Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[N:8]1.[N:12]1([C:17]2[CH:45]=[CH:44][C:20]([CH2:21][C:22]3[C:23]([O:42][CH3:43])=[N:24][C:25]4[C:30]([C:31]=3[Cl:32])=[CH:29][C:28]([C:33]([C:35]3[N:39]([CH3:40])[C:38]([CH3:41])=[N:37][CH:36]=3)=[O:34])=[CH:27][CH:26]=4)=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[N:13]1.O>O1CCCC1>[N:12]1([C:17]2[CH:18]=[CH:19][C:20]([CH2:21][C:22]3[C:23]([O:42][CH3:43])=[N:24][C:25]4[C:30]([C:31]=3[Cl:32])=[CH:29][C:28]([C:33]([C:35]3[N:39]([CH3:40])[C:38]([CH3:41])=[N:37][CH:36]=3)([C:11]3[N:7]([CH3:6])[N:8]=[N:9][CH:10]=3)[OH:34])=[CH:27][CH:26]=4)=[CH:44][CH:45]=2)[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: Cn1ccnn1
Reactant: COc1nc2ccc(C(=O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cnnn3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
A solution of n-butyllithium in hexanes (2.5 M, 0.32 mL, 0.81 mmol) was added dropwise to a stirring solution of 1-methyl-1H-1,2,3-triazole (70.4 mg, 0.848 mmol, prepared according to PCT Int. Appl., 2008098104) in tetrahydrofuran (1 mL) at −50° C. After 20 minutes, a solution (gently warmed with a heat gun to dissolve the ketone starting material) of (3-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone (200 mg, 0.42 mmol, Intermediate 21: step b) in tetrahydrofuran (1 mL) was added dropwise. After 5 minutes, the flask was allowed to warm to 23° C. After 20 minutes, water (1 mL) was added. The biphasic mixture was partitioned between saturated aqueous sodium chloride solution (25 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer was dried with sodium sulfate. The dried solution was filtered. Silica gel (2 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash column chromatography purification. Elution with dichloromethane initially, grading to 10% methanol-dichloromethane provided the title compound which was further purified by RP-HPLC eluting initially with 5% acetonitrile-water (containing 0.05% trifluoroacetic acid), grading to 95% acetonitrile-water (containing 0.05% trifluoroacetic acid) to provide the title compound as a white solid after partitioning the purified material between dichloromethane-saturated aqueous sodium bicarbonate solution, separating the layers, drying the organic layer with sodium sulfate, filtering the dried solution, and concentrating the filtrate to dryness. 1H NMR (400 MHz, CDCl3) δ ppm 8.21 (s, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.67 (d, J=1.7 Hz, 1H), 7.60-7.53 (m, 2H), 7.41-7.33 (m, 3H), 7.11 (d, J=1.4 Hz, 1H), 6.46-6.39 (m, 1H), 6.08-6.02 (m, 1H), 4.27 (s, 2H), 4.08 (s, 3H), 3.89 (s, 3H), 3.35 (s, 3H), 2.20 (s, 3H); MS (ESI): mass calcd. for C29H27ClN8O2, 554.2. m/z found, 555.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:18])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:17]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:23]([Cl:38])=[CH:22][N:21]=1.Cl.C(O)(C)C.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>O1CCOCC1>[Cl:38][C:23]1[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[N:25][C:20]([NH:18][C:4]2[C:3]([O:2][CH3:1])=[CH:17][C:7]3[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:21][CH:22]=1
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CC(C)O
Product: COCCN1CCc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)cc2CC1
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
8-Methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (165 mg, 0.000659 mol), N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (220 mg, 0.00066 mol), 4 M of Hydrogen chloride in 1,4-Dioxane (200 uL) and Isopropyl alcohol (6.6 mL, 0.086 mol;) were combined in a microwave vessel. Heat at 130° C. for 20 min. The mixture was treated with 500 mgs of MP-carbonate resin and stirred for 20 min. The mixture was filtered and concentrated and put on high vac overnight. The crude solid was dissolved in DCM and purified on an ISCO column (40 g, SiO2, 100% DCM to MeOH/DCM gradient) to afford N-((1R,2R)-2-{5-Chloro-2-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonam (99 mg, 48%). MP: 92-94° C. 1H-NMR (CDCl3, 400 MHz): 1H-NMR (CDCL3) δ 7.96 (s, 1H), 7.32 (s, 1H), 6.67 (s, 1H), 5.37-5.31 (m, 2H), 3.99-3.95 (broad m, 1H), 3.88 (s, 1H), 3.56 (br s, 2H), 3.38 (s, 1H), 3.28-3.24 (m, 1H), 2.99-2.70 (complex series of m, 11H), 2.26-2.20 (m, 2H), 1.88-1.80 (m, 2H), 1.41-1.28 (m, 6H), 0.92-0.85 (m, 2H); LC/MS: 552.92 (M+H).
