Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([S:36](Cl)(=[O:38])=[O:37])[CH:35]=1>N.CO>[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([S:36]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:38])=[O:37])[CH:35]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1S(=O)(=O)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 5-Fluoro-2-methylbenzenesulfonyl chloride (21 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (2.7 mg). MS m/z 361 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([CH3:18])[C:10](=[O:19])[NH:9]2)=[CH:4][CH:3]=1.[Cl:20][CH2:21][C:22](Cl)=[O:23].C(N(CC)CC)C>C(O)(=O)C>[Cl:20][CH2:21][C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([CH3:18])[C:10](=[O:19])[NH:9]2)=[CH:6][CH:7]=1)=[O:23]
Reactant: O=C(Cl)CCl
Reactant: CC1C(=O)NC(c2ccc(N)cc2)c2ccccc21
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC1C(=O)NC(c2ccc(NC(=O)CCl)cc2)c2ccccc21

Procedure:
9.75 g. (0.0386 moles) of 1-(4'-aminophenyl)-1,4-dihydro-4-methyl-3(2H)-isoquinolinone are reacted, in 80 ml. of glacial acetic acid, with 5.64 g. (0.05 moles) of chloroacetyl chloride, in the presence of 5.06 g. (0.05 moles) of triethylamine. The reaction conditions are the same as described in Example 1. The crude product is recrystallized from butanol to yield 4.9 g. of the title compound; m.p. 238°-239°C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[O:10][C:9](S)=[CH:8][C:7](=[O:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:11]2[O:10][C:9]([N:31]3[CH2:32][CH2:33][N:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[CH2:29][CH2:30]3)=[CH:8][C:7](=[O:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1c(OCc2ccccc2)ccc2c(=O)cc(S)oc12
Reactant: c1ccc(N2CCNCC2)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1c(OCc2ccccc2)ccc2c(=O)cc(N3CCN(c4ccccn4)CC3)oc12
Yield: 84.5 %

Procedure:
Part B: 8-Methyl-7-(phenylmethoxy)-2-mercapto-4H-1-benzopyran-4-one (2.0 g, 6.7 mmol), 1-(2-pyridyl)piperazine (1.19 g, 7.3 mmol) and TsOH (25 mg) is added to toluene and heated at reflux for 20 hours. The reaction temperature is lowered to room temperature and the toluene removed in vacuo. The resulting dark oil is diluted with EtOAc and the resulting crystals collected on a filter to afford 2.42 g of product. MP 148°-9° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][CH3:23]>CC(C)=O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCBr
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1ccc2c(c1)CCCC2=O

Procedure:
A solution of 2.50 g of 6-hydroxy-1-tetralone in 20 ml of acetone, 2.54 g of potassium carbonate and 2 ml of 1-bromobutane were heated under reflux for four days. After evaporation the residue was diluted carefully in 20 ml of 1N hydrochloric acid and extracted three times with ethyl acetate. Then the extracts were washed with aqueous saturated solutions of sodium hydrogen carbonate and sodium chloride and dried over sodium sulfate. After evaporation the resulting residue was purified by chromatography with diethyl ether/petroleum ether (1:2) to yield 3.08 g (91.5% of the theoretical yield) of 6-n-butoxy-1-tetralone in the form of a nearly colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH:27][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][CH:13]=3)[CH:5]=[CH:4][N:3]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(CCN)cc1
Reactant: CC(=O)c1cccc(-c2ccnc(Cl)n2)c1
Product: COc1ccc(CCNc2nccc(-c3cccc(C(C)=O)c3)n2)cc1

Procedure:
Intermediate 38 was coupled with 2-(4-Methoxy-phenyl)-ethylamine following procedure F. LC-MS showed the product had the expected M+H+ of 348.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[C:22](O)=[O:23]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cc(Cl)cc(Cl)c4)cc23)CC1
Yield: 85.3 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 17.2 mg (0.09 mMol) 3,5-dichlorobenzoic acid, 10.3 mg of the title compound were recovered.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([O:15]C)=[O:14])[CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc2cc(C(C)=O)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)c1cc2ccc(C(=O)O)cc2o1
Reaction time: 8 h
Yield: 93124.7 %

