Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1([CH3:15])[CH2:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5]1.[N+:18]([O-])([O-:20])=[O:19].[NH4+].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1([CH3:15])[CH2:9][C:8](=[O:10])[C:7]2[CH:11]=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: COC(OC)C1(C)CC(=O)c2ccccc2O1
Reactant: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(OC)C1(C)CC(=O)c2cc([N+](=O)[O-])ccc2O1
Yield: 55 %

Procedure:
In 15 ml of chloroform were dissolved 1.99 (8.1 mmole) of the compound obtained in step 1 and 0.64(8.1 mmole) of ammonium nitrate; and, 4.5 ml (32 mmole) of anhydrous trifluoroacetic acid was added thereto at room temperature. The resultant mixture was stirred at room temperature for 3 hours; and, the reaction was terminated with a saturated NaHCO3 aqueous solution. The resultant solution was extracted with dichloromethane (50 ml×2), washed with 50 ml of water and with 20 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain residue, which was purified by silica gel column chromatography using a mixture of hexane and ethyl acetate (4:1) as an eluent to obtain 1.24 g (yield 55%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:29]=[CH:28][C:27](Br)=[CH:26][C:3]=1[C:4]([C:6]1[N:11]=[C:10]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:25])[CH2:20][C:21]([F:24])([F:23])[F:22])[CH2:14][CH2:13]2)[CH:9]=[CH:8][CH:7]=1)=[O:5].[CH:31](B1OC(C)(C)C(C)(C)O1)=[CH2:32].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:29]=[CH:28][C:27]([CH:31]=[CH2:32])=[CH:26][C:3]=1[C:4]([C:6]1[N:11]=[C:10]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:25])[CH2:20][C:21]([F:24])([F:23])[F:22])[CH2:14][CH2:13]2)[CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)c1cccc(N2CCCN(C(=O)CC(F)(F)F)CC2)n1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C=Cc1cnc(N)c(C(=O)c2cccc(N3CCCN(C(=O)CC(F)(F)F)CC3)n2)c1
Yield: 21.5 %

Procedure:
A mixture of 1-(4-(6-(2-amino-5-bromonicotinoyl)pyridin-2-yl)-1,4-diazepan-1-yl)-3,3,3-trifluoropropan-1-one (355 mg, 0.73 mmol), vinyl boronic acid pinacol ester (0.15 ml, 0.88 mmol), tetrakis(triphenylphosphine)palladium(0) (42 mg) and a 2M aqueous solution of sodium carbonate (2 ml) in ethanol (1 ml) and toluene (3 ml) was heated under microwave irradiation at 110° C. for 5 hours. The reaction mixture was concentrated in vacuo. The residue was slurried in ethyl acetate, filtered to remove the inorganic salts and concentrated to dryness in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as an orange solid (68 mg, 21% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.C(N(CC)CC)C.[CH3:26][C@H:27]1[CH2:32][O:31][CH2:30][CH2:29][NH:28]1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][C@@H:27]2[CH3:26])[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1
Reactant: O=S(=O)(Cc1cc(Cl)nc(Cl)n1)c1ccccc1
Reactant: C[C@H]1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccccc2)nc(Cl)n1
Temperature: -5 °C
Yield: 76.5 %

Procedure:
2,4-dichloro-6-[(phenylsulfonyl)methyl]pyrimidine (2.8 g, 9.24 mmol) was dissolved in DCM (20 mL) and stirred (under nitrogen) at −5° C. Triethylamine (1.42 mL, 10.17 mmol) was added to give a clear brown solution. (3S)-3-methylmorpholine (935 mg, 9.24 mmol) was dissolved in DCM and added dropwise keeping the reaction below −5° C. The cooling bath was then removed and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was then washed with water (50 mL), dried over magnesium sulphate, filtered and concentrated in vacuo. The crude material was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM to give the desired material as a white solid (2.6 g).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:20]([OH:22])=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:4][C:3]=1[F:24].[NH:25]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH2:26]1>>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:24])=[C:2]([N:25]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=4)[CH2:26]3)[N:11]=2)[C:6](=[O:23])[C:7]([C:20]([OH:22])=[O:21])=[CH:8]1
Reactant: c1cc(C2CCNC2)ccn1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(c4ccncc4)C3)c(F)cc2c1=O
Yield: 56 %