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[NH2:14][C@H:15]([C:22]([NH:24][C@H:25]([C:30]([OH:32])=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1.C([BH3-])#N.[Na+]>>[C:3]([CH:2]([NH:14][C@H:15]([C:22]([NH:24][C@H:25]([C:30]([OH:32])=[O:31])[CH2:26][CH:27]([CH3:28])[CH3:29])=[O:23])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:5])=[O:4]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1c[nH]cn1)C(=O)O
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(CCc1ccccc1)C(=O)O)C(=O)O

Procedure:
In the manner described in example 24, one can condense 2-oxo-4-phenylbutyric acid and L-histidinyl-L-leucine in the presence of sodium cyanoborohydride to yield N-(1-carboxy-3-phenylpropyl)-L-histidinyl-L-leucine.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:15]([N:17]1[C:23]2[N:24]=[CH:25][C:26]([CH2:28][CH2:29][OH:30])=[CH:27][C:22]=2[C:21](=[O:31])[N:20]([CH3:32])[C:19]2[CH:33]=[CH:34][CH:35]=[N:36][C:18]1=2)[CH3:16].O[C:38]1[CH:45]=[CH:44][C:41]([CH:42]=[O:43])=[CH:40][C:39]=1[CH3:46].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH2:15]([N:17]1[C:23]2[N:24]=[CH:25][C:26]([CH2:28][CH2:29][O:30][C:38]3[CH:45]=[CH:44][C:41]([CH:42]=[O:43])=[CH:40][C:39]=3[CH3:46])=[CH:27][C:22]=2[C:21](=[O:31])[N:20]([CH3:32])[C:19]2[CH:33]=[CH:34][CH:35]=[N:36][C:18]1=2)[CH3:16]
Reactant: CCN1c2ncc(CCO)cc2C(=O)N(C)c2cccnc21
Reactant: Cc1cc(C=O)ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1c2ncc(CCOc3ccc(C=O)cc3C)cc2C(=O)N(C)c2cccnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
A solution of DIAD (395 μL, 2.15 mmol) in THF (0.8 mL) was added dropwise to a solution of 11-ethyl-5,11-dihydro-8-(2-hydroxyethyl)-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (430 mg, 1.44 mmol), 4-hydroxy-3-methylbenzaldehyde (200 mg, 1.47 mmol) and PPh3 (564 mg, 2.15 mmol) in THF (15 mL) at 25° C. The mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (EtOAc:toluene, 1:3) to yield the title compound (385 mg, 64% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH3:29][C:30]1[NH:31][C:32]2[C:37]([CH:38]=1)=[CH:36][C:35]([Cl:39])=[CH:34][CH:33]=2>>[Cl:39][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:27])([F:26])[F:28])(=[O:17])=[O:18])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=1)[C:30]([CH3:29])=[CH:38]2
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Product: Cc1cc2cc(Cl)ccc2n1Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1
Yield: 71 %

Procedure:
Following the general method as outlined in Example 1 (Method A), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 2-methyl-5-chloroindole, the title compound was isolated as a yellow solid in 71% yield (95% purity by HPLC).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH2:18])[CH:10]=[CH:11][C:12]=3[OH:17])[C:7](=[O:19])[C:6]=2[C:5]([OH:20])=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH:3]=1.OS(O)(=O)=O.NC1C2C(=O)C3C(=C(N)C=C([Cl:51])C=3O)C(=O)C=2C(O)=C(C2C=CC(OC)=CC=2)C=1>O=[Mn]=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH2:18])[C:10]([Cl:51])=[CH:11][C:12]=3[OH:17])[C:7](=[O:19])[C:6]=2[C:5]([OH:20])=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH:3]=1
Reactant: COc1ccc(-c2cc(N)c3c(c2O)C(=O)c2c(N)cc(Cl)c(O)c2C3=O)cc1
Reactant: COc1ccc(-c2cc(N)c3c(c2O)C(=O)c2c(N)ccc(O)c2C3=O)cc1
Agent: O=[Mn]=O
Agent: O=S(=O)(O)O
Product: COc1ccc(-c2cc(N)c3c(c2O)C(=O)c2c(N)c(Cl)cc(O)c2C3=O)cc1
