Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([C:19]4([O:25][CH3:26])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[N:15]3[CH3:18])=[C:11]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:10]=2)[C:7]2[CH:33]=[CH:34][CH:35]=[CH:36][C:6]=2[N:5]=1)([CH3:3])[CH3:2].[CH3:37][S:38]([CH:41]=[CH2:42])(=[O:40])=[O:39]>O>[CH:1]([C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([C:19]4([O:25][CH3:26])[CH2:24][CH2:23][CH2:22][N:21]([CH2:42][CH2:41][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:20]4)[N:15]3[CH3:18])=[C:11]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[N:10]=2)[C:7]2[CH:33]=[CH:34][CH:35]=[CH:36][C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: C=CS(C)(=O)=O
Reactant: COC1(c2nc3c(N4CCOCC4)nc(-n4c(C(C)C)nc5ccccc54)nc3n2C)CCCNC1
Solvent: O
Product: COC1(c2nc3c(N4CCOCC4)nc(-n4c(C(C)C)nc5ccccc54)nc3n2C)CCCN(CCS(C)(=O)=O)C1
Reaction time: 4 h
Yield: 76.2 %

Procedure:
A mixture of 2-(2-isopropylbenzoimidazol-1-yl)-8-(3-methoxypiperidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (150 mg, 0.31 mmol) and methanesulfonylethene (32 μL, 0.37 mmol) in IMS (5 mL) was allowed to stir for 4 h at room temp. before pouring the reaction mixture into H2O. The resulting precipitate was collected by filtration and dried under vacuum affording 713 (141 mg, 77%). LCMS (method I): RT 2.82 min, [M+H]+ 597.2. 1H NMR (DMSO, 400 MHz): δ 7.92-7.91 (1 H, m), 7.65-7.64 (1 H, m), 7.24-7.23 (2 H, m), 4.25 (4 H, brd s), 4.00-3.85 (4 H, m), 3.8-3.75 (4 H, m), 3.40-3.20 (2 H, m), 3.15-3.00 (4 H, m), 2.95 (3 H, s), 2.81-2.76 (4 H, m), 2.30-2.20 (1 H, m), 2.10-2.95 (2 H, m), 1.84-1.74 (2 H, m), 1.36 (6 H, dd, J=6.77, 2.96 Hz)
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([CH2:50][C:51]([O:53][CH2:54][C:55]4[CH:60]=[CH:59][C:58]([N+:61]([O-:63])=[O:62])=[CH:57][CH:56]=4)=[O:52])[CH2:46][CH2:45]3)=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[C@H:26]([C:42]([N:44]2[CH2:45][CH2:46][N:47]([CH2:50][C:51]([O:53][CH2:54][C:55]3[CH:56]=[CH:57][C:58]([N+:61]([O-:63])=[O:62])=[CH:59][CH:60]=3)=[O:52])[CH2:48][CH2:49]2)=[O:43])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
8.0 ml of trifluoroacetic acid and 160 μl of trifluoromethanesulfonic acid were added, whilst ice-cooling, to a suspension of 1120 mg of (2S,4S)-4-(4-methoxybenzylthio)-2-[4-(4-nitrobenzyloxycarbonylmethyl)-1-piperazinecarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine in 1.75 ml of anisole, and the resulting mixture was stirred at room temperature for 1.5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was repeatedly washed with diethyl ether by decantation and dried in vacuo, to afford 1.58 g of the title compound, as a powder.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:13]([O:15][CH:16]2[CH2:20][CH2:19][CH:18]([C:21](O)=[O:22])[CH:17]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(Cl)(=O)C([Cl:35])=O>ClCCl.CN(C=O)C>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:13]([O:15][CH:16]2[CH2:20][CH2:19][CH:18]([C:21]([Cl:35])=[O:22])[CH:17]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(OC1CCC(C(=O)O)C1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(OC1CCC(C(=O)Cl)C1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A solution of 855 mg 3-(SR)-(1-(RS)-(3,5-bis(trifluoromethyl)phenyl)-ethoxy)-2-(RS)-phenylcyclopentane-1-(RS)-carboxylic acid in 20 mL of dry dichloromethane was treated with 2 drops of DMF followed by 0.36 mL of oxalyl chloride. After 1 hour the reaction was evaporated and the residual yellow oil was concentrated twice more from dichloromethane.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[S:22][N:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][C:18]3[S:22][N:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:23])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ncns3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2ncns2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40.3 %

