Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=O)[C:9](=[O:22])[N:10]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][C:4]=1[C:24]([O:26][CH3:27])=[O:25].O=P(Cl)(Cl)[Cl:30].CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:30][C:8]1[C:9](=[O:22])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6]([N:7]=1)=[CH:5][C:4]([C:24]([O:26][CH3:27])=[O:25])=[C:3]([O:2][CH3:1])[CH:12]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc2[nH]c(=O)c(=O)n(Cc3ccc(OC)cc3)c2cc1OC
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2nc(Cl)c(=O)n(Cc3ccc(OC)cc3)c2cc1OC
Temperature: 110 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of methyl 7-methoxy-1-[(4-methoxyphenyl)methyl]-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (24 g, 64.80 mmol) in toluene (300 mL) was added POCl3 (14.8 g, 96.52 mmol) and N,N-dimethylaniline (15.7 g, 129.75 mmol). The resulting solution was stirred overnight at 110° C. and concentrated in vacuo. The product was precipitated by the addition of methanol (150 mL) and collected by filtration to afford methyl 3-chloro-7-methoxy-1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a green solid (17 g, 65%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[CH3:27])[CH:20]=[CH:19][CH:18]=1>>[CH2:13]([O:12][C:10]([C:2]1[N:1]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[CH3:27])[CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:11])[CH3:14]
Reactant: Cc1cccc2cccc(CBr)c12
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: CCOC(=O)c1cc2ccccc2n1Cc1cccc2cccc(C)c12

Procedure:
Using general procedure A (Exp. 1.3.), 1,8-dimethyl-naphthalene was reacted with N-bromosuccinimide to give 1-bromomethyl-8-methyl-naphthalene as white solid. MS: 234.1 ([M]+). Using general procedure B, ethyl 2-indole carboxylate was coupled with 1-bromomethyl-8-methyl-naphthalene to give 1-(8-methyl-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 314.4 ([M−H]−).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH:20]1[CH2:23][N:22]([C:24]([N:26]2[CH2:32][CH2:31][CH2:30][N:29]([CH:33]3[CH2:36][CH2:35][CH2:34]3)[CH2:28][CH2:27]2)=[O:25])[CH2:21]1)(=O)=O>CN(C=O)C.ClCCl>[CH:33]1([N:29]2[CH2:30][CH2:31][CH2:32][N:26]([C:24]([N:22]3[CH2:23][CH:20]([O:1][C:2]4[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=4)[CH2:21]3)=[O:25])[CH2:27][CH2:28]2)[CH2:34][CH2:35][CH2:36]1
Reactant: CS(=O)(=O)OC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(OC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)cn1
Temperature: 90 °C
Reaction time: 72 h
Yield: 35 %

Procedure:
3-Hydroxy-6-methylpyridine (24 mg, 0.22 mmol) and K2CO3 (33 mg, 0.24 mmol) were stirred in DMF (1 ml) for 30 minutes and 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-yl methanesulfonate (66 mg, 0.20) was added. The reaction was stirred at 90° C. for 3 days and then diluted with dichloromethane (30 ml) and washed with saturated NaHCO3 (3×15 ml), dried (MgSO4), filtered and concentrated at reduced pressure. The residue was purified by FCC (DCM/MeOH/NH3 with gradient, 98:2:1 to 90:10:1) to give the title product as off-white solid (24 mg, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:28][CH2:27][CH2:26][CH:25]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[OH-].[Na+].Cl>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:28][CH2:27][CH2:26][CH:25]2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCCC3c3ccccc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCCC3c3ccccc3)CC2)cc1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 60.6 %

Procedure:
To an ice cooled solution of methyl 4-(1-(5-chloro-2-(2-phenylpyrrolidin-1-yl)nicotinamido)cyclopropyl)benzoate (D142) (189 mg, 0.40 mmol). in a mixture methanol/tetrahydrofuran (10 ml/10 ml), 2N NaOH (10 ml) was added. The reaction mixture was heated to 40° C. for 2 hours then cooled to 0° C., acidified with 2.5N HCl (pH=1-2) and stirred at 0° C. for 10 min. The formed solid was collected by filtration and dried to provide title compound (E1) (112 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:16]([CH2:27][CH2:28][CH:29]=O)[C:15]=2[CH:31]=1)=[O:4].[C:32]1([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:16]([CH2:27][CH2:28][CH2:29][N:41]3[CH2:42][CH2:43][N:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:39][CH2:40]3)[C:15]=2[CH:31]=1)=[O:4]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COC(=O)CCCCCOc1ccc2nc(-c3ccc(OC)cc3)n(CCC=O)c2c1
Product: COC(=O)CCCCCOc1ccc2nc(-c3ccc(OC)cc3)n(CCCN3CCN(c4ccccc4)CC3)c2c1

