Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:30])=[N:27][CH:28]=1)=O.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1.CC(O)=O>CCOC(C)=O.C1COCC1>[Cl:41][C:42]1[CH:43]=[CH:44][C:45]([C:48]2[CH:53]=[CH:52][C:51]([NH:54][CH2:15][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:30])=[N:27][CH:28]=3)=[CH:50][CH:49]=2)=[CH:46][CH:47]=1
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(-c2ccccc2C=O)cn1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)CCNC(=O)c1ccc(-c2ccccc2CNc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (90 mg, 0.42 mmol) was added to a THF solution (1.5 mL) of tert-butyl 3-(5-(2-formylphenyl)picolinamido)propanoate (100 mg, 0.28 mmol), 4′-chloro-[1,1′-biphenyl]-4-amine (86 mg, 0.42 mmol), and AcOH (16 μL, 0.28 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20]=2[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:31][CH:30]=2)=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12])([O:3]C)=[O:2].[OH-].[Na+:44]>>[Na+:44].[Na+:44].[C:1]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20]=2[CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][N:38]3[CH2:39][CH2:40][CH2:41][CH2:42]3)=[CH:33][CH:34]=2)=[CH:15][C:10]=1[C:11]([O-:13])=[O:12])([OH:3])=[O:2].[C:1]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20]=2[CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][N:38]3[CH2:39][CH2:40][CH2:41][CH2:42]3)=[CH:33][CH:34]=2)=[CH:15][C:10]=1[C:11]([O-:13])=[O:12])([OH:3])=[O:2]
Reactant: COC(=O)CCCOc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCOc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1C(=O)[O-]
Yield: 98 %

Procedure:
The title compound was prepared in 98% yield from methyl 2-(3-carbomethoxypropoxy)-5-[3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophen-2-yl]benzoate (Part A) by essentially following the procedure outlined in Example 1, Part D, (except using 2.0 equivalents of 1 N NaOH solution).
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10]([C:20]3[C:28]([OH:29])=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)([CH2:18]O)[C:9]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C(OCC)(=O)C>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:28]4[O:29][CH2:18]3)[C:9]2=[O:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1ccc2c(c1)C(CO)(c1cc3c(cc1O)OCO3)C(=O)N2C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCO4)C(=O)N2C(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
To a solution of 1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-5-methyl-1,3-dihydro-2H-indol-2-one (1.31 g, 2.72 mmol) in ethyl acetate (50.0 mL) was added tributylphosphine (0.82 g, 4.07 mmol). A solution of di-tert-butyl azodicarboxylate (0.94 g, 4.07 mmol) in ethyl acetate (45.0 mL) was added to the above reaction mixture over a period of 5 minutes. After stirring for 10 minutes under N2, the reaction was quenched with saturated aqueous ammonium chloride (60.0 mL). The organic layer was separated and washed with 1.0 N hydrochloric acid solution (3×100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate/hexane (10-50%) to afford the title compound (0.98 g, 78% yield): 1H NMR (300 MHz, CDCl3) δ 7.40-7.25 (m, 10H), 7.02, (s, 1H), 6.96 (s, 1H), 6.79 (d, 1H), 6.50 (s, 1H), 6.36 (d, 1H), 6.08 (s, 1H), 5.86 (d, 2H), 4.82 (ABq, 2H), 2.20 (s, 3H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O-:14])([O-])=[O:12].[K+].[K+]>C1COCC1>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][C:11](=[O:12])[O:14][C:1]([CH3:7])([CH3:6])[CH3:2])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 189.3 %

