Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[O:6]
Reactant: COC(=O)C(C)Br
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cccc(C=O)c1
Yield: 94.4 %

Procedure:
By the method of Example 1, Step F, 10.0 g (0.0819 mole) of 3-hydroxybenzaldehyde and 16.0 g (0.0982 mole) of methyl 2-bromopropionate were reacted in the presence of 13.6 g (0.0983 mole) of anhydrous potassium carbonate in 50 mL of N,N-dimethylformamide, yielding 16.1 g of methyl 2-(3-formylphenoxy)propionate as an orange liquid. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [C:1]([N:4]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20](=[O:32])[N:21]([CH2:23][CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([O:28]C)=[O:27])[CH:22]=2)=[O:16])[C@@H:7]([CH3:33])[CH2:6]1)(=[O:3])[CH3:2].CO.[OH-].[Na+].Cl>O1CCCC1>[C:1]([N:4]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20](=[O:32])[N:21]([CH2:23][CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([OH:28])=[O:27])[CH:22]=2)=[O:16])[C@@H:7]([CH3:33])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)(C)CCn1cc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)ccc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(=O)n(CCC(C)(C)C(=O)O)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}-2-oxopyridin-1(2H)-yl]-2,2-dimethylbutanoic acid was prepared from methyl 4-[5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}-2-oxopyridin-1(2H)-yl]-2,2-dimethylbutanoate. methyl 4-[5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}-2-oxopyridin-1(2H)-yl]-2,2-dimethylbutanoate (0.010 g, 0.017 mmol) was hydrolyzed to the acid by dissolving in tetrahydrofuran and methanol and sodium hydroxide (1N) was added. The mixture was stirred at room temperature overnight. The mixture was cooled to rt, acidified to pH=5 with 1N HCl to form a white precipitate (0.006 g, 63%). The solid was filtered to give 4-[5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}-2-oxopyridin-1(2H)-yl]-2,2-dimethylbutanoic acid.
Reaction SMILES: CC1(C)CO[CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:30])[CH2:20][C@@H:21]3[OH:29])=[CH:16][CH:15]=4)[CH2:12][CH2:11]2)[CH3:9])[O:4]C1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.CCCCCC>CC(C)=O>[OH:29][C@@H:21]1[C@@:22]2([CH3:23])[C:17](=[CH:16][CH:15]=[C:14]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[CH:8]([CH:5]=[O:4])[CH3:9])[CH2:18][C@@H:19]([OH:30])[CH2:20]1
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CC(C=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 81.3 %

Procedure:
In 10 ml of acetone was dissolved 4.3 mg (0.010 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregna-5,7-diene-1α,3β-diol, followed by addition of 1 ml of a 1 mmole/l solution of p-toluenesulfonic acid in acetone (containing 0.001 mmole of p-toluenesulfonic acid). The mixture was refluxed for 2 hours. The reaction mixture thus obtained was cooled to room temperature and the solvent was distilled off under reduced pressure. The residue was dissolved in 40 ml of methylene chloride and this methylene chloride solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution in that order and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1:5, v/v) to give 2.8 mg of 1α,3β-dihydroxypregna-5,7-diene-20-carbaldehyde (yield: 82%).
Reaction SMILES: [O:1]=[C:2]1[CH:5]([N:6]2[C:10](=[O:11])[C:9]3=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]3[C:7]2=[O:16])[CH2:4][N:3]1[CH:17]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([O:20][CH3:21])=[S:19].N1C=CC=CC=1.S(Cl)(Cl)(=O)=O>ClCCl>[O:1]=[C:2]1[CH:5]([N:6]2[C:7](=[O:16])[C:8]3=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]3[C:10]2=[O:11])[CH2:4][N:3]1[C:17](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([O:20][CH3:21])=[S:19]
Reactant: COC(=S)C(Cc1ccccc1)N1CC(N2C(=O)c3ccccc3C2=O)C1=O
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=S)C(=Cc1ccccc1)N1CC(N2C(=O)c3ccccc3C2=O)C1=O