Procedure:
Starting from 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.51 g, 1.5 mmol) and 4-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1, provided the title compound (0.39 g, 56%) as an off-white solid, mp 253°-255° C. (dec).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:15][CH2:14][C:13]2[C:16]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29](=[O:38])[NH:30][CH:31]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:25][CH:24]=3)=[C:17]([Cl:20])[CH:18]=[CH:19][C:12]=2[CH2:11][CH2:10]1)=O)(C)(C)C>CCOC(C)=O.CO>[Cl:20][C:17]1[CH:18]=[CH:19][C:12]2[CH2:11][CH2:10][NH:9][CH2:15][CH2:14][C:13]=2[C:16]=1[CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:38])[NH:30][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CNc3ccc(C(=O)NC4CCCCCC4)cc3)c2CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(NC1CCCCCC1)c1ccc(NCc2c(Cl)ccc3c2CCNCC3)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
Add hydrogen chloride into a mixture of 3-tert-butoxycarbonyl-7-chloro-6-[(4-cycloheptylcarbamoyl-phenylamino)-methyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (590 mg, 1.12 mmol) in EtOAc/methanol (1:1, 60 mL) until the mixture is saturated. Stir for 1 h at 40° C. and concentrate in vacuo. Purify the residue by SCX chromatography to obtain 7-chloro-6-[(4-cycloheptylcarbamoyl-phenylamino)-methyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (450 mg, 1.06 mmol). Use a method similar to the General Procedure 2-1 to obtain the title compound as an off-white solid (560 mg, 92%). MS (ES+) m/z: 426 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:33]4[C:28](=[CH:29][C:30]([N+:34]([O-])=O)=[CH:31][CH:32]=4)[N:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:11][CH:10]=1.[H][H]>CO.[Pd]>[NH2:34][C:30]1[CH:29]=[C:28]2[C:33]([C:24]([N:21]3[CH2:20][CH2:19][N:18]([C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=4)=[O:17])[CH2:23][CH2:22]3)=[CH:25][CH:26]=[N:27]2)=[CH:32][CH:31]=1
Reactant: O=C(Nc1ccc(F)cc1)N1CCN(c2ccnc3cc([N+](=O)[O-])ccc23)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2c(N3CCN(C(=O)Nc4ccc(F)cc4)CC3)ccnc2c1

Procedure:
A suspension of 4-[4-(4-fluorophenylaminocarbonyl)piperazin-1-yl]-7-nitroquinoline trifluoroacetate (130 mg) and 10% Pd/C (20 mg) in MeOH is stirred in a hydrogen atmosphere for 30 min. The reaction mixture is filtered and concentrated giving the title product.
Reaction SMILES: [N+:1]([C:4]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH:10]2[N:6]([CH2:7][CH2:8][CH2:9]2)[CH2:5]1)([O-])=O>C1COCC1.[Ni]>[C:13]1([C:4]2([NH2:1])[CH2:12][CH2:11][CH:10]3[N:6]([CH2:7][CH2:8][CH2:9]3)[CH2:5]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])C1(c2ccccc2)CCC2CCCN2C1
Agent: [Ni]
Solvent: C1CCOC1
Product: NC1(c2ccccc2)CCC2CCCN2C1
Reaction time: 2 h

Procedure:
To a solution of 62 mg (0.252 mmol) 6-nitro-6-phenyl-octahydro-indolizine in 2.0 ml THF was added 150 ul Raney Nickel (50% in water). The mixture was stirred under a hydrogen atmosphere for 2 hours. The apparatus was purged with argon. The catalyst was filtered, washed with THF and the filtrate was concentrated in vacuo to provide 57 mg (y: 100%) of the title compound as a colorless oil. MS (m/e): 217.4 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([OH:5])[CH2:3][CH3:4].[C:6](Cl)(=[O:14])[O:7][CH2:8][O:9][C:10](=[O:13])[CH2:11][CH3:12]>>[C:6](=[O:14])([O:7][CH2:8][O:9][C:10](=[O:13])[CH2:11][CH3:12])[O:5][CH:2]([CH2:3][CH3:4])[CH3:1]
Reactant: CCC(C)O
Reactant: CCC(=O)OCOC(=O)Cl
Product: CCC(=O)OCOC(=O)OC(C)CC

Procedure:
A mixture of 2-butanol (0.092 mL, 1 mmol), 7c (0.17 g, 1 mmol), and powdered molecular sieve (0.15 g, 4Å) in alcohol-free CHCl3 (2 mL) is refluxed for 18 h. Following filtration through filter-aid and evaporation 0.2 g (98%) of the title compound is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25]C(=O)C)=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:30][CH3:31])=[O:4].C([O-])(O)=O.[Na+].O>CO>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:29]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:30][CH3:31])=[O:4]
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(OC(C)=O)cc1)O3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(O)cc1)O3
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.1 %