Procedure:
6-[(5-(Methoxycarbonyl)pentyl)oxy]-2-(4-methoxy-phenyl)-1-(3-oxo-propyl)-benzimidazole is reacted with N-phenyl-piperazine according to general operating instructions 8. 6-[(5-(Methoxycarbonyl)pentyl)oxy]-2-(4-methoxy-phenyl)-1-[3-(4-phenyl-piperazin-1-yl)-propyl]-benzimidazole is obtained as a yellow oil.
Reaction SMILES: C1(O)C=CC=CC=1.[OH:8][C@@H:9]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1)[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].CC1C=CC(S(O[CH2:38][CH:39]2[CH2:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[O:41][CH2:40]2)(=O)=O)=CC=1>>[O:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:48][CH:39]([CH2:38][O:26][C:22]2[CH:21]=[C:20]([C@H:9]([OH:8])[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:25]=[CH:24][CH:23]=2)[CH2:40]1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccccc3C2)cc1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2COc3ccccc3C2)c1

Procedure:
Alkylation of phenol (7, Intermediate I) with chroman-3-ylmethyl 4-methylbenzenesulfonate following the method used in Example 12 gave tert-butyl ((3R)-3-(3-(chroman-3-ylmethoxy)phenyl)-3-hydroxypropyl)carbamate as a colorless oil. Yield (71%); 1H NMR (400 MHz, DMSO-d6) δ 7.21 (t, J=7.6 Hz, 1H), 7.10-7.05 (m, 2H), 6.91 (s, 1H), 6.88 (d, J=7.6 Hz, 1H), 6.85-6.83 (m, 1H), 6.81-6.79 (m, 1H), 6.75 (d, J=8.4 Hz, 1H), 5.19 (d, J=4.8 Hz, 1H), 4.53-4.48 (m, 1H), 4.31-4.28 (m, 1H), 3.99-3.91 (m, 2H), 2.98-2.93 (m, 2H), 2.92-2.90 (m, 1H), 2.71-2.69 (m, 2H), 1.66 (q, J=6.8 Hz, 2H), 1.36 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([NH:11][C:12](=[NH:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[C:4]([CH:22]([CH3:24])[CH3:23])[CH:3]=1.Cl[CH2:26][CH:27]=O.C(=O)(O)[O-].[Na+].CC(O)C>O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([N:11]2[CH:27]=[CH:26][N:21]=[C:12]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[C:4]([CH:22]([CH3:24])[CH3:23])[CH:3]=1
Reactant: COc1cccc(C(=N)Nc2c(C(C)C)cc(Br)cc2C(C)C)c1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COc1cccc(-c2nccn2-c2c(C(C)C)cc(Br)cc2C(C)C)c1
Yield: 78.6 %

Procedure:
A 500 ml round bottom flask was charged with N-(4-bromo-2,6-diisopropylphenyl)-3-methoxybenzimidamide (19.73 g, 50.7 mmol), 2-chloroacetaldehyde (12.83 ml, 101 mmol), sodium bicarbonate (12.77 g, 152 mmole) and 2-Propanol (300 ml). The reaction was allowed to reflux for 16 hours. The reaction mixture was diluted with deionized water and extracted with ethyl acetate, the organic portion was combined and subjected to a column chromatography (SiO2 gel; 20% THF in heptane) to yield the desired product (16.47 g, 79%).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6](OS(C(F)(F)F)(=O)=O)[C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[CH:4]=1)#[N:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C=O>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[CH:4]=1)#[N:2]
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc2ccc(C#N)cc2c1OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2ccc(C#N)cc2c1-c1ccccc1
Temperature: 100 °C
Yield: 101.1 %