Procedure:
Methyl 2-acetyl-1-benzofuran-6-carboxylate (155 mg, 0.71 mmol) is dissolved in MeOH (3 ml) and H2O (0.5 ml). 2N NaOH (0.39 ml, 0.78 mmol) is added drop-wise, and the reaction is stirred overnight. The volatiles are removed in vacuo, and the residue is dissolved in H2O (3 ml). Concentrated HCl is used to adjust the pH to 3, and the resulting precipitate is isolated via filtration and dried overnight to afford 135 g (93%) of 2-acetyl-1-benzofuran-6-carboxylic acid as a yellow solid. MS for C11H8O4, (ESI−) m/z: 202.7 (M−H)−.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C:10]1([CH3:23])[CH3:22]>N1C=CC=CC=1>[C:5]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C:10]1([CH3:23])[CH3:22])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CN(Cc2ccccc2)CCC1N
Solvent: c1ccncc1
Product: CC(=O)NC1CCN(Cc2ccccc2)CC1(C)C
Reaction time: 1 h

Procedure:
Acetic anhydride (3 ml) was added to a stirred solution of 4-amino-1-benzyl-3,3-dimethylpiperidine (2.0 g, 9.17 mmol) in pyridine (5 ml) and stirred for 1 hr. The reaction mixture was concentrated to furnish 4-acetylamino-1-benzyl-3,3-dimethyl piperidine as an oil. Yield 1.8 g (76%), C16H24N2O, m/z 261 (M+1), PMR (CDCl3): 0.84 (s, 3H), 0.98 (s, 3H), 1.64 (m, 2H), 2.02 (s, 3H), 2.12 (m, 2H), 2.44 (d, 1H), 2.84 (d, 1H), 3.44 (d, 2H), 3.7 (m, 1H), 5.3 (bs, 1H), 7.31 (m, 5H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].N12CCCN=C1CCCCC2.[NH:31]1[CH2:35][CH2:34][CH:33]([CH2:36][NH:37][CH2:38][CH2:39][OH:40])[CH2:32]1>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:31]3[CH2:35][CH2:34][CH:33]([CH2:36][NH:37][CH2:38][CH2:39][OH:40])[CH2:32]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: OCCNCC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(CNCCO)C3)c(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A mixture of 0.50 g (1.84 mmole) of 1-ethyl-6,7,8-trifluoro-4-oxo-quinoline-3-carboxylic acid, 5 ml acetonitrile, 0.28 g (1.84 mmole) 1,8-diazabicyclo[5.4.0]undec-7-ene and 0.28 g (1.94 mmole) of 2-[(3-pyrrolidinylmethyl)amino]ethanol was refluxed one hour and then stirred at room temperature overnight. The reaction was filtered and the precipitate washed with ether until dry to give 0.58 g of 1-ethyl-6,8-difluoro-1,4-dihydro-7-[3-[[(2-hydroxyethyl)amino]methyl]-1-pyrrolidinyl]-4-oxo-3-quinoline carboxylic acid, mp 215°-216° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:21]#[C:22][Si](C)(C)C)[CH:9]=[C:10]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[N:6]2[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-]>CO>[NH2:1][C:2]1[C:7]2=[C:8]([C:21]#[CH:22])[CH:9]=[C:10]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1c1cc(C#C[Si](C)(C)C)c2c(N)ncnn12
Agent: O=C([O-])[O-]
Solvent: CO
Product: C#Cc1cc([C@@H]2O[C@H](CO)[C@@H](O)[C@@]2(C)O)n2ncnc(N)c12
Yield: 27.9 %