Procedure:
Methyl 2-(2-oxo-3-phthalimido-1-azetidinyl)-3-phenylthiopropionate (5.1 g.) and pyridine (4.0 g.) were dissolved in dichloromethane (100 ml.), and to the solution, there was added dichloromethane (20 ml.) solution containing sulfuryl chloride (2.0 g.) at 35° to 40° C. in the course of 70 minutes with stirring. The stirring was continued at the same temperature for an hour. After the reaction, the reaction mixture was evaporated to dryness under reduced pressure. Ethyl acetate (100 ml.) and water (50 ml.) were added to the residue obtained, and the resultant mixture was stirred for a while. The ethyl acetate layer was separated from the mixture and the remaining aqueous solution was extracted with ethyl acetate. This extract and the above ethyl acetate layer were combined, washed with three portions of diluted hydrochloric acid, three portions of saturated aqueous sodium bicarbonate, two portions of water and then dried over magnesium sulfate. The solvent was removed by distillation from the solution under reduced pressure to give an oily residue (4.95 g.), which was subjected to column chromatography on silica gel(30 g.). Elution was carried out with chloroform and the fractions containing a desired compound were collected. The solvent was removed by distillation from the solution under reduced pressure to give methyl 2-(2-oxo-3-phthalimido-1-azetidinyl)-3-phenylthioacrylate (a mixture of trans and cis isomer) (4.23 g.).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>CN(C=O)C>[CH:15]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:17])[CH3:16]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1ccc(C=O)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
Mix 4-hydroxybenzaldehyde (1.23 g, 10.1 mmol), imidazole (1.37 g, 20.2 mmol), and triisopropylsilyl chloride (2.60 mL, 12.1 mmol) in DMF (10 mL) and stir at room temperature for 2 hours. Quench the reaction with saturated aqueous NH4Cl (50 mL) and extract with EtOAc (3× 100 mL). Wash the organic layers with H2O and brine (50 mL each). Combine the organic layers, dry over MgSO4, concentrate and purify by flash chromatography, eluting with 2.5% Et2O/hexanes to afford 4-triisopropylsilyloxybenzaldehyde (2.78 g, 99%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.I[CH3:10]>C(=O)([O-])[O-].[Ag+2].C(Cl)(Cl)Cl>[CH3:10][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1
Reactant: Cc1cccc(O)n1
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1cccc(C)n1
Temperature: 25 °C
Reaction time: 40 h
Yield: 80.8 %

Procedure:
A mixture of 2-hydroxy-6-methylpyridine (6.85 g, 62.8 mmol), silver carbonate (22.5 g, 81.6 mmol), iodomethane (39.1 mL, 628 mmol) and chloroform (200 mL) was stirred at ambient temperature for 40 h in the dark. The reaction mixture was filtered through celite. The collected solid was washed with ether. The combined filtrates were concentrated in vacuo to give a liquid (6.25 g), which was identical to the product from Part A.
Reaction SMILES: [Br:1]C1C=CC(C(O)=O)=CC=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]([CH:26]([OH:28])[CH3:27])=[C:21]([CH:23]([CH3:25])[CH3:24])[N:22]=2)=[CH:14][CH:13]=1>>[Br:1][C:16]1[CH:17]=[CH:12][CH:13]=[CH:14][C:15]=1[C:18]1[O:19][C:20]([CH:26]([OH:28])[CH3:27])=[C:21]([CH:23]([CH3:25])[CH3:24])[N:22]=1
Reactant: CC(C)c1nc(-c2ccc(Br)cc2)oc1C(C)O
Reactant: O=C(O)c1ccc(Br)cc1
Product: CC(C)c1nc(-c2ccccc2Br)oc1C(C)O

Procedure:
By the sequence above as preparation 78, 4-bromo-benzoic acid is converted to 1-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:15][Si:16]([CH3:33])([CH3:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O.O>[CH3:15][Si:16]([CH3:32])([CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C=Cc1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1