Reaction time: 1 h

Procedure:
A mixture of 2.1 g of 4,8-diamino-1,5-dihydroxy-2-p-methoxyphenylanthraquinone (which can be prepared from 1,5-dihydroxy-4,8-dinitroanthraquinone, for method see German Offenlegungsschrift No. 3,007,198), 32 g of 60% H2SO4, and 3 g of active MnO2 is stirred for 1 hour at 20°, the mixture is filtered and 1 g of NaCl is added to the filtrate, which contains the corresponding quinoneimine. After stirring for half an hour, the mixture is poured into ice-water and the product is filtered off. The crude product is chromatographed over silica gel using petroleum ether/ether mixtures. The main product obtained is 4,8-diamino-6-chloro-1,5-dihydroxy-2-p-methoxyphenylanthraquinone, m.p. 310° (decomposition); Rf 0.41 (silica gel; 3:2 ether/petroleum ether). 4,8-diamino-7-chloro-1,5-dihydroxy-2-p-methoxyphenylanthraquinone, Rf 0.45 (silica gel; 3:2 ether/petroleum ether) is also formed.
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@H:7]([O:9][CH2:10][CH3:11])[C@H:6]([NH:12][C:13]2[C:18]([CH2:19][CH3:20])=[N:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:15]([CH2:29][CH3:30])[N:14]=2)[CH2:5]1)(=[O:3])C.ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H:52]([O:53]CC)CNC2)=NC=1CC.ClC(OC)=O>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[N:17]=[C:18]([CH2:19][CH3:20])[C:13]([NH:12][C@H:6]2[C@@H:7]([O:9][CH2:10][CH3:11])[CH2:8][N:4]([C:1]([O:53][CH3:52])=[O:3])[CH2:5]2)=[N:14][C:15]=1[CH2:29][CH3:30]
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Agent: COC(=O)Cl
Product: CCO[C@H]1CN(C(=O)OC)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine and methyl chloroformate, and making non-critical variations provided the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.34–7.26, 5.20, 4.73, 4.09, 3.95, 3.74, 3.60, 3.50, 3.39, 3.31, 3.26, 2.69, 2.47, 1.32–1.25, 1.15; IR (diffuse reflectance) 2971 (s), 2350 (w), 2341 (w), 2063 (w), 1940 (w), 1921 (w), 1710 (s), 1568, 1551, 1499, 1466 (s), 1452 (s), 1392 (s), 1373, 1102, cm−1; HRMS (FAB) calcd for C22H28Cl2N4O3+H 467.1617, found 467.1619. Anal. Calcd for C22H28Cl2N4O3: C, 56.54; H, 6.04; N, 11.99. Found: C, 56.64; H, 6.27; N, 11.92.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:11])=[CH:6][C:7]=1[C:8]([OH:10])=O)=[O:2].[N:12]1([CH2:17][CH2:18][NH2:19])[CH:16]=[CH:15][N:14]=[N:13]1>>[N:12]1([CH2:17][CH2:18][NH:19][C:8]([C:7]2[CH:6]=[C:5]([CH3:11])[NH:4][C:3]=2[CH:1]=[O:2])=[O:10])[CH:16]=[CH:15][N:14]=[N:13]1
Reactant: NCCn1ccnn1
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Yield: 79 %

Procedure:
2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2.0 g, 13.06 mmol) reacted with 2-[1,2,3]triazol-1-yl-ethylamine (1.76 g, 15.67 mmol) to give 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (2.55 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][C:14]=1[CH3:20])[O:8][CH:7]([C:21]([F:24])([F:23])[F:22])[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:5]2.[CH2:30]([Sn](CCCC)(CCCC)C#C)[CH2:31]CC>C1(C)C=CC=CC=1.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:30]#[CH:31])=[CH:15][C:14]=1[CH3:20])[O:8][CH:7]([C:21]([F:24])([F:23])[F:22])[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(I)cc3C)cc2OC1C(F)(F)F