Procedure:
To a solution of [1-hydroxy-4-methyl-6-([1,2,4]thiadiazol-5-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (100 mg, 0.30 mmol) in THF (2.5 mL) and H2O (1 mL) was added LiOH (0.063 g, 1.50 mmol) at 0° C. The resulting solution was stirred at room temperature for 20 minutes. The mixture was diluted with H2O and acidified to pH 3 with 1N HCl at 0° C. The resulting mixture was purified by prep HPLC to give the title compound (37 mg, 45%) as a white solid. 1H NMR (CD3OD) δ7.06 (d, 1H), 6.84 (d, 1H), 5.44 (dd, 1H), 3.04 (dd, 1H), 2.30 (s, 3H), 2.18 (dd, 1H). MS found: (M+H)+: 307.
Reaction SMILES: [F:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:3]=1[CH2:17]O.P(Br)(Br)[Br:20].O>C(OCC)C>[Br:20][CH2:17][C:3]1[C:4]([C:13]([F:16])([F:15])[F:14])=[N:5][N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]=1[F:1]
Reactant: BrP(Br)Br
Reactant: OCc1c(C(F)(F)F)nn(-c2ccccc2)c1F
Solvent: CCOCC
Solvent: O
Product: Fc1c(CBr)c(C(F)(F)F)nn1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 253.5 %

Procedure:
A solution of 27.5 g (105.7 mmoles) of (5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol dissolved in 300 ml of diethyl ether was cooled to 0° C. Thereto was added 10.0 g (37.0 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 30.3 g (yield: 88.8%) of 4-bromomethyl-5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[C:7]([CH3:14])=[N:8][C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[CH3:14][C:7]1[C:6]([C:4]2[N:15]=[C:16]([NH2:18])[S:17][CH:3]=2)=[C:11]([CH3:12])[CH:10]=[C:9]([CH3:13])[N:8]=1
Reactant: Cc1cc(C)c(C(=O)CBr)c(C)n1
Reactant: NC(N)=S
Agent: Br
Solvent: CCO
Product: Cc1cc(C)c(-c2csc(N)n2)c(C)n1
Yield: 62.1 %

Procedure:
A mixture of 2-bromo-1-(2,4,6-trimethylpyridin-3-yl)ethanone hydrobromide (9.00 g, 27.9 mmol) and thiourea (2.12 g, 27.9 mmol) in 95% EtOH (39.8 mL) was heated at reflux for 120 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(2,4,6-trimethylpyridin-3-yl)thiazol-2-amine (3.80 g) as yellow solids in 62% yield: 1H NMR (500 MHz, CDCl3) δ 6.87 (s, 1H), 6.31 (s, 1H), 5.07 (bs, 2H), 2.49 (s, 3H), 2.38 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[CH2:10][CH2:9][CH2:8][NH:7]2)=[CH:2]1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[CH2:10][CH2:9][CH2:8][N:7]2[S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[CH:2]1
Reactant: c1cc(C2CCCN2)cs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccsc2)cc1

Procedure:
The title compound, white solid, m.p. 114° C. and MS: m/e=308.2 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-thien-3-yl-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:19]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)CC1
Yield: 97.5 %

Procedure:
To a solution of tert-butyl 4-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate 27 (0.5 g, 1.05 mml) in methanol (30 mL) was added 5% Pd/C (0.5 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl 4-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate 28 (0.395 g, 98%) as a colorless foam.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:9]([C:3]1[CH:4]=[C:5]([N:6]2[CH:14]=[CH:18][CH:17]=[CH:16]2)[CH:7]=[CH:8][C:2]=1[F:1])([O-:11])=[O:10]
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(-n2cccc2)ccc1F