Procedure:
A mixture of 5.0 g. ethyl 4-aminocinnamate, 9.14 g. of 14-(trimethylsilyl)tetradecyl bromide and 3.6 g. of powdered anhydrous potassium carbonate in hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated to provide ethyl 4-[14-(trimethylsilyl)tetradecylamino]cinnamate. The ester is hydrolyzed with.sodium hydroxide in a 1:9 water:ethanol solution at steam bath temperature for 10 hours. The hot solution is then acidified with acetic acid, cooled and filtered and the solid is washed with water. Recrystallization from chloroform yields the title product as a white solid.
Reaction SMILES: [BrH:1].C(O)(=O)C.O=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[CH2:8][S:9][C:10]#[N:11].O>C(O)(=O)C>[Br:1][C:10]1[S:9][CH:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:11]=1
Reactant: Br
Reactant: N#CSCC(=O)c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(-c2csc(Br)n2)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
A 25% hydrogen bromide/acetic acid (35 ml) solution was added to a solution of 2-oxo-2-[3-(trifluoromethyl)phenyl]ethyl thiocyanate (3.88 g, 15.8 mmol) in acetic acid (35 ml), and the mixture was stirred at 130° C. for 2 hours and at room temperature for 1 hour. Water was poured to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.88 g (59.1%) of the desired product as an oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:5]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:6][C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH:13]=1)[CH:8]([CH3:10])[CH3:9])[OH:4].C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[C:46](Cl)(=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48]>O>[CH3:48][C:47]([CH3:50])([CH3:49])[C:46]([NH:1][CH2:2][C@@H:3]([C@@H:5]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:6][C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH:13]=1)[CH:8]([CH3:10])[CH3:9])[OH:4])=[O:51]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN)C(C)C)ccc1OC
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNC(=O)C(C)(C)C)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The stirred solution of 0.025 g of tert-butyl {1(S)-(2-amino-1(S)-hydroxyethyl)-3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl}carbamate (Example 36b) and 0.230 ml of ethyl acetate is admixed at 0° C. successively with 0.230 ml of 2M sodium carbonate solution and 0.007 ml of pivaloyl chloride, and stirred at room temperature over another 4 hours. The reaction solution is admixed with water and extracted with ethyl acetate (2×). The combined organic phases are washed successively with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a colourless oil. Rf=0.61 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=5.05 (gradient I).
Reaction SMILES: CS(C)=O.[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](Cl)=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[C:18]([NH2:20])=[O:19].[Cl:21][C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30]([NH:32][CH:33]1[CH2:35][CH2:34]1)=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[Cl:21][C:22]1[CH:27]=[C:26]([CH:25]=[CH:24][C:23]=1[NH:29][C:30]([NH:32][CH:33]1[CH2:34][CH2:35]1)=[O:31])[O:28][C:11]1[C:10]2[C:15](=[CH:16][C:7]([O:6][CH3:5])=[C:8]([C:18]([NH2:20])=[O:19])[CH:9]=2)[N:14]=[CH:13][CH:12]=1
Reactant: O=C(Nc1ccc(O)cc1Cl)NC1CC1
Reactant: COc1cc2nccc(Cl)c2cc1C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(N)=O
Temperature: 70 °C
Reaction time: 23 h
Yield: 88 %

Procedure:
To dimethylsulfoxide (20 mL) were added 7-methoxy-4-chloroquinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), followed by heating and stirring at 70° C. for 23 hours. After the reaction mixture was allowed to cool down to room temperature, water (50 mL) was added, and the produced crystals were collected by filtration to give 1.56 g of the titled compound (88% yield).
Reaction SMILES: [F:1][C:2]([C:6]1[N:11]2[CH2:12][C@@H:13]([CH2:15][O:16]S(C3C=CC(C)=CC=3)(=O)=O)[O:14][C:10]2=[N:9][C:8](=[O:27])[CH:7]=1)([F:5])[CH2:3][CH3:4].[CH3:28][C:29]1([CH3:40])[CH2:38][CH2:37][CH2:36][C:35]2[CH:34]=[C:33](O)[CH:32]=[CH:31][C:30]1=2>>[F:5][C:2]([C:6]1[N:11]2[CH2:12][C@@H:13]([CH2:15][O:16][C:33]3[CH:32]=[CH:31][C:30]4[C:29]([CH3:40])([CH3:28])[CH2:38][CH2:37][CH2:36][C:35]=4[CH:34]=3)[O:14][C:10]2=[N:9][C:8](=[O:27])[CH:7]=1)([F:1])[CH2:3][CH3:4]
Reactant: CC1(C)CCCc2cc(O)ccc21
Reactant: CCC(F)(F)c1cc(=O)nc2n1C[C@@H](COS(=O)(=O)c1ccc(C)cc1)O2
Product: CCC(F)(F)c1cc(=O)nc2n1C[C@@H](COc1ccc3c(c1)CCCC3(C)C)O2
Yield: 32 %

