Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[Cl:6][C:7]1[CH:20]=[CH:19][C:10]2[N:11]([CH2:15][CH2:16][CH2:17]O)[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[Cl:6][C:7]1[CH:20]=[CH:19][C:10]2[N:11]([CH2:15][CH2:16][CH2:17][N:31]3[CH2:30][CH2:29][C:28]([C:25]4[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=4)([OH:34])[CH2:33][CH2:32]3)[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1CCCO
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2cc(Cl)ccc2n1CCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Yield: 24 %

Procedure:
A mixture of 6.7 parts of 5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate, 4.2 parts of 4-(4-chlorophenyl)-4-piperidinol, 3.2 parts of sodium carbonate and 32 parts of 4-methyl-2-pentanone is stirred and heated at 50°-60° C for 1.50 hours. The reaction mixture is poured onto ice-water. The precipitated product is filtered off and dissolved in trichloromethane. The solution is washed with water, dried, filtered and evaporated. The solid residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is stirred in a small amount of trichloromethane. The product is filtered off and crystallized from 4-methyl-2-pentanone, yielding 2 parts (24%) of 5-chloro-1-{3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 190.8° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][O:10][CH:9]([C:13]2([CH3:18])OCC[O:14]2)[CH2:8]1)=[O:6])[CH:2]=[CH2:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[C:13]([CH:9]1[O:10][CH2:11][CH2:12][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH2:8]1)(=[O:14])[CH3:18]
Reactant: C=CCOC(=O)N1CCOC(C2(C)OCCO2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: C=CCOC(=O)N1CCOC(C(C)=O)C1
Yield: 75.1 %

Procedure:
A solution of 4-allyloxycarbonyl-2-[2-methyl-1,3-dioxolan-2-yl)morpholine (2.20 g) in acetone (22 ml) was stirred at ambient temperature for 5 days in the presence of p-toluenesulfonic acid monohydrate (1.10 g). The mixture was concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (25 g) and eluted with a mixture of hexane and ethyl acetate (9:1, V/V) to give 2-acetyl-4-allyloxycarbonylmorpholine (1.37 g) as a syrup.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C@:8]2([CH2:25][CH2:24][C@H:23]3[C@@H:13]([CH2:14][CH:15]=[C:16]4[C@:21]3([CH3:22])[CH2:20][CH2:19][C@H:18]([O:26][C:27](=[O:29])[CH3:28])[CH2:17]4)[C@@H:10]2[CH2:11][CH:12]=1)[CH3:9])(=O)=O.C(B(CC)[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)C>>[CH3:28][C:27]([O:26][C@@H:18]1[CH2:17][C:16]2[C@@:21]([CH3:22])([C@@H:23]3[C@@H:13]([CH2:14][CH:15]=2)[C@@H:10]2[CH2:11][CH:12]=[C:7]([C:39]4[CH:40]=[CH:35][CH:36]=[N:37][CH:38]=4)[C@@:8]2([CH3:9])[CH2:25][CH2:24]3)[CH2:20][CH2:19]1)=[O:29]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(OS(=O)(=O)C(F)(F)F)=CC[C@@H]32)C1
Reactant: CCB(CC)c1cccnc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(c4cccnc4)=CC[C@@H]32)C1

Procedure:
The Suzuki reaction between 3β-acetoxyandrosta-5,16-dien-17-yl trifluoromethanesulphonate (II) and diethyl(3-pyridyl)borane affords crude abiraterone acetate which is purified by silica gel chromatography, eluting with a mixture of ethyl ether and petroleum ether, and finally crystallised from hexane.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:31]2([CH3:32])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:26])[CH2:18][CH2:19][C@H:20]([F:25])[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:34][C:35](=[O:37])[CH3:36])[CH2:6]1)(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].[Br:43]N1C(C)(C)C(=O)N(Br)C1=O>CCCCCC>[C:1]([O:4][C@@H:5]1[C@@:31]2([CH3:32])[C:9](=[CH:10][CH:11]([Br:43])[C@@H:12]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:26])[CH2:18][CH2:19][C@H:20]([F:25])[C:21]([OH:24])([CH3:22])[CH3:23])[CH2:8][C@@H:7]([O:34][C:35](=[O:37])[CH3:36])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CC[C@H](F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Product: CC(=O)O[C@@H]1CC2=CC(Br)[C@H]3[C@@H]4CC[C@H]([C@H](C)CC[C@H](F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 80 °C