Procedure:
To a suspension of 4-fluoro-3-nitroaniline (20g, 0.13mol) in toluene (200mi) is added 2,5-dimethoxytetrahydrofuran (33ml, 0.26mol) and a catalytic amount of pTSA. The mixture is refluxed for 2.5 hours. After cooling the solvent is removed by evaporation and the residue is purified by column chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1:1) as the eluent. Yield: 23.1g (87%). Mp 79-81° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: NCCC(=O)O
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Product: O=C(O)CCN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 90.3 %

Procedure:
4-nitrophthalic anhydride (0.25 g, 0.0013 mol) and β-alanine (0.115 g, 0.0013 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.31 g (90%) 141 as a very pale yellow powder: mp=206-208° C.; Rf0.84 (A): Rf0.81 (B): Rf0.55 (D): IR (cm−1): 2800-3125 (OH), 3109 (C═CH), 2646 (C—H), 1780 (C═O), 1718 (bs, C═O), 1621 (C═C), 1536 (N═O), 1441 (C═C), 1395 (C—O), 1346 (N═O), 1228 (C—O), 724 (C═CH); MS m/z (rel intensity) 263 (100), 191 (36).
Reaction SMILES: [ClH:1].Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][CH2:55][N:56]2[CH2:61][CH2:60][CH:59]([OH:62])[CH2:58][CH2:57]2)CC1>>[ClH:1].[ClH:1].[OH:62][CH:59]1[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:57][CH2:58]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (106, see example 55) and amine 21 analogously to the method described in example 1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([O:18]C2C=CC=CC=2)=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][C:40](=[O:55])[C:41]1[CH:46]=[CH:45][C:44]([CH2:47][NH:48][CH2:49][CH2:50][CH2:51][N:52]([CH3:54])[CH3:53])=[CH:43][CH:42]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:18])[N:48]([CH2:47][C:44]2[CH:45]=[CH:46][C:41]([C:40]([NH:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[NH:32][C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:31])=[O:55])=[CH:42][CH:43]=2)[CH2:49][CH2:50][CH2:51][N:52]([CH3:53])[CH3:54])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCCNCc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Reactant: O=C(Nc1cccc(OCc2ccccc2)c1)Oc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CCCN(Cc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1)C(=O)Nc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 15 %

Procedure:
1-Benzyloxy-3-(phenoxycarbonylamino)benzene (Reference Compound No. 5-1, 3.7 g, 12 mmol) was added to a solution of the mixture containing N-(2-t-butoxycarbonylaminophenyl)-4-(3-dimethylaminopropylaminomethyl)benzamide (Reference Compound No. 4-5, 10 g, 24 mmol) in DMSO (30 mL), and then the reaction mixture was stirred at room temperature for 15 hours. Water (300 mL) was added thereto, the whole was extracted with ethyl acetate (250 mL) twice, and then the organic layer was washed with brine (250 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 1.1 g of the title reference compound as a white amorphous product. (Yield 15%)
Reaction SMILES: N1C2C(=CC=C3C=CC=CC3=2)C[CH2:2]1.[C:14]1([N:20]2[C:28]3[C:23](=[C:24]([OH:33])[CH:25]=[C:26]4[CH:32]=[CH:31][CH:30]=[CH:29][C:27]4=3)C(C)(C)C2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O-]S(C(F)(F)F)(=O)=O.NC1C=CC=CC=1>[Pd]>[NH:20]([C:28]1[C:27]2[C:26](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[C:24]([O:33][CH3:2])[CH:23]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1(C)CN(c2ccccc2)c2c1c(O)cc1ccccc21
Reactant: c1ccc2c3c(ccc2c1)CCN3
Agent: [Pd]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: Nc1ccccc1
Product: COc1cc(Nc2ccccc2)c2ccccc2c1