Procedure:
The title compound was prepared from toluene-4-sulfonic acid (S)-5-(1,1-difluoro-propyl)-7-oxo-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.188 mmol) and 5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (0.281, mmol,) according to the procedure described in Example 9. This afforded 24.0 mg (32%) of title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.C([O:18][C:19](=[O:30])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([Cl:29])[CH:23]=1)C>>[Cl:29][C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][C:19]([OH:30])=[O:18])[CH:27]=[CH:26][C:25]=1[O:28][CH2:2][C:3]1[C:4]([S:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCc1ccc(O)c(Cl)c1
Reactant: Cc1ccc(CCl)c(SC2CCCC2)n1
Product: Cc1ccc(COc2ccc(CCC(=O)O)cc2Cl)c(SC2CCCC2)n1
Yield: 49.3 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-6-methyl-pyridine (35 mg, 0.15 mmol) obtained in Step C of Preparation Example 36 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (36 mg, 0.17 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (30 mg, 58%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[C:12](Cl)[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O-:27].[Na+]>CO>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[C:12]([O:27][CH3:26])[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[O-]
Reactant: C[C@H](Nc1nc(Cl)cc(-n2cnc3ccccc32)n1)c1ccccc1
Agent: [Na+]
Solvent: CO
Product: COc1cc(-n2cnc3ccccc32)nc(N[C@@H](C)c2ccccc2)n1
Temperature: 60 °C

Procedure:
To a suspension of 2-[(S)-1-phenylethylamino]-4-[benzimidazol-1-yl]-6-chloropyrimidine (EXAMPLE 306 Step B) (34.5 mg, 0.098 mmol) in methanol (1 mL) was added sodium methoxide (56 μL, 25 wt. % in MeOH) dropwise. The mixture was heated at 60° C. for 2 h (the mixture became homogeneous), then was cooled and the solvent was removed under reduced pressure. The crude mixture was purified by flash chromatography using 1:4 EtOAc:hexane system to give 26 mg of the title compound. Mass spectrum 346.0 (CI, M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[CH2:10][CH2:11][CH:12]([CH:14]=O)[CH2:13][C:7]=3[C:6]=2[CH:16]=1.[CH3:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]3[O:31][CH2:30][C@H:29]([CH2:32][NH2:33])[O:28][C:24]3=2)[N:19]=1.[BH3-]C#N.[Na+].CC(O)=O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[CH2:10][CH2:11][CH:12]([CH2:14][NH:33][CH2:32][C@@H:29]4[O:28][C:24]5=[C:25]6[C:20](=[CH:21][CH:22]=[C:23]5[O:31][CH2:30]4)[N:19]=[C:18]([CH3:17])[CH:27]=[CH:26]6)[CH2:13][C:7]=3[C:6]=2[CH:16]=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](CN)O3
Reactant: O=CC1CCc2oc3ccc(F)cc3c2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CNCC1CCc2oc4ccc(F)cc4c2C1)O3
Reaction time: 3 h

Procedure:
8-fluoro-1,2,3,4-tetrahydrodibenzo[b,d]furan-2-carbaldehyde (0.040 g, 0.18 mmol), [(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methylamine (0.042 g, 0.18 mmol), and NaBH3CN (0.023 g, 0.38 mmol) were stirred together in MeOH (1.2 mL) under a N2 atmosphere. To this mixture was added AcOH (0.023 mL) and reaction was allowed to stir for 3 h. The reaction mixture was concentrated and the resulting oil was purified by flash chromatography on silica gel to afford title compound as a mixture of two diastereomers (0.068 g, 88%). The diastereomers were separated by HPLC on a Chiracel AD column (2×25 cm), eluting with 100% ethanol; MS (ES) m/z=433.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([O:5][CH2:4]1)[CH3:3].[Cl-].[NH4+].[C:8]1([CH3:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Cu]I>[CH3:1][C:2]([OH:5])([CH2:4][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:3]
Reactant: CC1(C)CO1
Reactant: Cc1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(O)CCc1ccccc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
13.92 g of copper(I) iodide were added to the supernatant obtained according to example 1, and the flask was cooled to −10° C. Then, 52.70 g of isobutylene oxide were added gradually over a period of 1 hour using a dropping funnel, and the temperature was maintained between −10° C. and −6° C. A mild exotherm was observed during this latter process. After stirring the mixture for a further 2 hours at 0° C., a sample was taken for analysis by gas chromatography. This sample was worked up with ammonium chloride solution. The reaction mixture was worked up by addition of 400 ml of saturated ammonium chloride solution, and 200 ml of toluene were added. The organic phase was separated off and washed twice with 400 ml each time of saturated ammonium chloride solution. After drying over magnesium sulfate, the product was obtained by distillation in vacuo with a purity of >97%. A total of 88.9 g of 2-methyl-4-phenylbutan-2-ol were obtained, corresponding to a yield of 74%.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C:10](=O)[C:4]2=[N:3][CH:2]=1.Cl.[NH2:17][OH:18].CC([O-])=O.[Na+]>CO>[CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C:10](=[N:17][OH:18])[C:4]2=[N:3][CH:2]=1
Reactant: O=C1CCc2ccccc2-n2ccnc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=C1CCc2ccccc2-n2ccnc21
Reaction time: 8 h
Yield: 87.8 %