Procedure:
a solution of Compound 16 (2.0 mg, 5.3 μmol) in methanol (0.20 mL) was stirred with MP-carbonate (2.9 mmol/g, 18 mg, 53 μpmol) for 30 min. The solution was decanted from the resin and concentrated in vacuo, affording rendering Compound 17 (0.45 mg, 28%) as a white solid: ESI-MS m/z 305.2 ([M+H]+); 1H NMR (d6-DMSO) δ 7.92 (s, 1H), 6.97 (s, 1H), 5.35 (s, 1H), 4.91-4.73 (m, 3H), 4.38 (s, 1H), 3.76-3.57 (m, 4H), 0.80 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:18]=[C:19]([C:21]3[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=3)[S:20][C:13]=12.[NH4+].[Cl-]>CO.O.[Fe]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:18]=[C:19]([C:21]3[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=3)[S:20][C:13]=12
Reactant: Cn1cnc(-c2cc3nccc(Nc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Cn1cnc(-c2cc3nccc(Nc4ccc(N)cc4F)c3s2)c1
Temperature: 25 °C
Yield: 136.4 %

Procedure:
To a stirred suspension of nitro compound 417 (370 mg, 1.00 mmol) in a mixture of MeOH (20 mL) and water (10 mL) were added iron powder (280 mg, 5.01 mmol) and NH4Cl (107 mg, 2.00 mmol). The reaction mixture was heated to reflux for 2 hrs, cooled to room temperature and filtered through celite. The filtrate was concentrated, diluted with minimal amount of methanol and treated with AcOEt/hexanes, to afford title compound 418 (463 mg, quantitative yield, ammonium salt) as a yellow solid. LCMS: 340.0 (M+H)+.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N(S(F)(F)[F:24])C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]([F:24])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FS(F)(F)N(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccccc1
Solvent: ClCCl
Product: O=C(F)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A solution of benzoic acid (122 mg, 1 mmol) in CH2Cl2 (5.0 mL) was added to diphenylaminosulfur trifluoride (771 mg, 3.0 mmol ) under N2 and stirred for 16 h at room temperature. After work-up as above benzoyl fluoride (124 mg, quantitative yield) was obtained. The product was identified by g.c.m.s. M+ =124
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:21]([O:24][CH2:25][CH2:26][CH2:27]Br)(=[O:23])[CH3:22]>>[CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:27][CH2:26][CH2:25][O:24][C:21](=[O:23])[CH3:22])[C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)OCCCBr
Reactant: CCCCCCOc1c(O)c2c(O)cccc2oc1=O
Product: CCCCCCOc1c(O)c2c(OCCCOC(C)=O)cccc2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-hexyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 3-bromopropyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-hexyloxy-4-hydroxy-5-(3-acetoxypropoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[C:17]3[C:12](=[C:13]([F:18])[CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:19])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[N:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28][CH:27]=1>>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[C:11]([NH2:19])=[N:10][C:9]2([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:30]2[CH:31]=[N:26][CH:27]=[N:28][CH:29]=2)[CH:3]=1)[C:20]1[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=1
Reactant: NC1=NC(c2ccncc2)(c2ccc(F)c(Br)c2)c2cccc(F)c21
Reactant: OB(O)c1cncnc1
Product: NC1=NC(c2ccncc2)(c2ccc(F)c(-c3cncnc3)c2)c2cccc(F)c21
Yield: 29 %