Procedure:
A second preferred synthesis method suitable for the synthesis of benzoindoline compounds, e.g., N-phenyl-3,3-dimethyl-4-hydroxy-benzoindoline 9, is also shown in FIG. 1. In this method, the 3-methoxynapthalene-1-triflate 2 is derivatized with a primary amine, e.g., aniline, using a palladium catalyzed triflate coupling reaction to give a secondary amine, e.g., 1-anilino-3-methoxynapthalene 5. The secondary amine 5 is acetylated using an acid chloride, e.g., an haloacetylchloride, to give a disubstituted amide, e.g., 1-amido-3-methoxynapthalene 6. The tertiary amide 6 is cyclized using a Lewis-acid-catalyzed Friedel-Crafts cyclization procedure to give compound 7, e.g., using AlCl3. Compound 7 is than reduced, e.g., using LAH, to give compound 8. Subsequent methoxy group deprotection by a boron tribromide deprotection procedure gives the benzoindoline, e.g., N-phenyl-3,3-dimethyl-4-hydroxy-benzoindoline 9. An example of this synthesis is provided in Example 2 below.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:16]([O-])=O)=[C:9]([O:14][CH3:15])[CH:10]=2)[CH2:5]1.[H][H]>C(OCC)(=O)C.[Pd].CO>[F:1][CH2:2][CH2:3][N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH2:16])=[C:9]([O:14][CH3:15])[CH:10]=2)[CH2:5]1
Reactant: [H][H]
Reactant: COc1cc2c(cc1[N+](=O)[O-])CN(CCF)CC2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2c(cc1N)CN(CCF)CC2
Yield: 99.6 %

Procedure:
2-(2-fluoroethyl)-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (assumed 1.07 mmol from previous reaction) was dissolved in ethyl acetate (5 mL), treated with 10% palladium on carbon (50 mg, Aldrich), and then diluted with methanol (10 mL). The mixture was stirred under 60 psi of hydrogen pressure for 16 h in a Fischer-Porter apparatus. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 2-(2-fluoroethyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-isoquinolinamine (239 mg, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 2.80-2.93 (m, 6 H), 3.51 (bs, 2 H), 3.61 (s, 2 H), 3.80 (s, 3 H), 4.58-4.75 (dt, JHF=47.6, J=4.9 Hz, 2 H), 6.37 (s, 1 H), 6.50 (s, 1 H).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.Cl.[F:26][C:27]1([F:31])[CH2:30][NH:29][CH2:28]1.CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:29]4[CH2:30][C:27]([F:31])([F:26])[CH2:28]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: FC1(F)CNC1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CC(F)(F)C3)ccc12
Temperature: 25 °C
Yield: 58.6 %