Procedure:
(3S,8S)-3-(4-Acetoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (120 mg) was dissolved in methanol (5 mL). To this solution was added NaHCO3 (400 mg). The mixture was stirred at rt for 2-3 h. After completion of the reaction, the mixture was poured into water (10 mL) and was extracted with EtOAc (30 mL). The organic layer was washed with water, brine, dried and concentrated to get the desired product as a white solid (110 mg) LCMS (m/z): 461.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[S:29][C:30]([C:33]([O:35]CC)=[O:34])=[CH:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[S:29][C:30]([C:33]([OH:35])=[O:34])=[CH:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: CCOC(=O)c1cnc(-c2ccc(-c3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(O[C@@H](C)COC)c3)[nH]2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3ncc(C(=O)O)s3)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.5 %

Procedure:
Ethyl 2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole-5-carboxylate (53.5 mg, 0.096 mmol) synthesized in Example (5c) was dissolved in ethanol (4 mL). An aqueous sodium hydroxide solution (5M, 2 mL) was added, and stirring was carried out at 70° C. for 30 minutes. After cooling to room temperature, hydrochloric acid (2M, 5 mL) and ethyl acetate (10 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, to afford the desired compound (52.5 mg, yield ˜100%) as a pale yellow solid.
Reaction SMILES: [CH:1]([O:5][C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25]([OH:27])=[O:26])=[CH:12][N:11]=1)([CH2:3][CH3:4])[CH3:2].[N+](=[CH2:33])=[N-]>ClCCl.C(OCC)C>[CH3:33][O:26][C:25](=[O:27])[CH2:24][C:13]1[C:14]2[C:19](=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[C:10]([CH2:9][C:8]2[CH:28]=[CH:29][CH:30]=[C:6]([O:5][CH:1]([CH2:3][CH3:4])[CH3:2])[CH:7]=2)=[N:11][CH:12]=1
Reactant: CCC(C)Oc1cccc(Cc2ncc(CC(=O)O)c3cc(OC)c(OC)cc23)c1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(C)Oc1cccc(Cc2ncc(CC(=O)OC)c3cc(OC)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
To a stirred solution of [1-(3-sec-butoxy-benzyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid (200 mg, 0.49 mmol) in dichloromethane (4 Ml) was added 0.2N diazomethane in diethyl ether solution (6 mL). The reaction mixture was stirred at room temperature for 15 hrs. The solvent was evaporated to afford of [1-(3-sec-butoxy-benzyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid methyl ester (200 mg, 96% yield) as a light yellow oil. The crude product was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)=[CH2:16]>COCCOC.O>[Br:8][C:4]1[CH:3]=[C:2]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:15]=[CH2:16])[CH:22]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: C=Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C=Cc1cccc(-c2cccc(Br)c2)c1
Temperature: 80 °C
Yield: 59.5 %

Procedure:
A solution of 1,3-dibromobenzene (5.3 mL, 43.9 mmol), potassium carbonate (14.0 g, 101 mmol) and 3-vinylphenylboronic acid (5 g, 33.8 mmol) in DME (100 mL) and water (20 mL) (in a pressure vessel) was sparged with nitrogen for 15 min. Pd(PPh3)3 (1.17 g, 1.014 mmol) was added and then the reaction was heated to 80° C. overnight. The reaction was cooled to r.t. and evaporated on the rotovap. The residue was diluted in EtOAc and washed with water then brine, dried over MgSO4, filtered and evaporated to give the crude material. The crude material was purified by flash chromatography on the Biotage (0-5% EtOAc:Hex) to give 3-bromo-3′-vinylbiphenyl (5.21 g, 20.10 mmol, 60% yield) as a clear liquid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.33 (d, J=10.79 Hz, 1H) 5.84 (dd, J=17.57, 0.75 Hz, 1H) 6.80 (dd, J=17.57, 10.79 Hz, 1H) 7.32 (t, J=7.78 Hz, 1H) 7.38-7.48 (m, 3H) 7.51 (dddd, J=13.24, 7.84, 1.76, 1.00 Hz, 2H) 7.56-7.61 (m, 1H) 7.76 (t, J=1.88 Hz, 1H).
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)=[O:6].[BH4-].[Na+].Cl>CO>[OH:6][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)[CH2:4][CH2:3][CH2:2][I:1]
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCI)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C(=O)O)c1ccc(C(O)CCCI)cc1
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a solution of 50 mg of 4-(4iodo-1-oxobutyl)-α,α-dimethylphenylacetic acid, prepared in accordance with Example 3, in 3 mL of methanol was added 50 mg of NaBH4. The mixture was stirred for 30 minutes, acidified with 2N HCl, and the methanol removed in vacuo. The concentrate was extracted with EtOAc. The organics were dried over Na2SO4, filtered, and concentrated to afford 40 mg of 4-(1-hydroxy-4-iodobutyl)-α,α-dimethylphenylacetic acid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:21][C:20]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:19]=3[CH:18]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:36][C:37](=O)[NH:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]3=[O:51])=[CH:41][C:40]=2[F:52])=CC=1)([O-])=O>>[F:52][C:40]1[CH:41]=[C:42]([N:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]2=[O:51])[CH:43]=[CH:44][C:39]=1[NH:38][C:37]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:21][C:20]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:19]=3[CH:18]=2)=[O:16])[CH2:9]1)=[O:36]
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NC[C@H]1CCNC1)c1cc2ccc(Cl)cc2s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1cc2ccc(Cl)cc2s1