Procedure:
A mixture of 0.260 g. (0.0005 mole) of [1α,3β,24S]-24-fluorocholest-5-en-1,3,25-triol 1,3-diacetate, 0.25 g. of sodium bicarbonate, 0.096 g. (0.00033 mole) of 1,3-dibromo-5,5-dimethylhydantoin, and 13 ml. of hexane was heated at reflux (80° C.) for 1 hr and cooled. The mixture was filtered and the solids were triturated with hexane and filtered. The combined filtrates were evaporated to dryness to yield [1α,3β,7ξ,24S]-7-bromo-24-fluorocholest-5-en-1,3,25-triol 1,3-diacetate.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[N+:31]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38])([O-:33])=[O:32]>C(Cl)Cl>[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH:22][C:37](=[O:38])[C:36]1[CH:40]=[CH:41][CH:42]=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1cccc([N+](=O)[O-])c1)OCc1ccccc1
Yield: 100.1 %

Procedure:
To a mixture of O-benzylglycine p-toluenesulfonic acid salt (6.41 g) and triethylamine (4.04 g) in methylene chloride (100 ml) was added portionwise 3-nitrobenzoyl chloride (3.71 g) under cooling in an ice-bath and stirring. The resultant mixture was stirred for 1 hour under the same condition and for 1 hour further at ambient temperature. From the reaction mixture, methylene chloride was removed in vacuo and to the residue were added water and ethyl acetate with stirring. The separated organic layer was washed with diluted hydrochloric acid, aqueous sodium bicarbonate and water twice respectively. The extract was dried over magnesium sulfate and evaporated in vacuo to give N-(3-nitrobenzoyl)glycine benzyl ester (5.98 g). 1H-NMR (CDCl3, δ): 4.31 (2H, d, J=5.2 Hz), 5.24 (2H, s), 6.99 (1H, br, t, J=5.2 Hz), 7.38 (5H, s), 7.64 (1H, t, J=7.9 Hz), 8.15 (1H, d, t, J=7.9 Hz, 2.2 Hz), 8.35 (1H, d, t, J=7.9 Hz, 2.2 Hz), 8.64 (1H, t, J=2.2 Hz); APCI-MS (CHCl3) (m/z): 315 (M+ +1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[C:5]([CH:11]=[CH2:12])[CH:4]=1.P(Br)(Br)[Br:14].O>C(OCC)C>[Br:14][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:11]=[CH2:12]
Reactant: C=Cc1cc(OC)ccc1CO
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: O
Product: C=Cc1cc(OC)ccc1CBr

Procedure:
To a solution of (4-methoxy-2-vinylphenyl)-methanol (7.90 g, 48.2 mmol) in diethyl ether (100 mL) at 0° C. is added PBr3 (5.0 mL, 53 mmol) over 1 min. Water is added carefully to destroy excess PBr3. The mixture is partitioned carefully between EtOAc and NaHCO3 (plus a small amount of KOH to adjust pH to 7˜8). The organic extract is dried with MgSO4 and concentrated to give the title compound and it is used directly in the next step: 1H NMR (CDCl3) δ 3.83 (s, 3H), 4.57 (s, 2H), 5.44 (dd, J=1, 11 Hz, 1H), 5.74 (dd, J=1, 17 Hz, 1H), 6.81 (dd, J=3, 8 Hz, 1H), 7.03 (d, J=2 Hz, 1H), 7.06 (dd, J=11, 17 Hz, 1H), 7.25 (d, J=8 Hz, 1H).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH:26]=O)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[C:31]1([CH:37]2[CH2:41][CH2:40][CH2:39][NH:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:38]5[CH2:39][CH2:40][CH2:41][CH:37]5[C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: c1ccc(C2CCCN2)cc1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5c5ccccc5)c4)cc23)CC1
Yield: 22.1 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.11 mmol) in DMSO (2.0 mL) was added 2-phenylpyrrolidine (147 mg, 1.0 mmol). The reaction mixture was then reacted in a microwave at 120° C. for 10 min. Sodium triacetoxyborohydride (220 mg, 1.0 mmol) was then added and the reaction was reacted at room temperature overnight. It was then purified by Gilson Preparatory HPLC to give 14.0 mg of the title compound (22%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:14][C:15]1[C:22]([CH3:23])=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[CH3:24].S(=O)(O)[O-].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.CN(C)C(=O)C>[OH:14][C:15]1[C:22]([CH3:23])=[CH:21][C:18]([C:19]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=3)[N:1]=2)=[CH:17][C:16]=1[CH3:24]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3ccc([N+](=O)[O-])cc3c(=O)[nH]2)cc(C)c1O
Temperature: 155 °C
Yield: 18.8 %