Procedure:
In a microwave vial 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (100 mg, 0.27 mmol), 3,3-difluoro-azetidine hydrochloride (347.07 mg, 2.68 mmol) and DIPEA (519.43 mg, 4.02 mmol) in ACN (1.5 mL) was heated at 120° C. for 2 hours under microwave irradiation. After cooling to room temperature, the mixture was concentrated and purified through reverse phase HPLC to provide the desired product (68 mg, 59%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.88 (1H), 6.69 (1H), 4.54 (4H), 3.24 (t, J=6.24 Hz, 2H), 2.04 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 3H), 1.27-1.30 (m, 2H). m/z: 430 [M+H]
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]([C:10]3[C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:14][C:13]([C:22]#[N:23])=[CH:12][CH:11]=3)[CH2:8][CH2:7][CH2:6][C:5]=12.[Li+].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[CH3:25][C:9]1([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([C:22]#[N:23])=[CH:12][CH:11]=2)[N:4]2[CH:3]=[N:2][CH:1]=[C:5]2[CH2:6][CH2:7][CH2:8]1
Reactant: N#Cc1ccc(C2CCCc3cncn32)c(-c2ccccc2)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(c2ccc(C#N)cc2-c2ccccc2)CCCc2cncn21
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)biphenyl-3-carbonitrile (53 mg, 0.177 mmol) in THF (2 mL) at −40° C. is added LHMDS (1.0 M in THF, 0.27 mL, 0.27 mmol). The resulting brown solution is stirred at −30° C. for 0.5 h. To the reaction mixture is added methyl iodide (0.017 mL, 0.272 mmol) and the mixture is warmed up to ambient temperature and stirred overnight. The reaction mixture is quenched by saturated aqueous NH4Cl and the reaction is partitioned between CH2Cl2 and brine. The organic layer is washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude oil, which is subject to flash chromatography (silica gel) eluting with MeOH:CH2Cl2 to yield the desired compound. MS (ESI) m/z 314 (M+H).
Reaction SMILES: [CH2:1]([N:6]1[C:10](=[O:11])[CH:9]([CH2:12][C:13]([OH:15])=[O:14])[S:8][CH:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH3:22][CH2:23]O>OS(O)(=O)=O>[CH2:1]([N:6]1[C:10](=[O:11])[CH:9]([CH2:12][C:13]([O:15][CH2:22][CH3:23])=[O:14])[S:8][CH:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCN1C(=O)C(CC(=O)O)SC1c1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC1SC(c2ccccc2)N(CCC(C)C)C1=O

Procedure:
A solution of 2-(3-Isopentyl-4-oxo-2-phenylthiazolidin-5-yl)acetic acid (2.2 g, 7.2 mmol) in EtOH (20 ml) and H2SO4 (1 ml) was refluxed for 16 hours. The solution was evaporated to dryness and the residue was taken up in EtOAc and washed with sat. aq. Na2CO3 (3×), brine and evaporated to give the desired product as an oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)O1.C(=O)([O-])[O-].[K+].[K+].[Br:23][C:24]1[CH:25]=[C:26](I)[C:27]([NH2:30])=[N:28][CH:29]=1>O1CCOCC1.O.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>[NH2:13][C:12]1[CH:11]=[CH:10][C:9]([C:26]2[C:27]([NH2:30])=[N:28][CH:29]=[C:24]([Br:23])[CH:25]=2)=[CH:15][CH:14]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Nc1ncc(Br)cc1I
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(-c2cc(Br)cnc2N)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
Tetrakis(triphenylphosphine)palladium (1.16 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.48 g) and potassium carbonate (4.15 g) were added to a solution of 5-bromo-3-iodopyridin-2-amine (2.99 g) in 1,4-dioxane (40 ml) and water (10 ml) at room temperature. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was then purified by silica gel chromatography [chloroform:methanol=9:1 (v/v)] to give 2.48 g of the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14](=[O:32])[NH:15][C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=2)[C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([S:36]([N:39]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][CH:47]=2)[CH2:41][CH2:40]1)(=[O:38])=[O:37])[CH2:34][CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14](=[O:32])[NH:15][C:16]1[CH:17]=[C:18]([C:23]2[CH:24]=[CH:25][C:26]([C:29](=[O:30])[NH:52][C:49]3[CH:50]=[CH:51][C:46]([CH2:45][N:42]4[CH2:41][CH2:40][N:39]([S:36]([CH2:33][CH2:34][CH3:35])(=[O:38])=[O:37])[CH2:44][CH2:43]4)=[CH:47][CH:48]=3)=[CH:27][CH:28]=2)[C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCS(=O)(=O)N1CCN(Cc2ccc(N)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)Nc1ccc(Cl)c(-c2ccc(C(=O)O)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(NC(=O)[C@H]5CCCCN5C(=O)OC(C)(C)C)ccc4Cl)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (R)-2-(4′-Carboxy-6-chloro-biphenyl-3-ylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (73 mg), 4-(4-(propane-1-sulfonyl)-piperazin-1-ylmethyl)-phenylamine (118 mg) and HBTU (91 mg) in dry DMF (4 ml) containing N-methylmorpholine (52 μl) was stirred at room temp for 18 h.