Procedure:
Over a solution of (trans)-2-phenylcyclopropanamine (intermediate A, 1.14 g, 1 eq) in 50 mL of THF, 1.25 g (1.05 eq) of K2CO3 was added and stirred 3 hours at room temperature. After removal of the solvent, CH2Cl2 was added, then washed with a saturated solution of NaHCO3 and brine. The organic layer was extracted, dried with MgSO4 and filtered. The crude was purified by silica gel chromatography (Hexane-MTBE 90:10) affording 1.89 g of tert-butyl(trans)-2-phenylcyclopropylcarbamate. Yield: 95%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:33]=[C:32]4[C:13]([CH2:14][CH2:15][C:16]5[N:20]=[C:19]([C@@H:21]6[CH2:25][C@H:24]([O:26][CH2:27][CH3:28])[CH2:23][N:22]6[C:29]([O-:31])=[O:30])[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:33]=[C:32]4[C:13]([CH:14]=[CH:15][C:16]5[N:20]=[C:19]([C@@H:21]6[CH2:25][C@H:24]([O:26][CH2:27][CH3:28])[CH2:23][N:22]6[C:29]([O:31][C:5]([CH3:11])([CH3:6])[CH3:4])=[O:30])[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1
Reactant: CCO[C@H]1C[C@@H](c2nc3c([nH]2)-c2cc4c(cc2CC3)-c2ccc(Cl)cc2CO4)N(C(=O)[O-])C1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCO[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(Cl)ccc2-5)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 143.7 %

Procedure:
To a solution of (2S,4S)-2-(9-chloro-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidine-1-carboxylate (0.99 g, 1.9 mmol) in CH2Cl2 (18 mL) was added MnO2 (4.52 g, 52.0 mmol). The resulting slurry was stirred at room temperature for 18 h. The reaction was filtered through celite, washed with CH2Cl2, and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 75% EtOAc (w/5% MeOH)/Hexanes) to afford tert-butyl(2S,4S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidine-1-carboxylate (0.71 g, 72%)
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C@H:17]([OH:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[C:21]=1[NH2:27])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1.Cl>[OH:28][C@@H:17]([CH2:16][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:18][O:19][C:20]1[C:21]2[NH:27][C:30](=[O:32])[NH:26][C:22]=2[CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cccc(OC[C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cccc(OC[C@@H](O)CN(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Reaction time: 14 h
Yield: 92.9 %

Procedure:
(S)-[3-(N,N-Dibenzylamino)-2-hydroxypropoxy]-2,3-diaminobenzene (4.4 g, 11.6 mmol) was suspended in a mixture of toluene (60 mL) and 2N HCl (100 mL) at ambient temperature with vigorous stirring. An excess of triphosgene (17.3 g, 58.3 mmol) was added, and the stirring continued for 14 hours. The biphasic mixture was cautiously quenched and neutralized with sodium bicarbonate, causing an off-white precipitate to form at the interface. The precipitate was filtered and dried in vacuo to yield 4.35 g (93%) of a pale solid that was used without further purification. TLC, NMR and MS all indicated high purity of the intermediate.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[O:11]1[C:15]2[CH:16]=[CH:17][C:18](B(O)O)=[CH:19][C:14]=2[O:13][CH2:12]1>>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:2]3[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=3)=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: Nc1c(F)cc(-c2ccc3c(c2)OCO3)cc1F
Yield: 59.8 %

Procedure:
The title compound (143 mg) was prepared from 4-bromo-2,6-difluoroaniline (200 mg, 0.96 mmol) and benzo[d][1,3]dioxol-5-ylboronic acid (207 mg, 1.25 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.23-7.18 (m, 3H), 7.08 (dd, J 1.8, 8.2, 1H), 6.91 (d, J 8.1, 1H), 6.01 (s, 2H), 5.24 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[I:22])[C:11](=[O:23])[N:10]([CH3:24])[C@@H:9]1[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[Sn](Cl)(Cl)Cl.[CH3:34][O:35]C(Cl)Cl>ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[C:18]([CH:34]=[O:35])[C:17]([O:20][CH3:21])=[CH:16][C:15]=2[I:22])[C:11](=[O:23])[N:10]([CH3:24])[C@@H:9]1[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(C[C@H]2C(=O)N(C)[C@H](C(C)(C)C)N2C(=O)OC(C)(C)C)c(I)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(I)c(C[C@H]2C(=O)N(C)[C@H](C(C)(C)C)N2C(=O)OC(C)(C)C)cc1C=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 11.4 %