Procedure:
Under nitrogen atmosphere, 1.2 g of 2-cyano-7-methoxy-8-trifluoromethanesulfonyloxynaphthalene, 0.66 g of phenylboronic acid, 0.12 g of tetrakis triphenylphosphine palladium and 1.5 ml of triethyl- amine were suspended in 20 ml of anhydrous N, N-dimethylformamide. The resulting suspension was stirred under heating at 100° C. for 1.5 hours and cooled to room temperature by allowing to stand. A saturated aqueous solution of ammonium chloride was added to the resulting reaction mixture, followed by the extraction with ethyl acetate (50 ml×2). The organic layers were combined, washed with brine, died over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography to give 0.95 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[Cl:42][C:43]1[CH:55]=[CH:54][C:46](CN2C=CC(N)=N2)=[CH:45][CH:44]=1>C(Cl)Cl>[Cl:42][C:43]1[CH:55]=[CH:54][C:46]([CH2:21][N:18]2[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=3)[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:17]2)=[CH:45][CH:44]=1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: Nc1ccn(Cc2ccc(Cl)cc2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(Cl)cc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (181 μL, 0.36 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (70 μL, 0.61 mmol) was added to the solution at 0° C. After 1 h, crude 1-(4-chloro-benzyl)-1H-pyrazol-3-ylamine (0.42 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford N-[1-(4-chloro-benzyl)-1H-pyrazol-3-yl]-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (117 mg, 74%) as a white solid: ESI-LRMS m/e calcd for C25H27C12N3O3S [M+] 519.1, found 520.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.20 (m, 2H, CH2), 1.40-1.93 (m, 8H, 4×CH2), 2.09-2.31 (m, 1H, CH), 3.24 (s, 3H, SO2CH3), 3.51-3.60 (m, 1H, CH), 5.09 (s, 2H, NCH2), 6.69 (d, J=2.3 Hz, 1H, Ar), 7.06 (d, Jo=8.3 Hz, 2H, Ar), 7.26-7.33 (m, 3H, Ar), 7.43 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.57 (d, Jm=1.7 Hz, 1H, Ar), 7.88-8.36 (m, 2H, Ar and NH).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][CH:11]2[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:8][CH:7]=1)(O)=O.[CH3:20][NH:21][C:22](=[O:30])[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[NH2:25].C1(C)C(C)=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:20][N:21]1[C:22](=[O:30])[C:23]2[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:25]=[C:1]1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH:11]2[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:18][CH:19]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: Cc1ccccc1C
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccccc2c1=O
Temperature: 175 °C

Procedure:
A suspension of 5-[4-[(carboxy)methoxy]benzyl]thiazolidine-2,4-dione obtained by following a procedure described in any of Examples 25-28 (100 g., 0.36 M), N-methyl anthranilamide (58.7 g, 0.39 M), xylene (100 ml) and p-toluenesulfonic acid (200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-Stark condenser. The reaction mixture was heated to reflux (Internal temperature 150-155° C., oil bath temperature 170-180° C.) for a period of 12-15 h while monitoring the reaction by TLC. After completion of the reaction, reaction mass was cooled to 80° C. and methanol (700 ml) was added slowly through a dropping funnel. The reaction mass was allowed to attain room temperature while stirring and the solid thus obtained was filtered and washed with methanol (150 ml) and dried at 100-120° C. for 1 h to afford 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione as a white solid (95 g, Y=68%, P=98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH:16]([CH2:20][OH:21])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:29]([C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1)([O-:31])=[O:30]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH:16]([CH2:20][O:21][S:38]([C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([N+:29]([O-:31])=[O:30])[CH:33]=4)(=[O:39])=[O:40])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: OCC1CN(C2CCN(c3ccc(Cl)cc3)CC2)CCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CN(C3CCN(c4ccc(Cl)cc4)CC3)CCO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a solution of {4-[1-(4-chlorophenyl)-4-piperidinyl]-2-morpholinyl}methanol obtained from step (vi) (125 mg, 0.384 mmol) in dichloromethane (CH2Cl2) (2 mL) was added triethylamine (0.240 mL, 1.72 mmol) followed by 3-nitrobenzenesulfonyl chloride (127.5 mg, 0.575 mmol) and the reaction mixture kept on stirring at room temperature overnight. The volatiles were removed in vacuo, residue dissolved in chloroform, washed sucessively with saturated aqueous sodium hydrogen carbonate (NaHCO3) and water (H2O). The organic layer was dried over sodium sulphate (Na2SO4), filtered, concentrated and the residue was purified by silica gel flash chromatography to give the subtitled compound (163 mg).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[NH2:19][C:20]1[C:25]([NH2:26])=[C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])=[C:30]([F:41])[CH:29]=2)[CH:23]=[CH:22][N:21]=1>C1COCC1>[O:4]=[C:2]1[NH:19][C:20]2=[N:21][CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:40])[C:36]([F:37])([F:38])[F:39])=[C:30]([F:41])[CH:29]=3)=[C:25]2[NH:26]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1nccc(Oc2ccc(NC(=O)C(F)(F)F)c(F)c2)c1N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)cc1F)C(F)(F)F
Temperature: 0 °C
Reaction time: 48 h
Yield: 49 %