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C#Cc1ccc(Oc2cc3c(cc2Cl)C=C(C(=O)OCC)C(C(F)(F)F)O3)c(C)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a solution of 0.28 g (0.52 mmol) of ethyl 6-chloro-7-(2-methyl-4-iodophenoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate and 12 mg (0.0104 mmol) of tetrakistriphenylphosphine-palladium in 3.5 mL of anhydrous toluene was added 168 uL (0.586 mmol) of tributyl(ethynyl)tin. The resulting solution was heated to 110° C. and shaken for three hrs. LC-MS indicated that the reaction was complete. After cooling to room temperature, the reaction was quenched with addition of 20% aqueous ammonium fluoride. The product was extracted with ethyl acetate. The organic phase was separated and washed with brine, dried over anhydrous magnesium sulfate. After removing the volatiles, the residues were purified by silica gel chromatography with EtOAc/hexane (1:9). The product was carried on to the next step.
Reaction SMILES: [OH-].[Na+].C([N+](CCCC)(CCCC)CCCC)CCC.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.[NH:31]1[C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([CH:40]=[O:41])[C:34]=2[CH:33]=[CH:32]1>C1C=CC=CC=1>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:31]2[C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([CH:40]=[O:41])[C:34]=3[CH:33]=[CH:32]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)cccc32)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.1 %

Procedure:
150 ml of 50% sodium hydroxide, 4.75 g of tetrabutylammonium hydrogenosulfate and 30.24 g of p-toluene sulfonyl chloride were added to a suspension of 20 g of indole 4-carboxaldehyde in 600 ml of benzene and the mixture was stirred for 90 minutes at ambient temperature. After decanting and extracting with benzene, the extracts were washed with water, dried and evaporated to dryness under reduced pressure. The 42.1 g of residue were dissolved in 210 ml of benzene at reflux, and the solution was allowed to cool to ambient temperature over 16 hours, then separated to obtained 23.96 g of the desired product melting at 144° to 146° C. The product was used as is for the following step.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([F:16])=[C:12]([CH3:15])[CH:13]=3)[C:8]([C:17]([O:19][CH3:20])=[O:18])=[C:7]2B(O)O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:25]1[N:30]=[CH:29][C:28]([S:31]([NH:34][C@@H:35]([CH3:40])[C:36]([F:39])([F:38])[F:37])(=[O:33])=[O:32])=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C(#N)C>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([F:16])=[C:12]([CH3:15])[CH:13]=3)[C:8]([C:17]([O:19][CH3:20])=[O:18])=[C:7]2[C:25]2[CH:26]=[CH:27][C:28]([S:31](=[O:33])(=[O:32])[NH:34][C@@H:35]([CH3:40])[C:36]([F:38])([F:37])[F:39])=[CH:29][N:30]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1c(B(O)O)n(C2CCCC2)c2cc(C)c(F)cc12
Reactant: C[C@H](NS(=O)(=O)c1ccc(Cl)nc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn2)n(C2CCCC2)c2cc(C)c(F)cc12