Procedure:
The title compound was synthesized as described for Example 12 in 29% yield, starting from 1-(3-bromo-4-fluorophenyl)-4-fluoro-1-(pyridin-4-yl)-1H-isoindol-3-amine (44 mg, 0.11 mmol) and 5-pyrimidinylboronic acid (18.66 mg, 0.15 mmol).
Reaction SMILES: [NH2:1][C:2]([CH:4]1[N:9]([CH2:10][CH2:11][CH2:12][CH:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:8][CH2:7][N:6]([CH2:28][C:29]([NH:31][C:32]2[C:37]([CH3:38])=[CH:36][C:35]([NH2:39])=[CH:34][C:33]=2[CH3:40])=[O:30])[CH2:5]1)=[O:3].C(O)(=O)C.[N-:45]=[C:46]=[O:47].[K+]>O>[NH2:1][C:2]([CH:4]1[N:9]([CH2:10][CH2:11][CH2:12][CH:13]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH2:8][CH2:7][N:6]([CH2:28][C:29]([NH:31][C:32]2[C:33]([CH3:40])=[CH:34][C:35]([NH:39][C:46]([NH2:45])=[O:47])=[CH:36][C:37]=2[CH3:38])=[O:30])[CH2:5]1)=[O:3]
Reactant: Cc1cc(N)cc(C)c1NC(=O)CN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)C(C(N)=O)C1
Reactant: [N-]=C=O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(NC(N)=O)cc(C)c1NC(=O)CN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)C(C(N)=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5.5 parts of 3-(aminocarbonyl)-N-(4-amino-2,6-dimethylphenyl)-4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazineacetamide in 70 parts of acetic acid was added dropwise a solution of 1.62 parts of potassium isocyanate in 20 parts of water. Upon completion, stirring at room temperature was continued for 30 minutes. Upon standing overnight at room temperature, the reaction mixture was evaporated. Water was added to the residue and the product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 2.55 parts of 3-(aminocarbonyl)-N-[4-[(aminocarbonyl)amino]-2,6-dimethylphenyl]-4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazineacetamide; mp. 142.5° C. (compound 168).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:12])[C@@H:9]([OH:11])[CH3:10].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(Cl)Cl>[OH:11][C@@H:9]([CH3:10])[CH2:8][O:12][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: C[C@H](O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H](C)O)cc1
Temperature: -20 °C
Reaction time: 18 h

Procedure:
Triethylamine was added to methylene chloride solution of (2S)-propane-1,2-diol, and then methylene chloride solution of p-toluenesulfonyl chloride was added thereto at −20° C. and stirred at room temperature for 18 hours to obtain (2S)-2-hydroxypropyl-4-methylbenzene sulfonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:16]([C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=Cc1cccc(F)c1
Solvent: CCO
Solvent: O
Product: O=C1CC(c2cccc(F)c2)Oc2ccc(Br)cc21
Yield: 36.9 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (15 g, 0.07 mol), 3-fluorobenzaldehyde (8.7 g, 0.07 mol) and borax (26.7 g, 0.07 mol) in ethanol (90 mL) and H2O (150 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O, and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-(3-fluorophenyl)chroman-4-one (8.3 g, 37%). 1H-NMR (CDCl3): 2.93 (d, 1H), 3.03 (m, 1H), 5.47 (d, 1H), 7.06 (d, 1H), 7.11 (m, 1H), 7.22 (m, 2H), 7.40 (m, 1H), 7.57 (d, 1H), 8.04 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([CH2:26][CH2:27][C:28]([OH:30])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:39]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[N:11]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][C:16]([CH2:26][CH2:27][C:28]([NH2:39])=[O:30])=[CH:15][CH:14]=2)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CCC(=O)O)ccc2c1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CCC(N)=O)ccc2c1=O
Yield: 92.7 %

Procedure:
A solution of 3-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)propanoic acid (0.33 g, 0.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.27 g, 1.4 mmol) and 1-hydroxybenzotriazole ammonium salt (0.21 g, 1.4 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The resulting reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-(3-amino-3-oxopropyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.31 g, 93.9%) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.[C:12](Cl)(=O)C>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)c1ccc(Br)cc1Cl
Solvent: CO
Product: COC(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-Bromo-2-chlorobenzoic acid (1.00 g, 4.25 mmol) was added to a solution of acetyl chloride (1.70 mL, 23.9 mmol) in methanol (30 mL). The mixture was allowed to stir at rt for 3 days, and was then concentrated in vacuo. This gave 0.84 g (80%) of the title compound. 1H NMR (400 MHz, CD2Cl2) δ 3.85 (s, 3H), 7.51 (d, 1H), 7.45 (d, 1H), 7.78 (d, 1H).
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH:15]1([CH2:18][NH:19][C:20](=[O:37])[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:22]=2)[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][NH:19][C:20]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[C:25]([C:2]3[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]4[CH2:12][CH2:11]4)=[O:7])=[CH:4][N:3]=3)[CH:26]=2)=[O:37])[CH2:17][CH2:16]1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1ccc(C(=O)NCC2CC2)cn1

