Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH3:34][NH:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:38]4[CH2:39][CH:36]([NH:35][CH3:34])[CH2:37]4)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: CNC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Br)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To 800 mg of N,N-dimethylformamide were added 260 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 130 mg of 3-methylaminoazetidine dihydrochloride, and 300 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour. After adding 0.5 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 247 mg of the title compound as a pale yellow powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[NH:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][C:23]=3[N:24]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:28](Br)[CH3:29]>C1COCC1>[CH2:28]([N:18]1[C:19](=[O:25])[CH2:20][CH2:21][CH2:22][C:23]2[N:24]=[C:14]([N:11]3[CH2:10][CH2:9][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:13][CH2:12]3)[N:15]=[CH:16][C:17]1=2)[CH3:29]
Reactant: O=C1CCCc2nc(N3CCN(Cc4ccccc4)CC3)ncc2N1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1C(=O)CCCc2nc(N3CCN(Cc4ccccc4)CC3)ncc21
Temperature: 60 °C
Reaction time: 5 h
Yield: 96.7 %

Procedure:
Added to 30 ml of THF were 0.65 g (1.84 mmol, Referential Example 51) of 2-(4-benzylpiperazino)-6-oxo-6,7,8,9-tetrahydro(5H)pyrimido[5,4-b]azepine and 0.15 g (3.75 mmol) of 60% NaH. The resultant mixture was stirred at 20° C. for 30 minutes. Thereafter, 3 g (27.8 mmol) of ethyl bromide was added and the reaction mixture was heated to 60° C. at which the reaction was conducted for 5 hours. After completion of the reaction, the solvent was distilled off and the residue was purified by silica gel column chromatography to obtain 0.65 g of a colorless oil (yield: 92%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)[NH2:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:25](Cl)(=[O:29])[C:26](Cl)=[O:27]>CO>[CH2:2]([O:9][C:10]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[C:12]2[C:11]=1[C:25](=[O:29])[C:26](=[O:27])[NH:13]2)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: Cl
Solvent: CO
Product: O=C1Nc2cc(OCc3ccccc3)cc(OCc3ccccc3)c2C1=O
Temperature: 170 °C

Procedure:
A mixture of 3,5-dibenzyloxyaniline hydrochloride (J. Org. Chem., 1975, 40, 1556; 10 g) and oxalyl chloride (15 ml) was heated to 170° C. for 3 hours. The mixture was cooled to ambient temperature, methanol (45 ml) was added and the mixture was heated to reflux for 1 hour. The mixture was cooled to ambient temperature and the precipitate was isolated, washed with methanol and dried under vacuum to give 4,6-dibenzyloxy-2,3-dioxoindoline (8.8 g); NMR Spectrum: (DMSOd6) 5.22 (s, 2H), 5.28 (s, 2H), 6.12 (s, 1H), 6.42 (s, 1H), 7.3–7.55 (m, 10H), 10.97 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](OC(OCC)OCC)[CH3:13]>>[CH2:12]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:2]=1[CH3:1])[CH3:13]
Reactant: CCOC(OCC)OCC
Reactant: Cc1c(Cl)cccc1C(=O)O
Product: CCOC(=O)c1cccc(Cl)c1C
Yield: 89 %

Procedure:
A mixture of 34 g. (0.2 mol) of 2-methyl-3-chlorobenzoic acid and 50 mL. of commercially available triethylorthoformate was refluxed for 6 hours, upon which bulb-to-bulb distillation gave 35.5 g. (89% yield) of ethyl-3-chloro-2-methylbenzoate as a clear liquid having a boiling point of 80° C. at a pressure of 0.1 mmHg.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C@@H:14]([N:16]=[N+]=[N-])[CH3:15])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C1C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C@@H:14]([NH2:16])[CH3:15])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](N=[N+]=[N-])c1cccc(C(=O)OC(C)(C)C)c1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: O
Product: C[C@H](N)c1cccc(C(=O)OC(C)(C)C)c1
Yield: 82.8 %