Procedure:
To a round-bottomed flask were added 2-amino-5-nitro-benzamide (0.681 g, 3.76 mmol), 4-hydroxy-3,5-dimethyl-benzaldehyde (0.565 g, 3.76 mmol), sodium bisulfite (0.747 g, 4.2 mmol), p-toluenesulfonic acid, monohydrate (0.072 g, 0.376 mmol) and N,N-dimethylacetamide (60 mL). The reaction mixture was refluxed at 155° C. for 16 h before being cooled to room temperature. Water was added and the precipitated solid was filtered off, washed with water and methanol to obtain a crude which was purified by column chromatography (silica gel (50 g) employing 1-20% methanol in dichloromethane as eluents, to obtain 2-(4-hydroxy-3,5-dimethyl-phenyl)-6-nitro-3H-quinazolin-4-one (0.220 g, 19%). The compound 2-(4-hydroxy-3,5-dimethyl-phenyl)-6-nitro-3H-quinazolin-4-one (0.220 g, 0.71 mmol) was hydrogenated in dimethyl formamide (20 mL) using palladium on activated carbon (0.076 g, 0.071 mmol) at room temperature for 14 h. The solvent was evaporated and the crude was purified by column chromatography (silica gel 25 g) employing 1-5% methanol in dichloromethane as eluents to obtain 6-amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one (0.132 g). The compound 6-amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one was dissolved in pyridine under nitrogen. Acetic anhydride was added at room temperature and stirred for 4 h. Pyridine was removed and the residue was dried. Methanol was added to the flask and a solution of potassium carbonate in water was added and stirred for 4 h. The solvent was removed, acidified with 1 N hydrochloric acid and the precipitated solid was filtered off and dried to obtain N-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide (0.037 g, 17%). Selected data: MS (ES) m/z: 324.1; MP 336.5° C. (decomposed).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([C:9]2[CH:32]=[C:14]3[C:15]4[C:20]([CH2:21][CH2:22][N:13]3[C:12](=[O:33])[CH2:11][N:10]=2)=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[CH:17][CH:16]=4)[CH:8]=1.[OH:34]O>COCCOC>[OH:34][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[CH2:21][CH2:22][N:13]1[C:12](=[O:33])[CH2:11][N:10]=[C:9]([N:7]3[CH:8]=[C:4]([CH2:3][O:2][CH3:1])[N:5]=[CH:6]3)[CH:32]=[C:14]12
Reactant: OO
Reactant: COCc1cn(C2=NCC(=O)N3CCc4c(B5OC(C)(C)C(C)(C)O5)cccc4C3=C2)cn1
Solvent: COCCOC
Product: COCc1cn(C2=NCC(=O)N3CCc4c(O)cccc4C3=C2)cn1
Reaction time: 8 h

Procedure:
Example 142-2. 2-(4-(methoxymethyl)-1H-imidazol-1-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (413 mg, 0.737 mmol) was dissolved in DME (10 mL) and hydrogen peroxide (30%, 3.40 mL, 33.3 mmol) was added at rt. The mixture was stirred overnight and the resulting crystals were filtered off (62 mg). UPLC-MS: MS 339.2 (M+H+); UPLC rt 0.63 min.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:12][CH2:13][CH2:14][CH2:15][S:16](Cl)(=[O:18])=[O:17]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][S:16]([CH2:15][CH2:14][CH2:13][Cl:12])(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Solvent: c1ccncc1
Product: Cc1cc([N+](=O)[O-])ccc1NS(=O)(=O)CCCCl

Procedure:
A solution of 5.51 g (36.2 mmol) of 2-methyl-4-nitroaniline and 6.41 g (36.2 mmol) of 3-chloropropanesulfonyl chloride in 20 ml of pyridine is stirred overnight at room temperature. The reaction mixture is then poured onto ice. The precipitate which deposits in the process is filtered off with suction and dried, giving N-(2-methyl-4-nitrophenyl)-3-chloropropane-1-sulfonamide as a yellowish solid; ESI 293.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16](O)=[O:17])=[CH:8]1.[NH2:20][CH2:21][C:22]1[C:23]([OH:30])=[N:24][C:25]([CH3:29])=[CH:26][C:27]=1[CH3:28].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[OH:30][C:23]1[C:22]([CH2:21][NH:20][C:16]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:19])[CH:8]=2)=[O:17])=[C:27]([CH3:28])[CH:26]=[C:25]([CH3:29])[N:24]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1ccccc1-n1cc(C(=O)O)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cn(-c3ccccc3C)c3ccccc23)c(O)n1

