Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C([Sn](CCCC)(CCCC)[C:43]1[S:44][CH:45]=[CH:46][N:47]=1)CCC.O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:44]1[CH:45]=[CH:46][N:47]=[C:43]1[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:27][CH2:28][CH2:29]2)=[CH:22][CH:21]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4nccs4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 130 °C

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (300 mg, 0.54 mmol), 2-(tributylstannyl)thiazole (337 μA, 1.1 mmol), and PdCl2(PPh3)2 (38 mg, 0.047 mmol) in 1,2-dimethoxyethane (10 ml) was added to a crimp top microwave vial, which was then sealed and heated under microwave irradiation conditions at 130° C. for 60 min. After cooling to room temperature the mixture was poured into water and extracted into ethyl acetate. The organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography (hexane/ethyl acetate; 0-100% ethyl acetate over 60 min) to give a yellow amorphous (quant.). 1HNMR (CDCl3) 400 MHz δ: 8.18 (1H, dd, J=7.7, 1.4 Hz), 8.02 (1H, d, J=4.0 Hz), 7.75 (1H, d, J=2.9 Hz), 7.44-7.37 (3H, m), 7.32 (1H, td, J=7.5, 1.7 Hz), 7.24 (1H, d, J=2.9 Hz), 7.15 (1H, td, J=7.4, 1.2 Hz), 6.97 (1H, d, J=8.0 Hz) 6.89-6.81 (1H, m), 6.61 (1H, dd, J=7.7, 4.9 Hz), 6.48 (1H, s), 5.18 (1H, s), 2.60-2.32 (4H, m), 2.17-2.08 (1H, m), 1.93-1.84 (1H, m), 1.48-1.21 (9H, m); LC/MS [M+H]: 563.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[N:4]([CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[CH:31][C:30]=1[O:38][CH3:39])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8](SC)[CH:7]=1.[CH:41]1C=C(Cl)C=C(C(OO)=O)C=1.[OH:52][S:53]([O-:55])=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:40])[N:4]([CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:34]=[C:33]([CH:35]([CH3:36])[CH3:37])[CH:32]=[CH:31][C:30]=1[O:38][CH3:39])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:53]([CH3:41])(=[O:55])=[O:52])[CH:7]=1
Reactant: COC(=O)N(Cc1cc(SC)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Reactant: O=S([O-])O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Temperature: 0 °C

Procedure:
Methyl{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[3-(methylthio)-5-(trifluoromethyl)benzyl]carbamate (18.0 mg, 0.031 mmol) (Example 129) in CH2Cl2 (1 mL) was cooled to 0° C. Next, m-CPBA (17.3 mg, 0.078 mmol) was added. The reaction was stirred at 0° C. for fifteen minutes and then was poured into NaHSO3 (10 mL). The mixture was extracted with EtOAc (50 mL), and the organic extracts were washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 50% EtOAc/hexanes afforded methyl{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[3-(methylsulfonyl)-5-(trifluoromethyl)benzyl]carbamate. Rf=0.61 (50% EtOAc/hexanes). LCMS=618.2 (M+1)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 8.01 (s, 1H), 7.73 (s, 1H), 7.59 (broad singlet, 1H), 7.44 (broad singlet, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.06 (s, 1H), 7.05 (s, 1H), 6.87 (d, J=2.5 Hz, 1H), 6.63 (d, J=8.5 Hz, 1H), 4.39 (broad singlet, 2H), 3.96 (broad singlet, 2H), 3.36 (s, 3H), 3.31 (s, 3H), 2.75 (m, 1H), 2.20 (s, 3H), 1.16 (d, J=7.0Hz, 6H).
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]([S:16]([NH2:19])(=[O:18])=[O:17])[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CS(C)=O>[Cl:12][C:11]1[C:2]([NH:19][S:16]([CH2:13][CH2:14][CH3:15])(=[O:18])=[O:17])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: CCCS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCCS(=O)(=O)Nc1nc2ccccc2nc1Cl
Temperature: 150 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
In DMSO were dissolved 2,3-dichloroquinoxaline (5.00 g, 25.1 mmol) and propane-1-sulfonamide (3.09 g, 25.1 mmol). Potassium carbonate (3.47 g, 25.1 mmol) was added and the mixture was stirred at 150° C. for 1 hour. A 1% aqueous acetic acid solution was added to the reaction mixture and the mixture was stirred at room temperature for 3 hours. The resulting solid was separated by filtration, washed with water, and purified by slurrying in diisopropyl ether to give Compound A1 (6.01 g, 84% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH2:9][C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[N:27][C:22]([NH:1][C:2]2[C:3]([O:19][CH3:20])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH:13]4[CH2:14][CH2:15]4)[CH2:9][C:8](=[O:16])[N:7]([CH3:17])[C:6]=3[CH:18]=2)=[N:23][CH:24]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)N(C)C(=O)CN(CC1CC1)C2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)N(C)C(=O)CN(CC1CC1)C2