Procedure:
6-[5-(Cyclopropylmethyl)carbamoyl-2-methyl-phenyl]-N-cyclopropylmethyl-nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) and N-(cyclopropylmethyl)-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B. LCMS: retention time 2.87 min, MH+364. NMR: δH [2H6]-DMSO 9.10, (1H, s), 8.83, (1H, t), 8.60, (1H, t), 8.30, (1H, dd), 7.92, (1H, s), 7.84, (1H, d), 7.71, (1H, d), 7.41, (1H, d), 3.19, (2H, t), 3.13, (2H, t), 2.37, (3H, s), 1.03, (2H, m), 0.44, (4H, m), 0.23, (4H, m).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[SH-:16].[Na+].Cl>O>[CH2:14]([O:13][C:11]([C:3]1[CH:4]=[N:5][C:6]2[N:7]([N:8]=[CH:9][N:10]=2)[C:2]=1[SH:16])=[O:12])[CH3:15]
Reactant: [SH-]
Reactant: CCOC(=O)c1cnc2ncnn2c1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cnc2ncnn2c1S
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.2 %

Procedure:
The product obtained in Step 1 (3.6 g) and sodium hydrosulfide (2.5 g) were dissolved in 50 ml of water, the solution was stirred at room temperature for 20 minutes, its pH was lowered to 1.0 with 6N hydrochloric acid, and the crystals thus formed were collected by filtration, affording 3.0 g of the objective compound as yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[CH2:22][S:23][CH2:24][C:25]([F:28])([F:27])[F:26].Cl.[CH3:30]CO>>[CH3:30][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[CH2:22][S:23][CH2:24][C:25]([F:28])([F:26])[F:27])[CH:4]=1
Reactant: CCO
Reactant: O=C(O)Cc1ccc(O)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Agent: Cl
Product: COC(=O)Cc1ccc(O)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
{4-Hydroxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid (3.6 mmol) and hydrogen chloride (4N in 1,4-dioxane) were combined in EtOH and stirred at 80° C. for 3 hours. After concentrating to dryness, the residue was purified by silica gel chromatography to give {4-hydroxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][C:8]=1[C@H:17]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19][C@H:18]1[C:29]([O:31]C)=[O:30])=[O:6])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:25]([O:24][C:22]([N:20]1[CH2:21][C@H:17]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([F:15])([F:16])[F:14])[C:7]=2[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[O:6])[C@H:18]([C:29]([OH:31])=[O:30])[CH2:19]1)=[O:23])([CH3:26])([CH3:28])[CH3:27]
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1c1cccc(C(F)(F)F)c1C(=O)OC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1c([C@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(=O)O)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a solution of (±)-cis-1-tert-butyl 3-methyl 4-(2-(isopropoxycarbonyl)-3-(trifluoromethyl)phenyl)pyrrolidine-1,3-dicarboxylate (0.90 g, 1.96 mmol) in 20 mL of 2:1 THF/H2O was added lithium hydroxide (52 mg, 2.15 mmol). The reaction mixture was allowed to stir at ambient temperature for 2 h. The reaction was partitioned between 1:1 hexane/EtOAc and dilute aq Na2CO3. The organic layer was discarded. The aqueous layer was acidified with 12 N HCl and extracted with EtOAc. The EtOAc layer was washed with brine, dried (MgSO4) and concentrated to afford 0.75 g (86%) of the title compound as a white foam, which was pure enough to be used without purification. LRMS (ES)+: 446 (M+H)+.