Procedure:
(S)-1-(3-Tert-butyloxycarbonylphenyl)-1-azidoethane (3.10 mmol) was dissolved in benzene (8 mL). Water (1 mL) was added followed by triphenylphosphine (6.18 mmol), and the resultant mixture heated to 80° C. for 2 h. The reaction was poured into 1N HCl solution, this solution then washed twice with diethyl ether. These ether washes were discarded and the aqueous phase made strongly basic (pH˜14) by the addition of 5N NaOH solution. This aqueous phase was then extracted 3× with diethyl ether. These ether extracts were combined, washed with brine, dried (MgSO4) and concentrated under reduced pressure to yield 568 mg of an oil which was used without further purification. 1H NMR (500 MHz, CDCl3): δ7.97 (m, 1H); 7.88 (m, 1H); 7.55 (d, J=7.5 Hz, 1H); 7.39 (t, J=7.8 Hz, 1H); 4.19 (q, J=6.6 Hz, 1H); 1.62 (s, 9H); 1.42 (d, J=6.7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]([CH3:20])([CH3:19])[CH2:7][CH:8]([NH:12][C:13](=[O:18])[CH2:14][N:15]([CH3:17])[CH3:16])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl[C:24]1[N:29]=[C:28]([NH:30][C:31]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:32]=2[C:33]([NH:35][CH3:36])=[O:34])[C:27]([Cl:42])=[CH:26][N:25]=1>>[Cl:42][C:27]1[C:28]([NH:30][C:31]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:32]=2[C:33]([NH:35][CH3:36])=[O:34])=[N:29][C:24]([NH:1][C:2]2[CH:22]=[CH:21][C:5]3[C:6]([CH3:19])([CH3:20])[CH2:7][CH:8]([NH:12][C:13](=[O:18])[CH2:14][N:15]([CH3:17])[CH3:16])[C:9](=[O:11])[NH:10][C:4]=3[CH:3]=2)=[N:25][CH:26]=1
Reactant: CN(C)CC(=O)NC1CC(C)(C)c2ccc(N)cc2NC1=O
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(=O)CN(C)C)CC3(C)C)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-dimethylamino-acetylamino)-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide was prepared from N-(8-Amino-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-2-dimethylamino-acetamide and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1221d. Title compound was isolated as a white solid. (55 mg, 45%). LCMS 585.30 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 9.67 (bs, 2H), 9.42 (s, 1H), 9.35 (s, 1H), 8.86 (d, J=7.8 Hz, 1H), 8.50 (d, J=4.9 Hz, 1H), 8.19 (s, 1H), 7.49-7.46 (m, 2H), 7.36-7.31 (m, 2H), 7.21 (s, 1H), 7.11 (d, J=8.7 Hz, 1H), 3.93 (s, 2H), 2.78 (s, 6H), 2.74 (d, J=4.1 Hz, 6H), 2.22-2.18 (m, 1H), 1.94-1.79 (m, 2H), 1.35 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([O:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[C:26](=[O:35])[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C(N(C(C)C)CC)(C)C.[NH:45]1[CH2:50][CH2:49][CH:48]([N:51]2[CH2:56][CH:55]=[CH:54][CH2:53][CH2:52]2)[CH2:47][CH2:46]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.ClCCl>[O:35]=[C:26]1[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([C:17]([O:16][C@H:12]([CH2:11][C:4]3[CH:5]=[C:6]4[C:10](=[C:2]([CH3:1])[CH:3]=3)[NH:9][N:8]=[CH:7]4)[C:13]([N:45]3[CH2:50][CH2:49][CH:48]([N:51]4[CH2:56][CH2:55][CH:54]=[CH:53][CH2:52]4)[CH2:47][CH2:46]3)=[O:14])=[O:18])[CH2:20][CH2:21]2)=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc2cn[nH]c12
Reactant: C1=CCN(C2CCNCC2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCC(N3CC=CCC3)CC2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carbonyloxy)propanoic acid (50 mg, 0.11 mmol), diisopropylethylamine (37 μL, 0.21 mmol), and 1-(piperidin-4-yl)-1,2,3,6-tetrahydropyridine (75.7 mg, 2.0 equiv) in dimethylformamide (0.50 mL) and dichloromethane (0.50 mL) at 0° C. was added PyBOP® (57.6 mg, 0.11 mmol). The reaction was stirred at 0° C. for 4 h. The reaction was concentrated and purified by column chromatography (95:5:1 to 90:10:1 dichloromethane/methanol/triethylamine). The resulting residue was dissolved in 5% methanol/dichloromethane and passed through a basic alumina column to give 35.9 mg (53%) as a white powder. 1H-NMR (CD3OD, 500 MHz) δ −0.35-0.15 (m, 0.7H), 0.60-0.93 (m, 1H), 1.15-2.20 (m, 11H), 2.30-3.25 (m, 11H), 3.75-4.58 (m, 4H), 5.35-5.75 (m, 3H), 7.01-7.14 (m, 1H), 7.18 (m, 1H), 7.28 (m, 1H), 7.36-7.50 (m, 2H), 7.53-7.73 (m, 2H), 7.90-8.01 (m, 1H). Mass spec.: 623.33 (MH)+.
Reaction SMILES: [NH2:1][C:2]([NH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12]C)=[O:11])=[N:3][C:4]#[N:5].[OH-].[Na+]>O>[OH2:11].[NH2:1][C:2]([NH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([OH:12])=[O:11])=[N:3][C:4]#[N:5]
Reactant: COC(=O)c1cccc(NC(N)=NC#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CN=C(N)Nc1cccc(C(=O)O)c1