Procedure:
65.3 Using general method H, 6-chloro-benzo[b]thiophene-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give (R)-3-{[(6-chloro-benzo[b]thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. White solid. MS 523.2 ([M−H]−)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[NH:13]1[C:17]2[CH:18]=[CH:19][S:20][C:16]=2[C:15]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([C:30](=[O:33])[CH2:31][CH3:32])=[CH:25][CH:24]=3)=[N:14]1.CO>O1CCCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:30]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:15]1[C:16]3[S:20][CH:19]=[CH:18][C:17]=3[NH:13][N:14]=1)=[CH:29]2)([OH:33])[CH2:31][CH3:32]
Reactant: CCC(=O)c1ccc2[nH]c(-c3n[nH]c4ccsc34)cc2c1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)(c1ccc2[nH]c(-c3n[nH]c4ccsc34)cc2c1)c1ccccn1
Reaction time: 0.33 h
Yield: 96.5 %

Procedure:
To a solution of 2-bromopyridine (224 mg, 1.42 mmol) in anhydrous tetrahydrofuran (2 mL) is added n-BuLi (1.6 M in hexane, 0.95 mL, 1.52 mmol) at −78° C. under nitrogen. After stirring for 20 minutes, to it is added a solution of 1-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl)-propan-1-one (140 mg, 0.473 mmol, Example 28) in anhydrous tetrahydrofuran (4 mL) drop wise. After 30 minutes, the cooling bath is removed and continued stirring at ambient temp for 30 minutes. The reaction is quenched by the addition of saturated ammonium chloride (4 mL) followed by water (4 mL). The reaction mixture is extracted with ethyl acetate (120 mL). Ethyl acetate phase is washed with water, brine and dried over sodium sulfate. Purification by chromatography (10 g silica gel cartridge, 30-60% ethyl acetate gradient in heptane) afforded product. It is then dissolved with minimum amount of methanol and triturated with water to give 1-pyridin-2-yl-1-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl]-propan-1-ol (171 mg, 31%, Example 31) as a beige solid; 1H NMR [(CD3)2SO)]: δ 13.195 (1H, s), 11.417 (1H, s), 8.472 (1H, d), 7.742-7.661 (4H, m) 7.259-7.166 (4H, m), 6.59 (1H, s), 5.697 (1H, s, OH), 2.361 (2H, m), 0.785 (3H, t); LC/MS: 375 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7](=[O:23])[N:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[S:9](=[O:18])(=[O:17])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:24]([O:27][C:28]1[CH:29]=[C:30]([OH:38])[CH:31]=[C:32]([O:34][CH2:35][CH2:36][CH3:37])[CH:33]=1)[CH2:25][CH3:26]>>[C:19]([N:8]1[C:7](=[O:23])[C:6]([NH:5][CH2:4][CH2:3][CH2:2][O:38][C:30]2[CH:31]=[C:32]([O:34][CH2:35][CH2:36][CH3:37])[CH:33]=[C:28]([O:27][CH2:24][CH2:25][CH3:26])[CH:29]=2)=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:9]1(=[O:18])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCCOc1cc(O)cc(OCCC)c1
Reactant: CC(C)(C)N1C(=O)C(NCCCBr)=C(c2ccccc2)S1(=O)=O
Product: CCCOc1cc(OCCC)cc(OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)c1