Procedure:
Method E3 (with triphosgene and Pyridine). N-(4-(2,3-Diaminopyridin-4-yl-oxy)-2-fluorophenyl)-2,2,2-trifluoroacetamide (500 mg, 1.5 mmol) was dissolved in dry THF (20 mL), pyridine (1 mL) was added and the solution was cooled at 0° C. Triphosgene (445 mg, 1.5 mmol) in dry THF (10 mL) was added dropwise. The reaction mixture was stirred at room temperature for 48 hours. The solvent was evaporated and the residue washed with water. The precipitate was recovered by filtration to afford the title compound (260 mg, 49%). 1H-NMR (δ, ppm, DMSO-d6): 6.57 (d, 1H, HPy,5), 6.98 (d, 1H, Harom,Ph), 7.36 (d, 1H, Harom,Ph), 7.50 (d, 1H, Harom,Ph), 7.75 (d, 1H, HPy,6), 11.26 (s, 1H, NHPy3), 11.30 (s, 1H, NHCOCF3), 11.48 (s, 1H, NHPy2). LC-MS (m/z): 356 (M, 100).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]1.C([Li])CCC.[CH2:13]([O:17][C:18]1[C:22](S(C)(=O)=O)=[N:21][S:20][N:19]=1)[CH2:14][CH2:15][CH3:16]>C1COCC1.CCCCCC>[CH2:13]([O:17][C:18]1[C:22]([O:7][CH:4]2[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]2)=[N:21][S:20][N:19]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CN1CCC(O)C1
Reactant: CCCCOc1nsnc1S(C)(=O)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCOc1nsnc1OC1CCN(C)C1

Procedure:
A solution of 1-methyl-3-pyrrolidinol (0.6 g, 0.0059 mol) in THF (20 mL) was treated with 1.6 M n-butyllithium in hexane (3.1 mL), 0.005 mol). To the solution was added 3-butyloxy-4-methanesulfonyl-1,2,5-thiadiazole (1.0 g, 0.0042 mol) and the reaction heated to reflux overnight. The solvent was evaporated, the residue acidified with cold 1N HCl, and the mixture extracted with ether. The aqueous fraction was made basic, extracted with EtOAc, and the extracts washed with water. The extracts were dried and the solvent evaporated to give a liquid. The HCl salt (0.7 g) crystallized from EtOAc, m.p. 157°-158° C. (Compound 28).
Reaction SMILES: [NH2:1][C:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:6][C:5]([O:12][CH3:13])([C:8]([F:11])([F:10])[F:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([CH2:39][C:40](Cl)=[O:41])[CH:33]=2)=[CH:28][C:27]=1[F:43]>ClCCl>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([CH2:39][C:40]([NH:1][C:2]3([C:14]([O:16][CH3:17])=[O:15])[CH2:3][CH2:4][C:5]([O:12][CH3:13])([C:8]([F:11])([F:10])[F:9])[CH2:6][CH2:7]3)=[O:41])[CH:33]=2)=[CH:28][C:27]=1[F:43]
Reactant: COC(=O)C1(N)CCC(OC)(C(F)(F)F)CC1
Reactant: Cc1ccc(-c2ccc(Cl)c(F)c2)cc1CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(=O)Cc2cc(-c3ccc(Cl)c(F)c3)ccc2C)CCC(OC)(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20.50 g (80.32 mmol) of methyl 1-amino-4-methoxy-4-(trifluoromethyl)cyclohexanecarboxylate (Example 22A) and 8.13 g (80.32 mmol) of triethylamine were dissolved in 280 ml of dichloromethane. 21.70 g (73.02 mmol) of (4′-chloro-3′-fluoro-4-methylbiphenyl-3-yl)acetyl chloride (Example 4AA), dissolved in 280 ml of dichloromethane, were added dropwise to this solution, and the reaction mixture was stirred at room temperature overnight. For work-up, the mixture was diluted with dichloromethane and the organic phase was washed with aqueous saturated sodium bicarbonate solution and with aqueous 1% strength citric acid. After drying over sodium sulphate, the organic phase was concentrated and the product was dried. This gave 37.05 g (98% of theory) of the title compound as a beige powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:12])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[NH:13]1[CH2:17][CH2:16][N:15]=[C:14]1S(O)(=O)=O>C(O)C(C)C>[Br:12][C:3]1[C:2]([NH:1][C:14]2[NH:15][CH2:16][CH2:17][N:13]=2)=[CH:11][CH:10]=[C:9]2[C:4]=1[N:5]=[CH:6][CH:7]=[N:8]2
Reactant: Nc1ccc2nccnc2c1Br
Reactant: O=S(=O)(O)C1=NCCN1
Solvent: CC(C)CO
Product: Brc1c(NC2=NCCN2)ccc2nccnc12
Temperature: 25 °C
Yield: 61 %