Procedure:
To a suspension of methyl 3-[amino(cyanoiminomethyl)]aminobenzoate (7.3 g, 33.47 mmol) in 20 mL of deionized water was added 1N sodium hydroxide (34 mL, aqueous) and the mixture heated at reflux for 2 h. The resulting mixture was filtered and the filtrate neutralized with 6N HCl. The turbid solution was filtered and the clear filtrate further acidified using 6N HCl to pH 4.0-4.5. The white solid was separated through filtration, washed with 30 mL of water, dried in air followed by drying in a pistol at toluene reflux in vacuo to give 1.26 (18%) of the title compound, mp>300° C. Further acidification gave more solid 3.96 g (58%) which was slightly impure.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]=[N+]=[N-])[CH:13]([OH:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]1([C:28](=[O:45])[CH2:29][CH:30]([CH2:34][S:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:37])=[O:36])[C:31](O)=[O:32])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:31](=[O:32])[CH:30]([CH2:34][S:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:37])=[O:36])[CH2:29][C:28]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:45])[C:13](=[O:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NC1CCCN(C(=O)OCc2ccccc2)CC1O
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1
Product: O=C(NC1CCCN(C(=O)OCc2ccccc2)CC1=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1

Procedure:
The crude 4-amino-3-hydroxy-azepane-1-carboxylic acid benzyl ester was coupled to 4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid and oxidized, as described above, to yield 4-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-3-oxo-azepane-1-carboxylic acid benzyl ester; 1H NMR: (DMSO) 8.46–8.42 (m, 1H), 7.44–7.24 (m, 10H), 5.18–5.04 (m, 2H), 4.52–4.33 (m, 4H), 4.04–3.76 (m, 2H), 3.58–3.30 (m, 11H), 3.11–3.03 (m, 1H), 2.96–2.78 (m, 1H), 2.72–2.57 (m, 1H), 1.84–1.55 (m, 4H); MS: (M+H)+ 600.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][CH:14]=1>>[O:12]=[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:19]([C:16]3[CH:17]=[CH:18][C:13]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:14][CH:15]=3)=[O:20])=[CH:3][CH:4]=2)[NH:9]1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc2ccc(=O)[nH]c2c1
Product: O=C(Nc1ccc2ccc(=O)[nH]c2c1)c1ccc(-c2ccccc2)cc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-amino-1H-quinolin-2-one (D89) (30 mg, 0.19 mmol) and 4-biphenylcarboxylic acid (44 mg, 0.22 mmol) as an off-white solid. 1H NMR (400 MHz, DMSO) δ (ppm): 11.80 (br, 1H), 10.58 (br, 1H), 8.09 (d, 2H), 8.04 (d, 1H), 7.85 (m, 3H), 7.77 (d, 2H), 7.62 (d, 1H), 7.52 (m, 3H), 7.44 (t, 1H), 6.39 (d, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6](=[S:8])[NH2:7].Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH2:15]([O:14][C:12]([C:11]1[N:7]=[C:6]([C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[S:8][CH:10]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)c1ncc[nH]1
Product: CCOC(=O)c1csc(-c2ncc[nH]2)n1
Temperature: 75 °C
Yield: 57.1 %

