1ccc(C(C)=O)c(F)c1
Reactant: S=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)cc(S)sc2c1
Temperature: 17.5 °C
Yield: 74.5 %

Procedure:
In accordance with the process disclosed in Aust. J. Chem. 40, 1179 (1987), the mixture of 2-fluoro-4-methoxyacetophenone (3 g, 22.73 mmol), N,N-dimethylformamide (25 ml), benzene (17.5 ml) and carbon disulfide (3.78 g, 50.01 mmol) was stirred and added with 55% sodium hydride (2.42 g, 55.47 mmol) over about 2.5 hours while inner temperature was maintained at 15-20° C. After additional stirring for 30 minutes, the reaction mixture was added with methanol (0.5 ml) and further stirred for 15 minutes. Benzene was removed under heating to increase inner temperature up to 125-130° C.; at that temperature range, the mixture was heated for 45 minutes and was allowed to cool to room temperature. The reaction mixture was added with water (80 ml) and acetic acid (2.5 ml) and extracted with ether (50 ml×2 times); water layer was filtered out and acidified with concentrated hydrochloric acid. The resulting precipitates were collected by filteration and were recrystallized from methanol-1,2-dichloroethane (1:1) to obtain 3.8 g (yield: 75%) of the titled compound.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:24]1([C@@H:30]([NH2:33])[CH2:31][CH3:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:34]([O:38][C:39]([NH:41][C@@H:42]([CH2:48][CH2:49][CH2:50][CH3:51])[C@H:43]([OH:47])[C:44](O)=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35]>ClCCl>[C:34]([O:38][C:39]([NH:41][C@@H:42]([CH2:48][CH2:49][CH2:50][CH3:51])[C@H:43]([OH:47])[C:44]([NH:33][C@H:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:31][CH3:32])=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC[C@H](N)c1ccccc1
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)N[C@@H](CC)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
229 mg of 1-hydroxybenzotriazole monohydrate, 287 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 148 mg of (S)-(−)-1-phenylpropylamine were added in sequence to a solution of 260 mg of 3(S)-(tert-butoxyformamido)-2(S)-hydroxyheptanoic acid in 10 ml of dichloromethane. The mixture was stirred at room temperature for 3 hours, then diluted with dichloromethane and washed in sequence with 5% citric acid solution, saturated sodium bicarbonate solution and saturated brine. The organic phase was dried over anhydrous magnesium sulphate and the solvent was evaporated to give 285 mg of 3(S)-(tert-butoxyformamido)-2(S)-hydroxy-N-(1(S)-phenylpropyl)heptanamide, MS: m/e 379.1 [M+H]+.
Reaction SMILES: C(O)(=O)C.[C:5]([C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1)(=[NH:7])[NH2:6].[CH3:18][CH:19]([C:25](=O)[CH3:26])[C:20](OCC)=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[OH:21][C:20]1[C:19]([CH3:18])=[C:25]([CH3:26])[N:6]=[C:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=2)[N:7]=1
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: CC(=O)Nc1ccc(C(=N)N)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(-c2nc(C)c(C)c(O)n2)nc1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a solution of compound of example 44 (0.01 g, 0.56 mmol) in water (2 mL) and ethanol (1 mL) was added ethyl 2-methyl-3-oxobutanoate (0.013 g, 0.89 mmol) and sodium carbonate (0.0107 g, 1.011 mmol) and the reaction mixture was stirred at room temperature for 26 hours. Ethanol was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: Cl[C:2]([N:4]1[CH2:7][CH:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH2:5]1)=[O:3].[CH3:16][NH2:17]>O1CCCC1.O>[Cl:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH:6]1[CH2:7][N:4]([C:2]([NH:17][CH3:16])=[O:3])[CH2:5]1
Reactant: O=C(Cl)N1CC(Oc2cccc(Cl)c2)C1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC(Oc2cccc(Cl)c2)C1
Reaction time: 16 h
Yield: 39.1 %

Procedure:
A solution of 1-chlorocarbonyl-3-(3-chlorophenoxy)azetidine (0.01275 mole) in 20 ml of tetrahydrofuran was treated with 4 ml (0.05 mole) of 40% aqueous methylamine and stirred for 16 hr. The reaction mixture was diluted with water until an oil began to separate, then extracted with 3×50 ml of benzene. The combined extracts were dried over magnesium sulfate and concentrated to a solid which was recrystallized from benzene/ligoin to yield 1.2 g (40.0%) of fine white crystals, m.p. 140°-141° C.
Reaction SMILES: [C:1]([O-:5])(=[O:4])[CH:2]=O.[NH4+:6].C([O-])(=O)C.[NH4+].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[CH:14]1[C:15]([CH:2]([NH2:6])[C:1]([OH:5])=[O:4])=[CH:16][CH:17]=[C:12]([OH:18])[CH:13]=1
Reactant: O=CC(=O)[O-]
Reactant: Oc1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Product: NC(C(=O)O)c1ccc(O)cc1
Yield: 40.4 %

Procedure:
29.5 g of ammonium glyoxylate, 75 g of ammonium acetate, 60 g of phenol and 130 ml of water are treated in the same manner as described in Example 1. 21.9 g of DL-p-hydroxyphenylglycine are thereby obtained as crystals. Yield: 40.5%, M.p. 225°-228° C. (decomp.).
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH:18]2[CH2:20][O:19]2)[CH:11]=1)(=O)C1C=CC=CC=1.[C:21]1([C:27]2[C:35]3[C:34]([N:36]4[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]4)=[N:33][CH:32]=[N:31][C:30]=3[S:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(O)C.CS(C)=O>[OH:19][CH:18]([CH2:20][NH:42][CH:39]1[CH2:40][CH2:41][N:36]([C:34]2[C:35]3[C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:28][S:29][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:37][CH2:38]1)[CH2:17][O:16][C:12]1[CH:11]=[C:10]([OH:9])[CH:15]=[CH:14][CH:13]=1
Reactant: NC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Reactant: O=C(Oc1cccc(OCC2CO2)c1)c1ccccc1
Solvent: CC(C)O
Solvent: CS(C)=O
Product: Oc1cccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5ccccc5)c34)CC2)c1
Yield: 20 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 3:1, 24 h), using 150 μmol 3-(oxiran-2-ylmethoxy)phenyl benzoate and 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine. The benzoic acid moiety was already lost during purification by prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 4:6:1) and subsequent prep. HPLC (reversed phase) to give the title compound with 20% yield.