Procedure:
A mixture of 1-(o-tolyl)-1H-indole-3-carboxylic acid (100 mg, 0.398 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (60 mg, 0.398 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (114 mg, 0.597 mmol). N-hydroxybenzotriazole (81 mg, 0.597 mmol), triethylamine (81 mg, 0.796 mmol) and dichloromethane (5 mL) was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and ethyl acetate (10 mL) was added. The resulting mixture was washed with water (10 mL) and brine in turns and then dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative-TLC (silica gel, dichloromethane:methanol=15:1) to give pure desired product of N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-1-(o-tolyl)-1H-indole-3-carboxamide as an off white solid (100 mg, 65%). LRMS (M+H+) m/z: calcd 385.18. found 385. 1H NMR (300 MHz, CD3OD) δ 8.16 (dd, J=6.1, 2.5 Hz, 1H), 7.87 (s, 1H), 7.44 (d, J=4.9 Hz, 2H), 7.41-7.26 (m, 2H), 7.26-7.12 (m, 2H), 6.93 (dd, J=6.3, 2.4 Hz, 1H), 6.11 (s, 1H), 4.53 (s, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 2.01 (s, 3H).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].Cl.[OH:13][C:14]1[CH:37]=[CH:36][C:35]([O:38][CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:34][C:15]=1[C:16]([NH:18][C:19]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22])=[O:17]>C(Cl)Cl>[OH:13][C:14]1[CH:37]=[CH:36][C:35]([O:38][CH:39]2[CH2:40][CH2:41][N:42]([S:8]([CH3:7])(=[O:10])=[O:9])[CH2:43][CH2:44]2)=[CH:34][C:15]=1[C:16]([NH:18][C:19]1[CH:27]=[C:26]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(OC2CCNCC2)ccc1O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Oc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under ice-cooling, pyridine (0.5 mL) and methanesulfonyl chloride (9.9 μL) were sequentially added to a methylene chloride (1 mL) suspension of 2-(2-hydroxy-5-(piperidin-4-yloxy)benzamido)-4-phenylbenzoic acid hydrochloride (0.030 g), followed by stirring at room temperature for 5 hours and 30 minutes. The solvent was evaporated under reduced pressure, and methanol (0.5 mL) and a 2 mol/L aqueous solution of sodium hydroxide (0.5 mL) were added to the residue, followed by stirring at 70° C. for 45 minutes. The reaction mixture was cooled to room temperature, and then 1 mol/L hydrochloric acid (5 mL) was added thereto. The solid substance was collected by filtration and the obtained solid substance was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: chloroform] to obtain 8.0 mg of 2-(2-hydroxy-5-(1-(methylsulfonyl)piperidin-4-yloxy)benzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:8].[CH:9]1([C:12]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])[CH2:11][CH2:10]1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][C:19]([C:21]([F:22])([F:23])[F:24])=[CH:20][C:12]=1[CH:9]1[CH2:10][CH2:11]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C1CC1
Reactant: N[C@@H]1CCCC[C@@H]1N
Product: N[C@H]1CCCC[C@H]1NC(=O)c1ccc(C(F)(F)F)cc1C1CC1

Procedure:
The title compound, yellow solid, MS: m/e=327.2 [(M+H)+], was prepared in accordance with the general method of intermediate G from cis-1,2-diaminocyclohexane and 2-cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate K).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH2:12][CH2:13][CH3:14])[NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([O-])(=O)C.[Na+].CO[CH:22]1[CH2:26][CH2:25][CH:24](OC)O1>C(O)(=O)C>[CH2:12]([C:4]1[NH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([N:1]2[CH:22]=[CH:26][CH:25]=[CH:24]2)[N:3]=1)[CH2:13][CH3:14]
Reactant: COC1CCC(OC)O1
Reactant: CCCc1nc(N)c(C(=O)OCC)[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1nc(-n2cccc2)c(C(=O)OCC)[nH]1
Temperature: 25 °C