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A mixture of 1-cyclopentyl-5-fluoro-3-(methoxycarbonyl)-6-methyl-1H-indol-2-ylboronic acid (2.2 mmol), (S)-6-chloro-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (0.53 g, 1.83 mmol), PdCl2dppf (0.15 g, 0.183 mmol), aq. K2CO3 (2.0 M, 3.6 mL, 7.2 mmol) in acetonitrile (10 mL) was stirred at room temperature over the weekend. The mixture was treated with ethyl acetate and washed with water and brine and then concentrated. The residue was purified by flash chromatography with 0-15% ethyl acetate in CH2Cl2 to provide (S)-methyl 1-cyclopentyl-5-fluoro-6-methyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-3-carboxylate (0.52 g, 54%). MS m/z 528.2 M+H+; 1H NMR (500 MHz, CDCl3): δ 9.21 (1H, d, J=1.8 Hz), 8.25 (1H, dd, J=8.2 Hz, J=2.2 Hz), 7.87 (1H, d, J=10.6 Hz), 7.73 (1H, d, J=8.2 Hz), 7.27 (1H, d, J=5.2 Hz), 5.09 (1H, d, J=9.6 Hz), 4.39-4.31 (1H, m), 4.17-4.10 (1H, m), 3.70 (3H, s), 2.44 (3H, d, J=1.8 Hz), 2.41-2.36 (2H, m), 2.20-1.96 (4H, m), 1.67-1.63 (2H, m), 1.45 (3H, d, J=7.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.O[CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:30]4[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]4)=[CH:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: CCN1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCN1CCC(Oc2ccc(C(=O)c3c(-c4ccc(OC)cc4)sc4cc(OC)ccc34)cc2)CC1
Yield: 55 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)benzo[b]thiophene (1.17 g, 3.00 mmol), 4-hydroxy-1-ethylpiperidine (775 mg, 6.00 mmol), triphenylphosphine (1.57 g, 6.00 mmol), and DEAD (6.00 mmol) were converted to product by the procedure of Example 1 to give 827 mg of the title compound. Yield: 55%. MS(FD) 501(M+). EA calculated for C30H31NO4S: C, 71.83; H, 6.23; N, 2.79. Found: C, 71.61; H, 5.94; N, 2.69.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9](Cl)[CH2:10][CH2:11][CH2:12]Cl)([CH3:4])([CH3:3])[CH3:2].O.O.O.O.O.O.O.O.O.[S-2:25].[Na+].[Na+]>CO>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][CH2:12][S:25]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(Cl)CCCCl
Reactant: [S-2]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCC1CCCS1
Reaction time: 5 h
Yield: 100.1 %

Procedure:
A solution of N-tbutoxycarbonyl-2.5-dichloroamylamine 221 (1.75 g, 6.8 mmol) in MeOH (70 mL) was stirred at rt and sodium sulphide nonahydrate (3 g, 12.5 mmol) was added. The mixture was heated at reflux for 1 hour, when TLC indicated that starting material was still present. Further sodium sulphide nonahydrate (1.5 g, 6 mmol) was added and reflux was continued for 5 hours. The MeOH was evaporated and the residue partitioned between water (50 mL) and DCM (100 mL). The layers were separated and the DCM washed with water (20 mL), 0.25 M HCl (20 mL) and brine (20 mL) and dried over MgSO4. Evaporation of the solvents gave 222 as a pale yellow solid (1.48 g, quant.) which was used without further purification.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[S:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=1.[CH3:14]O>CCOC(C)=O>[CH3:14][O:12][C:11]([C:9]1[S:10][C:6]([CH3:5])=[CH:7][CH:8]=1)=[O:13]
Reactant: Cc1ccc(C(=O)O)s1
Reactant: CO
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)s1
Yield: 97 %

Procedure:
Add thionyl chloride (153 ml, 2.1 mol) dropwise over 20 min to a solution of 5-methylthiophene-2-carboxylic acid (100 g, 0.703 mol) in MeOH (1 L) at 0° C. and stir. After the addition is complete, heat the reaction mixture to reflux for 3.5 hours. Cool and concentrate in vacuo to give a thick oil. Dilute the oil with EtOAc (500 ml) and sequentially wash with water (300 ml) then brine (300 ml). Dry the organic layer over sodium sulfate. Remove the solids by filtration. Collect the filtrate and concentrate under reduced pressure to give the title compound (106 g, 97%), which is used without further purification. ESI (m/z) 156(M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].Br[CH2:12][CH2:13]Br>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:9]#[N:10])[CH2:13][CH2:12]1