Procedure:
The title compound was prepared from 8-Amino-4-cyclopropylmethyl-7-methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to example 730 (0.062 g, 47%) Mp 131-132° C.; LCMS (m/e) 578 (M); 1H-NMR (DMSO, 400 MHz) δ 8.23 (s, 1H), 7.98 (s, 1H), 7.75 (s, 1H), 7.22-7.20 (d, 1H, J=8.59 Hz), 7.03 (s, 2H), 6.88-6.86 (d, 1H, J=7.83 Hz), 3.89 (s, 3H), 3.88-3.80 (m, 1H), 3.55 (d, 2H, J=3.03 Hz), 3.27 (s, 3H), 3.10-3.09 (d, 2H, J=3.82 Hz), 2.89 (s, 3H), 2.41-2.40 (d, 2H, J=6.82 Hz), 2.05-1.92 (m, 2H), 1.68-1.55 (m, 2H), 1.40-1.17 (m, 4H), 1.13-1.97 (m, 1H), 0.90-0.79 (m, 1H), 0.50-0.48 (d, 2H, J=7.83 Hz), 0.170-0.16 (d, 2H, J=4.55 Hz).
Reaction SMILES: C([O:5][C:6](=[O:22])[NH:7][CH:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)[CH:9]([CH:11]1[CH2:13][CH2:12]1)O)(C)(C)C.[H-].[Na+].O>C1COCC1>[CH:11]1([CH:9]2[O:22][C:6](=[O:5])[NH:7][CH:8]2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC(c1ccc(F)c(F)c1)C(O)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1NC(c2ccc(F)c(F)c2)C(C2CC2)O1
Temperature: 35 °C
Reaction time: 3 h
Yield: 100.6 %

Procedure:
To a well stirred solution of [2-cyclopropyl-1-(3,4-difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tert-butyl ester (1.7 g, 5.4 mmol) in THF (20 mL) was added 95% NaH (0.4 g, 16.2 mmol) at room temperature. The resulting suspension was stirred for 3 h at about 35° C. (warm water bath) and then quenched carefully with ice. The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried over Na2SO4, filtered and the solvent was removed in vacuo to yield 5-cyclopropyl-4-(3,4-difluorophenyl)-oxazolidin-2-one (1.3 g, 93% yield) as a 3:1 mixture of the trans:cis diastereomers. The diastereomers were separated by column chromatography over silica gel with 7:3 cyclohexane/ethylacetate as the eluting system. The trans isomer eluted first (Rf=2.5, 0.65 g) followed by the cis isomer (Rf=2.0, 0.2 g). The relative streochemistry was assigned by comparing the 1H NMR of the two isomers of 5-cyclopropyl-4-(3,4-difluorophenyl)-oxazolidin-2-one to the corresponding isomers of 4-(3,4-difluorophenyl)-5-methyl-oxazolidin-2-one as described in Example 19.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C=O)[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C2C=CC=C([CH:28]=[O:29])C=2C=C1.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([CH:28]=[O:29])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(C=O)cc21
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)n1ccc2c(C=O)cccc21