Procedure:
Under a nitrogen atmosphere, charge a reactor with 42 kg of (5,6-dihydroimidazo[1,2-a][1]benzazepin-4-one), 15.5 kg of hydroxylamine hydrochloride, 21.5 kg of sodium acetate anhydrous, and 171 kg of methanol. Heat the resulting brown suspension to 60 to 70° C. for 20 h (in process HPLC<3% 5,6-dihydroimidazo[1,2-a][1]benzazepin-4-one). Cool the reaction to 23 to 25° C. and stir for 8 h. Isolate the solid by centrifugation, rinsing with 33 kg of cold methanol. Transfer the resulting solid into a reactor and slurry with 210 kg of water at 85 to 90° C. for 2 h. Isolate the solid by centrifugation, rinsing the solid with 85 kg of water. Dry the resulting solid to give 39.65 kg of 5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-one oxime. MS=214 (M+1).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]([N:19]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)=[O:18])=[C:10]3[CH:9]=2)[C@@H:5]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=2)[CH2:4]1)#[N:2].[OH-:45].[Na+].OO>CO>[C:1]([C@@H:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]([N:19]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[CH2:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)=[O:18])=[C:10]3[CH:9]=2)[C@@H:5]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=2)[CH2:4]1)(=[O:45])[NH2:2]
Reactant: [OH-]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@@H](C#N)C[C@@H]4c4cccc(F)c4)cc23)cc1
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@@H](C(N)=O)C[C@@H]4c4cccc(F)c4)cc23)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 5-((2R,4S)-4-cyano-2-(3-fluorophenyl)pyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-35) (25 mg, 0.042 mmol) in MeOH (1 mL) was cooled to 0° C. A 1M NaOH solution (0.17 mL, 0.17 mmol) and 30% H2O2 (0.01 mL) were added to the reaction and stirred at 0° C. for 1 hour followed by room temperature for 1 hour. The reaction was concentrated to dryness and the residue was partitioned between EtOAc and H2O. The aqueous layer was extracted twice with EtOAc and the combined organics were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica chromatography with EtOAc/hexane gradient as eluent to yield 5-((2R,4S)-4-carbamoyl-2-(3-fluorophenyl)pyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-54). 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=7.7 Hz, 1 H), 7.78 (s, 1 H), 7.32-7.27 (m, 1H), 7.18 (d, J=8.5 Hz, 4 H), 7.14-7.09 (m, 1 H), 7.00-6.92 (m, 2 H), 6.89 (d, J=8.6 Hz, 4 H), 6.85 (s, 1 H), 6.15 (dd, J=2.7, 7.6 Hz, 1 H), 5.75 (bs, 1 H), 5.54 (bs, 1 H), 5.05 (d, J=7.7 Hz, 1 H), 4.72 (d, J=15.7 Hz, 2 H), 4.51 (d, J=15.8 Hz, 2 H), 4.04-3.97 (m, 1H), 3.88-3.82 (m, 1 H), 3.81 (s, 6 H), 3.23-3.11 (m, 1 H), 2.87-2.73 (m, 1 H), 2.19 (ddd, J=1.4, 6.5, 12.3 Hz, 1 H). MS m/z 608.3 (M+1)+.