Procedure:
The iodoanisole derivative 27 (460.20 mg, 0.94 mmol) was dissolved in anhydrous dichloromethane (10 mL) and cooled to 0° C. under argon. After stirring for 15 min a solution of SnCl4 (1M in dichloromethane, 10.4 mL, 10.4 mmol) was added drop wise. After completion of the addition of SnCl4, 1,1-dichloromethyl methyl ether (0.84 mL, 9.4 mmol) was added drop wise. The color of the solution turned from light yellow to greenish brown. The reaction mixture was stirred for 45 min at 0° C. and then quenched with a saturated solution of ammonium chloride (2.0 mL). The light brown suspension was stirred for 30 min at room temperature and extracted with dichloromethane. The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to afford a yellow oil. Flash chromatographic purification of the crude product gave pure (2S,5S)-tert-Butyl-5-(2′-iodo-4′-methoxy-5′-formylbenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate (28) as oil (57 mg, 10%).
Reaction SMILES: [Cl:1][C:2]1[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][N:5]([CH2:19][CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH2:16][CH:17]=O)[CH:13]=[CH:14][CH:15]=1.[CH3:41][O:42][C:43](=[O:46])[CH2:44][NH2:45].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH3:41][O:42][C:43](=[O:46])[CH2:44][NH:45][CH2:17][CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:4][C:3]2[CH:33]=[CH:34][CH:35]=[C:36]([C:37]([F:38])([F:40])[F:39])[C:2]=2[Cl:1])[CH2:19][CH:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:11]=1
Reactant: COC(=O)CN
Reactant: O=CCc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)CNCCc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-acetaldehyde (76 mg, 0.13 mmol) and glycine methyl ester (34 mg, 0.27 mmol) in 1,2-dichloroethane (15 ml) was stirred as room temperature for 10 minutes, and sodium triacetoxyborohydride (57 mg, 0.27 mmol) was added. Next two drops of glacial acetic acid was added. The reaction mixture was stirred at room temperature for 18 hour and then quenched with 0.01N aqueous HCl (15 ml) The biphasic mixture was separated and the aqueous layer was extracted with dichloromethane (3×). The organic layers were combined with the 1,2-dichloroethane solution and were washed with brine (1×), dried over sodium sulphate, filtered and concentrated in vacuo. Preparative HPLC (YMC 75×30 mm, 25 ml/min, 90-100% CH3CN) afforded title compound as an oil, 70 mg (81%).
Reaction SMILES: CN([CH:4]=[O:5])C.[Br:6][C:7]1[C:8]([Cl:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11].CI.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Br:6][C:7]1[C:8]([Cl:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([O:5][CH3:4])=[O:11]
Reactant: O=C(O)c1cccc(Br)c1Cl
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cccc(Br)c1Cl
Reaction time: 1 h
Yield: 79 %