Procedure:
4-Formyl-indole-1-carboxylic acid tert-butyl ester was synthesized by a procedure similar to 6-Formyl-indole-1-carboxylic acid tert-butyl ester from starting materials 1H-Indole-4-carbaldehyde and di-tert-butyl-dicarbonate to yield the product as a clear yellow oil (2 g, 80%). LC-MS (ES) calculated for C14H15NO3, 245.1; found m/z 244 [M−H]−.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2C)=[CH:3]1.[CH3:29][NH:30][CH2:31][CH2:32][OH:33].[CH3:34]N([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[OH:33][CH2:32][CH2:31][N:30]([CH3:29])[C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:34])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:27][CH:26]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: CNCCO
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N(C)CCO)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with 2-(methylamino)ethanol using BOP reagent in tetrahydrofuran to give the title compound as an off-white foam, MS (ESI+): m/z=433.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH3:15][C:16]1[C:20]([CH2:21][N:22]2[CH:26]=[C:25]([NH2:27])[CH:24]=[N:23]2)=[C:19]([CH3:28])[O:18][N:17]=1>>[CH3:15][C:16]1[C:20]([CH2:21][N:22]2[CH:26]=[C:25]([NH:27][C:5](=[O:7])[C:4]3[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:3]=3[O:2][CH3:1])[CH:24]=[N:23]2)=[C:19]([CH3:28])[O:18][N:17]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: COc1ccc(OC)c(C(=O)O)c1
Agent: Cl
Product: COc1ccc(OC)c(C(=O)Nc2cnn(Cc3c(C)noc3C)c2)c1
Yield: 13 %

Procedure:
Prepared as in Example 4-8 from 2,5-dimethoxybenzoic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 13%. MS M+H calculated 357.5, found 357.3.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=4[O:24][CH3:25])=[N:11][C:10]=3[N:9]([CH3:26])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@@H:47]1[CH2:51][CH2:50][O:49][CH2:48]1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.O1CCCC1>[CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([O:23][C@H:47]5[CH2:51][CH2:50][O:49][CH2:48]5)=[CH:19][C:18]=4[O:24][CH3:25])=[N:11][C:10]=3[N:9]([CH3:26])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reactant: O[C@@H]1CCOC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(O[C@H]2CCOC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a 10 ml tetrahydrofuran suspension of 150 ml (0.423 mmol) of the compound obtained in Example 36, 133 mg (0.508 mmol) of triphenylphosphine, 51 μl (0.635 mmol) of (R)-(−)-3-hydroxytetrahydrofuran, and 80 μl (0.508 mmol) of diethyl azodicarboxylate were slowly added at room temperature, and the mixture was stirred at room temperature for 1 hour. Further, 44 mg (0.169 mmol) of triphenylphosphine, 17 μl (0.212 mmol) of (R)-(−)-3-hydroxytetrahydrofuran, and 27 μl (0.169 mmol) of diethyl azodicarboxylate were added, and the mixture was stirred at room temperature for 1.5 hours. Then, the reaction mixture was diluted with ethyl acetate, and the dilution was washed with water and a saturated aqueous solution of sodium chloride in this order. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1˜1/2) to obtain 124 mg (69%) of the captioned compound.
Reaction SMILES: C1C=CC=CC=1.[C:7]1([C:13]2([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:19][C:20]([Cl:25])([Cl:24])[C:21](Cl)=[O:22]>C(N(CC)CC)C>[C:7]1([C:13]2([NH:18][C:21](=[O:22])[C:20]([Cl:25])([Cl:24])[Cl:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC1(c2ccccc2)CCCC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(NC1(c2ccccc2)CCCC1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 200 ml four-necked flask, there were charged benzene (100 ml), 1-phenylcyclopentylamine (8.1 g) and triethylamine (6.1 g), and trichloroacetyl chloride (9.1 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, the reaction mixture was washed with water to remove triethylamine hydrochloride. The benzene layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to give 12.4 g g of N-(1-phenylcyclopentyl)trichloroacetamide. M.P., 114°-115.5° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][N:10]1[C:16]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=2[CH:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]([NH2:28])[CH2:12][C:11]1=[O:29]>C1C=CC=CC=1>[CH3:9][N:10]1[C:16]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=2[CH:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]([N:28]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][C:11]1=[O:29]
Reactant: O=Cc1ccccc1
Reactant: CN1C(=O)CN(N)C(c2ccccc2)c2cc(Cl)ccc21
Solvent: c1ccccc1
Product: CN1C(=O)CN(N=Cc2ccccc2)C(c2ccccc2)c2cc(Cl)ccc21
Yield: 80.7 %