Procedure:
A mixture of 1H-Imidazole-2-carbothioic acid amide (200 mg, 1.57 mmol) and Ethyl bromopyruvate (340 mg, 1.57 mmol) is heated at 75° C. for about 5 hours. After the volatiles are evaporated in vacuo, the residue is partitioned between Ethyl acetate (40 mL) and aqueous NaHCO3 (10 ML). The organic layer is separated, washed with water, dried and concentrated. The residue is purified on a silica gel column with 3% MeOH in CH2Cl2 as eluent to give 200 mg of the titled compound. 1H NMR (CDCl3): δ 8.15 (s, 1H), 7.20 (br, 1H), 7.10 (br, 1H), 4.33 (q, 2H), 1.23 (t, 3H). LRMS calcd 223, found 224 (MH+).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[C:16]1([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][NH2:32])(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:32]([CH2:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[S:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:24])=[O:23])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: NCc1ccccc1S(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1ccccc1S(=O)(=O)c1ccccc1
Yield: 49.7 %

Procedure:
2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.38 g), 1-[2-(phenylsulfonyl)phenyl]methanamine hydrochloride (2.0 g) and potassium carbonate (2.03 g) were stirred in ethanol (20 ml) at 90° C. for 20 hr. The reaction mixture was poured into 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=4:1). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (3 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized to give the title compound (0.64 g).
Reaction SMILES: C([N:8]1[CH:14]2[CH2:15][N:11]([CH2:12][CH2:13]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:16]>[Pd].CCO>[ClH:16].[ClH:16].[N:11]12[CH2:15][CH:14]([CH2:13][CH2:12]1)[NH:8][CH2:9][CH2:10]2
Reactant: c1ccc(CN2CCN3CCC2C3)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: C1CN2CCC(C2)N1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
A mixture of 4-benzyl-1,4-diaza-bicyclo[3.2.1]octane (7.5 g, 37 mmol), 5% palladium on carbon (0.75 g, wet), concentrated HCl (7.5 mL) in EtOH (150 mL) was shaken under hydrogen (50 psi) for a period of 20 h at RT. The product precipitated out of the mixture and water was added in order to dissolve the product. The mixture was filtered through a pad of celite and washed with EtOH. The filtrate was concentrated in vacuo to a solid that was azeotroped with EtOH (3×50 mL). The resulting solid was triturated with hot isopropanol and stirred 18 h at RT. The resulting solid was collected by filtration giving 5.6 g (80%) of the title compound: 1H NMR (d6-DMSO, 400 MHz) δ 4.26 (br s, 1H), 3.72 (d, 1H, J=12 Hz), 3.60-3.53 (m, 1H), 3.48-3.35 (m, 7H), 2.33-2.27 (m, 2H); GCMS m/z 112
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5])[CH3:2].[Cl:21][S:22](O)(=[O:24])=[O:23]>ClCCl>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[S:8][C:9]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[C:17]([S:22]([Cl:21])(=[O:24])=[O:23])[CH:18]=2)=[C:10]([CH3:12])[N:11]=1)[CH3:2]
Reactant: CCNC(=O)Nc1nc(C)c(-c2ccc(OC)cc2)s1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CCNC(=O)Nc1nc(C)c(-c2ccc(OC)c(S(=O)(=O)Cl)c2)s1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
A suspension of 1-ethyl-3-[5-(4-methoxy-phenyl)-4-methyl-thiazol-2-yl]urea (Example 28c) (1.0 g, 3.44 mmol) in dichloromethane (15 ml) is added portionwise to chlorosulfonic acid (25 ml, excess) cooled at −10° C. The temperature is kept below 0° C. throughout the addition. The reaction mixture is left to warm up to room temperature. After 3 hours, the reaction mixture is poured carefully onto ice (2 litres). Once ice is melted, the aqueous layer is extracted with dichloromethane (DCM) (3×200 ml). The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated to afford 5-[2-(3-ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxy benzenesulfonylchloride.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.[F:17][C:18]([F:30])([F:29])[C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[CH:24][N:25]2[NH2:28])=[CH:21][CH:20]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[F:30][C:18]([F:17])([F:29])[C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[CH:24][N:25]2[NH:28][C:8]([C:7]2[C:2]([CH3:1])=[N:3][C:4]([C:11]3[N:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:5][CH:6]=2)=[O:10])=[CH:21][CH:20]=1
Reactant: Cc1nc(-c2ncccn2)ncc1C(=O)O
Reactant: Nn1ccc2ccc(C(F)(F)F)cc21
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ncccn2)ncc1C(=O)Nn1ccc2ccc(C(F)(F)F)cc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 25.1 %