Procedure:
To a DMF solution (30 ml) containing 2.70 g of 3-bromo-2-chlorobenzoic acid were added 1.10 ml of methyl iodide and 2.38 g of potassium carbonate in order at room temperature, followed by 1 hour of stirring. The reaction liquid was mixed with water and then diluted with ethyl acetate. After a layer separation operation, the organic layer was washed with water and saturated brine in that order, dried with anhydrous magnesium sulfate and then concentrated under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography using ethyl acetate-n-hexane (100:3) as the elution solvent to obtain 2.26 g (79%) of methyl 3-bromo-2-chlorobenzoate. FA: 250
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:9]2[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)C1CC1
Reactant: Clc1ccnc(Cl)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1nccc(C2CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
2,4-Dichloropyrimidine (15 g, 101 mmol), cyclopropylboronic acid (8.65 g, 101 mmol), Pda2(dppf)-CH2Cl2 adduct (8.22 g, 10.07 mmol), and potassium phosphate (53.4 g, 252 mmol) were combined in a 1 L round-bottom flask. THF (503 mL) was added and the suspension was heated to reflux with stirring overnight. The reaction was then cooled to room temperature, concentrated to ˜100 mL under reduced pressure, extracted with ethyl acetate, washed with saturated aqueous NaHCO3, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in hexanes to give 2-chloro-4-cyclopropylpyrimidine (10.124 g, 58.3 mmol, 57.9%) as an 89:11 mixture of regioisomers.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[CH:16]([N:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[CH2:15][CH2:14]3)=[O:10])=[CH:4][C:3]=1[NH:33][C:34]1[N:39]=[C:38]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH:37]=[CH:36][N:35]=1>Cl.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[CH:16]([N:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)[CH2:15][CH2:14]3)=[O:10])=[CH:4][C:3]=1[NH:33][C:34]1[N:39]=[C:38]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH:37]=[CH:36][N:35]=1
Reactant: Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCN(C(=O)OC(C)(C)C)CC2)cc1Nc1nccc(-c2cccnc2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCNCC2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 4-{5-[({4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl}amino)carbonyl]-2,3-dihydro-1H-inden-1-yl}piperazin-1-carboxylate (2 g, 3.3 mmol) was dissolved in 4 N HCl in dioxane (10 mL). The solution was concentrated to obtain the solid product after being stirred at room temperature for 3 hours. The product (100 mg) was purified by high performance liquid chromatography at pH=10 to obtain the subtitle compound. MS (M+1)=506.26. 1HNMR (DMSO-d6, ppm): δ 10.08 (s, 1H); 9.20 (s, 1H); 8.93 (s, 1H); 8.62 (d, J=4.8 Hz, 1H); 8.44 (d, J=5.2 Hz, 1H); 8.40 (d, J=8.0 Hz, 1H); 8.00 (s, 1H); 7.72 (s, 1H); 7.70 (d, J=8.0 Hz, 1H); 7.45 (dd, J=8.2 Hz, 4.8 Hz, 1H); 7.41 (d, J=8.2 Hz, 1H); 7.36 (d, J=5.2 Hz, 1H); 7.31 (d, J=8.0 Hz, 1H); 7.12 (d, J=8.8 Hz, 1H); 4.22 (t, J=6.8 Hz, 1H); 2.80 (m, 2H); 2.60 (m, 4H); 2.35 (m, 2H); 2.22 (m, 2H); 2.15 (s, 3H); 2.00 (m, 2H).
Reaction SMILES: [C:1]([NH:5][NH:6]C(OC(C)(C)C)=O)([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[CH:22][C:16]=1[C:17]([N:19]=[C:20]=[O:21])=O.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([N:5]1[C:20](=[O:21])[NH:19][C:17]([C:16]2[CH:22]=[C:23]([CH:24]=[CH:25][C:15]=2[Cl:14])[CH2:26][NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NNC(=O)OC(C)(C)C
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)n1nc(-c2cc(CNC(=O)C(F)(F)F)ccc2Cl)[nH]c1=O
Yield: 22.1 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using tert-butyl 2-tert-butylhydrazinecarboxylate (Intermediate-74, 0.233 g, 1.2 mmol), 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 0.400 g, 1.2 mmol), DCM (10 mL), trifluoro acetic acid (5.0 mL) to afford 0.100 g of the desired product. 1H NMR (400 MHz; DMSO d6): δ 1.52 (s, 9H), 4.42 (s, 2H), 7.39 (d, 1H), 7.41 (s, 1H), 7.58 (d, J=2.1 Hz, 2H), 10.0 (br s, 1H), 12.0 (br s, 1H); MS (in/z): 377.20 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16][CH2:15]4)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1>>[CH3:22][N:18]1[C:19]2[C:14](=[CH:13][C:12]([C:7]3[C:6]4[CH2:5][CH2:4][CH2:3][C@@H:2]([NH:1][S:27]([CH:24]5[CH2:26][CH2:25]5)(=[O:29])=[O:28])[C:11]=4[CH:10]=[N:9][CH:8]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:23]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCC[C@H]4N)ccc21
Product: CN1C(=O)CCc2cc(-c3cncc4c3CCC[C@H]4NS(=O)(=O)C3CC3)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 4, reaction of (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (example 61) with cyclopropanesulfonyl chloride gave the title compound as colorless solid. MS: 412.5 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19][C:20]([S:23](Cl)(=[O:25])=[O:24])([CH3:22])[CH3:21]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:23]([C:20]([CH3:22])([CH3:21])[CH3:19])(=[O:25])=[O:24])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CC(C)(C)S(=O)(=O)Cl
Product: CC(C)(C)S(=O)(=O)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with 2-methylpropane-2-sulfonyl chloride (synthesized according to the literature procedure) to obtain the desired product. 1H NMR (300 MHz, CDCl3): δ 7.50 (m, 1H), 7.43 (dd, J=1.8 & 10.5 Hz, 1H), 7.28 (br s, 1H), 7.10 (dd, J=9.0 & 17.7 Hz, 1H), 6.48 (br s, D2O exchangeable, 1H), 6.19 (t, J=7.8 & 9.6 Hz, 1H), 5.58 (br s, D2O exchangeable, 1H), 1.39 (s, 9H); m/z=383 [M−1]−.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:24](=[O:25])[C:23]3[N:15]([C:16]4[CH:17]5[CH2:26][CH:20]([C:21]=4[CH:22]=3)[CH2:19][CH2:18]5)[CH2:14][CH2:13]2)=[CH:10][C:9]([F:27])=[CH:8][C:7]=1Br)(=[O:3])[CH3:2].[CH3:29][N:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]3)=[CH:48][N:47]=2)[C:31]1=[O:59].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:24](=[O:25])[C:23]3[N:15]([C:16]4[CH:17]5[CH2:26][CH:20]([C:21]=4[CH:22]=3)[CH2:19][CH2:18]5)[CH2:14][CH2:13]2)=[CH:10][C:9]([F:27])=[CH:8][C:7]=1[C:34]1[CH:33]=[C:32]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:53][CH2:54][N:55]([CH3:58])[CH2:56][CH2:57]3)=[CH:48][N:47]=2)[C:31](=[O:59])[N:30]([CH3:29])[CH:35]=1)(=[O:3])[CH3:2]
Reactant: CN1CCN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2C2CCC3C2)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2C2CCC3C2)C1=O
Temperature: 130 °C
Yield: 30 %