Procedure:
1 ml. (9.1 mmoles) of benzaldehyde is added to a solution of 2.0 g. (6.6 mmoles) of 1-methyl-4-amino-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 20 ml. of benzene, and the mixture is stirred at room temperature overnight. At the end of the reaction the mixture is evaporated to dryness under reduced pressure, the residue is triturated with 20 ml. of ether, and the solid substance is filtered off. 2.1 g. (80.7 %) of 1-methyl-4-benzalamino-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are obtained. M.p.: 157°-158° C. (after recrystallization from ethanol). Rf(4) = 0.7.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][CH2:37][O:38][C:39]1[CH:45]=[C:44]([CH:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH3:54])[CH2:48][CH2:47]2)[CH:43]=[CH:42][C:40]=1[NH2:41].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[CH:43][C:44]([CH:46]4[CH2:47][CH2:48][N:49]([CH2:52][CH2:53][CH3:54])[CH2:50][CH2:51]4)=[CH:45][C:39]=3[O:38][CH2:37][CH3:36])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: CCCN1CCC(c2ccc(N)c(OCC)c2)CC1
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCCN1CCC(c2ccc(Nc3nccc(-c4c(-c5ccc(OC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OCC)c2)CC1
Temperature: 120 °C
Yield: 57.8 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 2-(2-ethyloxy)-4-(1-propyl-4-piperidinyl)aniline (48 mg, 0.18 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (75 mg, 0.104 mmol, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.33 (d, J=6.78 Hz, 1H), 8.41 (s, 1H), 8.26 (d, J=5.13 Hz, 1H), 8.10 (d, J=1.83 Hz, 1H), 7.76 (dd, J=8.52, 1.92 Hz, 1H), 7.64-7.72 (m, 2H), 7.40-7.46 (m, 1H), 7.33-7.40 (m, 1H), 7.26 (d, J=8.61 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.90-6.97 (m, 2H), 6.77 (d, J=8.24 Hz, 1H), 6.61 (d, J=5.31 Hz, 1H), 4.08 (q, J=6.96 Hz, 2H), 3.96 (s, 3H), 2.90-3.01 (m, 2H), 2.39-2.45 (m, 1H), 2.20-2.32 (m, 2H), 1.90-2.02 (m, 2H), 1.70-1.79 (m, 2H), 1.58-1.70 (m, 2H), 1.39-1.50 (m, 2H), 1.27 (t, J=6.96 Hz, 3H), 0.84 (t, J=7.33 Hz, 3H). MS (ESI): 718 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH:20]1[CH2:26][C:25](=O)[O:24][C:22](=[O:23])[CH2:21]1>ClCCl.Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:25]([CH2:26][CH:20]([C:11]3[CH:12]=[CH:13][C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:10]=3)[CH2:21][C:22]([OH:24])=[O:23])[NH:9][C:4]=2[CH:3]=1
Reactant: O=C1CC(c2ccc3ccccc3c2)CC(=O)O1
Reactant: Nc1ccc(Cl)cc1N
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)CC(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
4-Chloro-1,2-phenylenediamine (143 mg) and 3-(2-naphthyl)glutaric anhydride (240 mg) were dissolved in dichloromethane (3 ml) with heating. The dark solution was stirred at rt for 1 h. The precipitate formed was collected by suction filtration, washed with dichloromethane, and dried in vacuo to give a mixture of regioisomeric amides (0.32 g) as brownish solid. This solid was dissolved in 4M HCl in 1,4-dioxane (4 ml) and the dark solution was heated to reflux for 1 h. After removal of the solvent in vacuo the residue was taken up in acetic acid (5 ml), treated with charcoal, and filtered. From the filtrate the solvent was removed and the residue triturated with acetone to give 4-(5-chloro-2-benzimidazolyl)-3-(2-naphthyl)butanoic acid HCl (138 mg) as colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]2[C:26]([NH:27][CH3:28])=[C:25](I)[N:24]=[CH:23][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1.[CH2:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:31]#[CH:32].C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]2[C:26]3[N:27]([CH3:28])[C:31]([CH2:30][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:32][C:25]=3[N:24]=[CH:23][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1
Reactant: CNc1c(I)ncnc1Nc1ccc(Oc2cccc(OC(F)(F)F)c2)c(Cl)c1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1c(CNC(=O)OC(C)(C)C)cc2ncnc(Nc3ccc(Oc4cccc(OC(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 65.3 %