Procedure:
A solution of ethyl 4-amino-2-propylimidazole-5-carboxylate from above (9.34 g, 47 mmol) and sodium acetate (23.2 g) in acetic acid (100 mL) was heated to reflux and treated with 2,5-dimethoxy-tetrahydrofuran (6.75 mL, 52 mmol). The reaction was held at reflux for 30 minutes, then cooled back to room temperature with an ice bath. The majority of the acetic acid was evaporated under reduced pressure, then the residue was partitioned between ethyl acetate and 10% aqueous K2CO3 (120 mL) each. The organic layer was dried over MgSO4 and evaporated. The residue was purified by flash chromatography on silica gel, eluting with CH2Cl2 -ethyl acetate (80:20). Evaporation of solvents gave a solid which was recrystallized from hexane/EtOAc (1:1) to give 7.4 g of the title compound, mp 134°-135° C.; MS (CI), 248 (m +1).
Reaction SMILES: C(O[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:12][CH:13]=2)[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[N:23]=2)[CH:7]=1)=[O:5])C.Cl.[CH3:30][NH:31][O:32][CH3:33].C[Al](C)C>C1(C)C=CC=CC=1>[CH3:33][O:32][N:31]([CH3:30])[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([C:17]([F:18])([F:20])[F:19])=[CH:12][CH:13]=2)[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[N:23]=2)[CH:7]=1)=[O:5]
Reactant: CNOC
Reactant: CCOC(=O)c1cn(Cc2cccc(Br)n2)c2nc(C(F)(F)F)ccc2c1=O
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2nc(C(F)(F)F)ccc2c1=O

Procedure:
A mixture of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (0.72 g, 1.6 mmol, 1 equiv) and methylmethoxyamine hydrochloride (0.16 g, 1 equiv) in 2 mL of toluene was treated with AlMe3 (0.5 M in toluene, 3.5 mL, 1.1 equiv) at rt for 1 h. The reaction was quenched by slow addition of saturated aqueous solution of sodium potassium tartrate. The organic layer was dried over sodium sulfate, filtered and evaporated to give crude 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-3carboxylic acid methoxy-methyl-amide.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[C:10]1([C:16]([O:18][CH3:19])=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.Cl.[CH3:21][C:22]1[N:23]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=2)[CH:24]=[CH:25][N:26]=1>>[F:1][C:2]1[C:7]([O:8][CH2:31][C:30]2[CH:29]=[CH:28][C:27]([N:23]3[CH:24]=[CH:25][N:26]=[C:22]3[CH3:21])=[CH:34][CH:33]=2)=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[C:10]1([C:16]([O:18][CH3:19])=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: COC(=O)C1(c2cc(F)cc(O)c2F)CCOCC1
Reactant: Cc1nccn1-c1ccc(CCl)cc1
Agent: Cl
Product: COC(=O)C1(c2cc(F)cc(OCc3ccc(-n4ccnc4C)cc3)c2F)CCOCC1
Yield: 49 %

Procedure:
Methyl 4-(2,5-difluoro-3-hydroxyphenyl)-3,4,5,6-tetrahydropyran-4-carboxylate was reacted with 4-(2-methylimidazol-1-yl)benzyl chloride hydrochloride according to the procedure described in Example 2H to give the titled compound in 49% yield as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([NH:10][C@H:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[C-:22]#[N:23].O>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C@H:11]1([NH:10][C:7]2[O:8][CH2:9][C:4]3[CH:3]=[C:2]([C:22]#[N:23])[CH:21]=[CH:20][C:5]=3[N:6]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1
Reactant: [C-]#N
Reactant: Brc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Temperature: 160 °C
Yield: 41.1 %

Procedure:
A stirred mixture of (6-bromo-4H-benzo[d][1,3]oxazin-2-yl)-(R)-indan-1-yl-amine (Example 32) (2.0 g, 5.83 mmol), zink cyanide (1.03 mg, 8.77 mmol) and tetrakis-(triphenylphosphine)-palladium (673 mg, 0.58 mmol) in N,N-dimethylformamide (20 ml) was heated at 160° C. for 15 min in a microwave reactor. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2×70 ml). The combined organic layers were washed with brine (2×20 ml), dried (magnesium sulfate) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as light yellow foam (693 mg, 41%). MS (ISN): m/e=288.2 (M−H−).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22](N)=[O:23])[CH:17]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:25].[K+]>C(O)C>[C:10]1([C:7]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:25])=[O:23])[CH:17]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH3:9])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCC(c1ccccc1)(c1ccccc1)c1ccnc(C(N)=O)c1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: CCC(c1ccccc1)(c1ccccc1)c1ccnc(C(=O)O)c1

Procedure:
Dissolve 3.8 g. of 4-(1,1-diphenylpropyl)-picolinamide in 50 ml. of ethanol, add 100 ml. of 10% aqueous potassium hydroxide and heat the resulting mixture at reflux overnight. Remove the ethanol under reduced pressure, add water to the residue and adjust to about pH 5 with 10% aqueous hydrochloric acid. Filter the resulting solid and crystallize the precipitate from ethanol to obtain thereby the compound of this example, yield -- 1.6 g., m.p. 191°-193° C.