Procedure:
The title compound was prepared from 4-[(3-bromopropyl)amino]-2-tert-butyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 3,5-dipropoxyphenol in a similar manner as described for Example 5. 1H NMR (500 MHz, CDCl3): δ 7.54-7.50 (m, 2H), 7.46-7.41 (m, 3H), 6.12-6.09 (m, 1H), 6.08-6.06 (m, 2H), 5.89-5.83 (m, 1H), 3.93-3.84 (m, 6H), 3.09-3.03 (m, 2H), 1.87-1.76 (m, 6H), 1.74 (s, 9H), 1.07-1.01 (m, 6H); 13C NMR (125 MHz, CDCl3): δ 161.2, 160.2, 159.9, 135.4, 131.8, 129.7, 128.8, 125.3, 107.1, 94.8, 94.6, 94.4, 94.0, 69.8, 66.4, 61.6, 42.7, 28.8, 27.8, 22.8, 10.8; Mass Spectrum: M+H+ 531.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N+:5]([O-])=[C:4]([O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:3]=1[CH3:21].P(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:3]=1[CH3:21]
Reactant: CCc1cc(Cl)c(C)c(Oc2c(C)cc(C)cc2C)[n+]1[O-]
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: CCc1cc(Cl)c(C)c(Oc2c(C)cc(C)cc2C)n1
Temperature: 25 °C

Procedure:
To a solution of 4-Chloro-6-ethyl-3-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine 1-oxide in methylene chloride was added PCl3 and the resulting mixture was heated at reflux for 20 min, cooled to rt. The mixture was concentrated to dryness. The residue was worked-up using standard procedure to give the title compound. After silica gel purification, the titel compound was prepared as a white solid, mp. 42-44° C. Anal. For C17H20ClNO calc. C, 70.46; H, 6.96; N, 4.83; found, C, 70.35; H, 7.13; N, 4.58.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4](=[O:15])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[C:16]([O-:19])(=[O:18])[CH3:17].[K+]>C(OC(=O)C)(=O)C>[C:16]([O:19][CH2:2][C:3]1[C:4](=[O:15])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2)(=[O:18])[CH3:17]
Reactant: COc1ccc2[nH]c(=O)c(CCl)cc2c1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2[nH]c(=O)c(COC(C)=O)cc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2.2 Grams of 3-chloromethyl-6-methoxycarbostyril was dissolved in 20 ml of acetic anhydride, then 12 g of potassium acetate was added thereto and stirred at 60°-70° C. for 3 hours. The reaction mixture was poured in an ice-water and the crystals precipitated were collected by filtration. Recrystallized from acetone to obtain 2 g of 3-acetoxymethyl-6-methoxycarbostyril in the form of colorless prism-like crystals.
Reaction SMILES: C([O:9][C:10]1[N:14]([C:15]([CH3:24])([CH3:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=[C:12]([CH:25]([CH3:27])[CH3:26])[C:11]=1Br)(=O)C1C=CC=CC=1.[CH3:29][O:30][C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:9][C:10]1[N:14]([C:15]([CH3:23])([CH3:24])[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:13]=[C:12]([CH:25]([CH3:26])[CH3:27])[C:11]=1[C:36]1[CH:37]=[CH:38][C:33]([C:31]([O:30][CH3:29])=[O:32])=[CH:34][CH:35]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)c1nn(C(C)(C)Cc2ccccc2)c(OC(=O)c2ccccc2)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2c(C(C)C)nn(C(C)(C)Cc3ccccc3)c2O)cc1
Temperature: 86 °C
Reaction time: 16 h
Yield: 31.1 %

Procedure:
4-Bromo-3-isopropyl-1-(2-methyl-1-phenylpropan-2-yl)-1H-pyrazol-5-yl benzoate (360 mg, 0.82 mmol) in 1,2-dimethoxyethane (4.8 ml) was mixed with 4-(methoxycarbonyl)phenylboronic acid (164 mg, 0.911 mmol), tetrakis(triphenylphosphine)palladium (80 mg, 0.07 mmol) and 2 M aqueous sodium carbonate (3.6 ml) and stirred at 86° C. for 16 hours under a nitrogen atmosphere. After completion of the reaction, the 1,2-dimethoxyethane was distilled off under reduced pressure, and the reaction solution was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was purified by intermediate pressure silica gel column chromatography (silica gel 12 g, ethyl acetate:hexane=1:20 to 1:4) to give 100 mg of the desired product as a pale yellow solid mixture of tautomers.