Procedure:
To a solution of N4-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-6-iodo-N5-methylpyrimidine-4,5-diamine (1.53 g), tert-butyl prop-2-ynylcarbamate (0.67 g) and triethylamine (1.19 mL) in acetonitrile (28 mL) were added bis(triphenylphosphine)palladium(II) dichloride (100 mg) and copper(I) iodide (32.5 mg) at room temperature. Under an argon atmosphere, the mixture was stirred at room temperature for 4.5 hrs, heated at 50° C., and the mixture was stirred for 6 hrs. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=7:3→3:7→basic silica gel, hexane:ethyl acetate=1:1→ethyl acetate) to give the title compound (1.05 g) as colorless crystals.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C4CCCCO4)[CH:19]=3)=[C:16]([CH3:31])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:32]C4CCCCO4)[CH:14]=3)[O:9]2)=[CH:4][CH:3]=1.[CH2:39]([NH:41][CH2:42][CH2:43][OH:44])[CH3:40].[F:45][CH2:46][CH2:47][CH2:48]I>>[CH2:39]([N:41]([CH2:48][CH2:47][CH2:46][F:45])[CH2:42][CH2:43][O:44][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=3)=[C:16]([CH3:31])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:32])[CH:14]=3)[O:9]2)=[CH:4][CH:3]=1)[CH3:40]
Reactant: CCNCCO
Reactant: FCCCI
Reactant: CC1=C(c2cccc(OC3CCCCO3)c2)C(c2ccc(I)cc2)Oc2ccc(OC3CCCCO3)cc21
Product: CCN(CCCF)CCOc1ccc(C2Oc3ccc(O)cc3C(C)=C2c2cccc(O)c2)cc1

Procedure:
The title compound was synthesized as described in general procedures F, I and J (z=1) using Intermediate 3 and 2-(ethylamino)ethanol in general procedure F, and 1-fluoro-3-iodopropane in general procedure I. 1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H), 8.94 (s, 1H), 7.19 (d, 2H), 7.13 (t, 1H), 6.78 (d, 2H), 6.76-6.72 (m, 1H), 6.68 (d, 1H), 6.67-6.62 (m, 1H), 6.62-6.60 (m, 1H), 6.48 (s, 2H), 5.84 (s, 1H), 4.50 (t, 1H), 4.39 (t, 1H), 3.91 (t, 2H), 2.72 (t, 2H), 2.58-2.45 (m, 4H), 2.03 (s, 3H), 1.80-1.71 (m, 1H), 1.71-1.65 (m, 1H), 0.93 (t, 3H). LCMS: 478.1 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N+:17]([O-])=O)=[CH:6][CH:5]=1>C(O)C>[NH2:17][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:11]=1[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1cnccc1Nc1ccc(CCO)cc1
Solvent: CCO
Product: Nc1cnccc1Nc1ccc(CCO)cc1
Yield: 98.2 %

Procedure:
4-[4-(2-Hydroxyethyl)phenylamino]-3-nitropyridine (5.18 g) and stannous chloride dihydrate (22.56 g) were suspended in ethanol (100 ml) and heated at reflux for 45 minutes. The mixture was concentrated under vacuum, basified to pH8 with 2M sodium hydroxide solution and then extracted with ethyl acetate (3×200 ml). The combined organic extracts were dried over Na2SO4, filtered and evaporated under vacuum to give the crude product, (4.5 g), which was used directly in the next step.