Procedure:
A microwave vial equipped with a magnetic stirrer was charged with (2-bromo-4-fluoro-6-{7-oxo-3,6-diazatetracyclo[9.2.1.02,10.03,8]tetradeca-2(10),8-dien-6-yl}phenyl)methyl acetate 334g (293 mg, 0.65 mmol), 1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridine-2-ylamino)-6-oxo-1,6-dihydropyridin-3-ylboronic acid 197f (450 mg, 1.3 mmol), PdCl2(dppf) (54 mg, 0.065 mmol), 2.0 M Na2CO3 (2.0 equiv), and 1,2-dimethoxyethane (18 mL). After three cycles of vacuum/argon flash, the mixture was heated at 130° C. under microwave irradiation for 0.5 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified on flash column chromatography eluting with 10:1 dichloromethane/methanol to afford 340a as a brown solid (130 mg, 33%). LCMS: [M+H]+ 666
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][S:13][C:14]3[CH:15]=[C:16]([CH:20]([S:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[S:21][CH2:22][CH2:23][C:24](O)=[O:25])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[I-].Cl[C:35]1C=CC=[CH:37][N+:36]=1C.CNC.[OH-].[Na+:46]>ClCCl.C(#N)C.C1(C)C=CC=CC=1.C(O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][S:13][C:14]3[CH:15]=[C:16]([CH:20]([S:21][CH2:22][CH2:23][C:24](=[O:25])[N:36]([CH3:37])[CH3:35])[S:27][CH2:28][CH2:29][C:30]([O-:32])=[O:31])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[Na+:46]
Reactant: O=C(O)CCSC(SCCC(=O)O)c1cccc(SCc2ccc3ccc(Cl)cc3n2)c1
Reactant: C[n+]1ccccc1Cl
Agent: CNC
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: CN(C)C(=O)CCSC(SCCC(=O)[O-])c1cccc(SCc2ccc3ccc(Cl)cc3n2)c1
Reaction time: 0.25 h

Procedure:
To a solution of diacid (Step 4) (360 mg) in dichloromethane (28 mL) and acetonitrile (7.1 mL) was added 2-chloro-1-methylpyridinium iodide (227 mg). The solution was cooled to 0 C. and triethylamine (123 μL) was added. After stirring for 15 min, 0.42 mL of a 2M solution of dimethylamine in toluene was added. The solution was stirred 1 hr at room temperature, washed with acidified 25% ammonium acetate, dried over sodium sulfate, filtered and evaporated to dryness. To the oil obtained after chromatography, in 2 mL of ethanol, was added 0.154 mL of 2N NaOH. After evaporating to dryness the title compound was obtained as a foam.