Procedure:
A solution of 4-methyl-[2,2′]bipyrimidinyl-5-carboxylic acid (259 mg, 1.2 mmol) and 6-trifluoromethyl-indol-1-ylamine (200 mg, 1 mmol) in DMF (5 mL) is stirred at 50° C. for 0.5 h. The mixture is treated with DMTMM (290 mg, 1.05 mmol) and stirred at 50° C. for 1 h. The mixture is diluted with saturated aqueous Na2CO3 (5 mL) and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is triturated with Et2O/heptane overnight. The precipitate is collected by filtration, washed with H2O (50 mL) and heptane (50 mL), and dried in vacuo to afford 4-methyl-[2,2′]bipyrimidinyl-5-carboxylic acid (6-trifluoromethyl-indol-1-yl)-amide (100 mg, 25%). MS: 399 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 12.16 (s, NH, 1H), 9.39 (s, 1H), 9.06 (d, 2H), 7.92 (s, 1H), 7.81 (m, 2H), 7.70 (t, 1H), 7.44 (d, 1H), 6.74 (d, 1H), 2.79 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=3)[O:8][C:4]=2[CH:3]=1.CO.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=3)[NH2:15])[O:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc3ccc(Br)cc3o2)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc(-c2nc3ccc(Br)cc3o2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a mixture of 6-bromo-2-(3-nitrophenyl)benzoxazole (Compound of Example 266) (5.96 g), nickel bromide(II) (204 mg), methanol (100 ml), tetrahydrofuran (100 ml) was added sodium borohydride (2.12 g) little by little at 0° C. The mixture was stirred at 0° C. for 10 minutes and at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4 and treated with activated carbon. The solvent was distilled off under reduced pressure, and resulting crystals were collected by filtration to obtain 3-(6-bromobenzoxazol-2-yl)aniline (4.46 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[CH:47]1([C:50](O)=[O:51])[CH2:49][CH2:48]1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH:47]1([C:50]([O:27][CH:24]([C:5]2[C:6]3[N:7]4[CH2:14][CH2:13][CH2:12][N:11]([C:15]5[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=5)[C:8]4=[N:9][C:10]=3[C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:25][CH3:26])=[O:51])[CH2:49][CH2:48]1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(OC(=O)C1CC1)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 73.1 %

Procedure:
To a solution of 1-[9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (122.3 mg, 0.316 mmol) in tetrahydrofuran (0.5 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (121.2 mg, 0.632 mmol), triethylamine (88 μL, 0.632 mmol), cyclopropanecarboxylic acid (37.8 μL, 0.474 mmol) and 4-dimethylaminopyridine (57.9 mg, 0.474 mmol). The reaction mixture was stirred at room temperature for 3.5 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The residue was recrystallized from diisopropyl ether/n-hexane to give the title compound as a colorless powder (105.2 mg, 0.231 mmol, 73%).
Reaction SMILES: [C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:44]1[CH:49]=[CH:48][C:47]([C:50](=[O:52])[CH3:51])=[CH:46][CH:45]=1>>[C:50]([C:47]1[CH:48]=[CH:49][C:44]([C:33]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:31]([CH2:30][N:15]([C:16]([C:18]3[S:22][C:21]4[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=4[C:19]=3[Cl:29])=[O:17])[CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:42])[C:1](=[O:2])[O:3][C:4]([CH3:6])([CH3:5])[CH3:7])[CH2:10][CH2:11]3)[CH:32]=2)=[CH:45][CH:46]=1)(=[O:52])[CH3:51]
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(C(C)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 9 (700 mg, 1.12 mmol) is coupled to 4′-bromoacetophenone (268 mg, 1.34 mmol) using Method A to give the title compound.