Procedure:
A mixture of 6-amino-5-bromo quinoxaline (prepared using the method reported by Danielewicz U.S. Pat. No. 3,890,319) (0.224 g, 2 mmol), imidazoline-2-sulfonic acid (0.30 g, 2 mmol) and isobutanol (3 ml) was heated to 125° C. and maintained at this temperature for 16 hours. The mixture was then cooled to room temperature and concentrated in vacuo to give a brown residue which was chromatographed (silica gel, 9:1 CHCl3 /CH3OH saturated with NH3 (g)) to yield 0.177 g (a yield of 61%) of the title compound as a yellow solid, which was characterized spectroscopically.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]([CH:16]1[C:21]2[CH:22]=[CH:23][S:24][C:20]=2[CH2:19][CH2:18][NH:17]1)[CH3:15]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:17]3[CH2:18][CH2:19][C:20]4[S:24][CH:23]=[CH:22][C:21]=4[CH:16]3[CH2:14][CH3:15])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CCC1NCCc2sccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CCC1c2ccsc2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Yield: 60 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4-ethyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH:26]=O)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[CH:36]1([NH2:39])[CH2:38][CH2:37]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH2:26][NH:39][CH:36]2[CH2:38][CH2:37]2)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:3])=[O:4]
Reactant: NC1CC1
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cc(-c2cc3cc(CNC4CC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 72.2 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (50 mg, 0.100 mmol) was dissolved in acetonitrile (2.9 mL), and the solution was treated with cyclopropylamine (0.069 mL, 1.0 mmol), acetic acid (0.115 mL, 2.00 mmol) and sodium triacetoxyborohydride (64 mg, 0.30 mmol) to obtain 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(cyclopropylaminomethyl)indol-2-yl]isoindolinone (39.1 mg, yield 72%).
Reaction SMILES: C(OC1CCN([C:11]2[CH:16]=[CH:15][C:14]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)=[CH:13][CH:12]=2)CC1)(=O)C.BrC1C=CC([C:33]2([F:40])[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=CC=1>CCOC(C)=O.O>[F:40][C:33]1([C:11]2[CH:12]=[CH:13][C:14]([B:17]3[O:18][C:19]([CH3:24])([CH3:25])[C:20]([CH3:22])([CH3:23])[O:21]3)=[CH:15][CH:16]=2)[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1
Reactant: CC(=O)OC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CN1CCC(F)(c2ccc(Br)cc2)CC1
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCC(F)(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C

Procedure:
The title compound was synthesized according to the method described for the synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl acetate, except substituting 4-(4-bromophenyl)-4-fluoro-1-methylpiperidine (133 mg, 0.49 mmol). The reaction was then allowed to cool to room temperature and was diluted with EtOAc and water was added. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated to give the title compound as a brown solid (281 mg, used without further purification). 1H NMR (400 MHz, MeOD) δ 7.76 (d, J=7.7 Hz, 2H), 7.41 (d, J=7.8 Hz, 2H), 2.94-2.91 (m, 2H), 2.59 (t, J=12.0 Hz, 2H), 2.45 (s, 3H), 2.30-2.22 (m, 1H), 2.20-2.12 (m, 1H), 2.01-1.95 (m, 2H); 19F NMR (400 MHz, MeOD) δ −162.38; MS ESI 320.1 [M+H]+, calcd for [C18H27BFNO2+H]+ 320.21.