Reactant: BrCCBr
Reactant: N#CCc1ccccc1Br
Product: N#CC1(c2ccccc2Br)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 1, using (2-bromo-phenyl)-acetonitrile and 1,2-dibromoethane.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([NH:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[N:19]=2)[CH:10]=1.[OH-:26].[Na+].OO>CS(C)=O>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]([NH2:14])=[O:26])=[C:11]([NH:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[N:19]=2)[CH:10]=1
Reactant: Cc1cc(C)nc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)ccc2C#N)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)nc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)ccc2C(N)=O)c1
Temperature: 35 °C
Reaction time: 0.67 h

Procedure:
To a mixture of rel-4-{[(1R,2S)-2-aminocyclohexyl]amino}-2-[(4,6-dimethylpyridin-2-yl)amino]benzonitrile (70 mg, 0.21 mmol) and sodium hydroxide (4.0 M in water, 0.25 mL, 1.0 mmol) in DMSO (2.5 mL) was added hydrogen peroxide (30% aqueous solution, 0.10 mL, 0.98 mmol). The reaction mixture was heated to 35° C. After 40 minutes, the reaction mixture was filtered and purified via reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to give rel-4-{[(1R,2S)-2-aminocyclohexyl]amino}-2-[(4,6-dimethylpyridin-2-yl)amino]benzamide. MS ESI calc'd. for C20H28N5O [M+H]+ 354. Found 354. 1H NMR (300 MHz, CD3OD) δ 7.67 (s, 1H), 7.47 (d, J=8.7 Hz, 1H), 6.55 (m, 2H), 6.21-6.25 (m, 1H), 3.55-3.52 (m, 1H), 3.17 (br s, 1H), 2.37 (s, 3H), 2.22 (s, 3H), 1.77-1.42 (m, 8H).
Reaction SMILES: [CH2:1]=O.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:36])=[C:8]([NH:10][C:11]([C:13]2[N:14]=[CH:15][NH:16][C:17]=2[C:18]([NH:20][C:21]2[NH:25][C:24]3[CH:26]=[C:27]([N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[CH:28]=[CH:29][C:23]=3[N:22]=2)=[O:19])=[O:12])[CH:9]=1.[Na]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:36])=[C:8]([NH:10][C:11]([C:13]2[N:14]=[CH:15][NH:16][C:17]=2[C:18]([NH:20][C:21]2[NH:22][C:23]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:31][CH2:32][N:33]([CH3:1])[CH2:34][CH2:35]4)=[CH:26][C:24]=3[N:25]=2)=[O:19])=[O:12])[CH:9]=1
Reactant: Cc1ccc(Cl)cc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2ccc(N3CCNCC3)cc2[nH]1
Reactant: C=O
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2cc(N3CCN(C)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round-bottom flask was charged with paraformaldehyde (2.0 mmol) and N4-(5-chloro-2-methylphenyl)-N5-(6-(piperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-imidazole-4,5-dicarboxamide (0.2 mmol), anhydrous DMF (5 mL) and sodium triacetoxybrohydride (1.0 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and purified by preparative scale —HPLC (aqueous ammonium acetate/acetonitrile) to give N4-(5-chloro-2-methylphenyl)-N5-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-imidazole-4,5-dicarboxamide. 1H-NMR (400 MHz, MeOH-d4): δ 8.15 (s, 1H), 7.92 (s, 1H), 7.38 (d, 3H), 7.24 (s, 1H), 7.18-7.14 (m, 2H), 6.96 (dd, 1H), 3.35-3.25 (m, 4H), 3.00-2.90 (m, 4H), 2.57 (s, 3H), 2.40 (s, 3H). MS (EI): 493 (MH+).