Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([NH:10]C(=O)OCC)=S.Cl.NO.CC[N:21](C(C)C)C(C)C.C(O)C>CO>[N:7]1[C:8]([NH2:10])=[N:21][N:1]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=12
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1cnccn1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CO
Product: Nc1nc2cnccn2n1
Temperature: 65 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 270a (6.00 g, 26.43 mmol, 1.0 eq.), hydroxylamine hydrochloride (3.32 g, 47.52 mmol, 1.8 eq.), DIPEA (12 mL), ethanol (40 mL), and methanol (40 mL). The reaction mixture was stirred at 65° C. for 16 hours. After the reaction was complete, it was cooled to room temperature and concentrated to a volume of around 20 mL under reduced pressure. The resulting suspension was collected by filtration and the solid was washed with 60:1 dichloromethane/ethanol (50 mL) to afford 270b (3.3 g, 92%) as a white solid. MS-ESI: [M+H]+ 136.3. 1H NMR (500 MHz, DMSO-d6) δ 8.84 (d, J=1.0 Hz, 1H), 8.70 (dd, J=1.0, 4.0 Hz, 1H), 7.98 (d, J=5.0 Hz, 1H), 6.47 (s, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:26]2)[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:26]2)=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)N[C@@H]1CCC[C@@H](Nc2nc(Cl)ncc2Cl)C1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCC[C@@H](NS(C)(=O)=O)C4)n3)cc2CC1

Procedure:
rel-N-((1R,3R)-3-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and rel-N-[(1R,3R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a white foam (113 mg, 63%). LCMS (m/e) 523 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.92 (s, 1H), 7.37 (d, 1H, J=8.1 Hz), 7.23 (s, 1H), 7.07 (d, 1H, J=8.1 Hz), 6.85 (s, 1H), 5.11 (d, 1H, J=7.4 Hz), 4.37 (d, 1H, J=6.7 Hz), 4.36-4.26 (m, 1H), 3.84-3.75 (m, 1H), 3.56 (t, 2H, J=5.7 Hz), 3.39 (s, 3H), 2.98-2.87 (m, 4H), 2.93 (s, 3H), 2.81-2.68 (m, 6H), 2.04-1.91 (m, 2H), 1.91-1.79 (m, 2H), 1.79-1.65 (m, 3H), 1.58-1.47 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:21])=[N:8][C:9]([NH2:20])=[C:10]([N+:17]([O-])=O)[C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:5])[CH3:2]>[Zn].C(O)(=O)C>[NH2:17][C:10]1[C:11]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7]([CH3:21])=[N:8][C:9]=1[NH2:20]
Reactant: CCCCNc1c(C(=O)OCC)c(C)nc(N)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCCNc1c(N)c(N)nc(C)c1C(=O)OCC
Reaction time: 0.17 h

Procedure:
29.6 g. of 6-amino-4-butylamino-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester are dissolved in 150 ml. of acetic acid. The solution is heated at reflux temperature. Zinc is added carefully until the mixture is colorless (about 20 g.). Heating is continued for an additional 10 minutes. The mixture is then evaporated to dryness and about 100 ml. of water are added. The solution is then neutralized with aqueous ammonia and extracted three times with 100 ml. portions of ether. The ether extracts are combined, dried with calcium chloride and the solvent is evaporated. The oily residue of 5,6-diamino-4-butylamino-2-methylnicotinic acid, ethyl ester crystallizes from methanol, yield: 21 g. (79%), m.p. 82°-83° (methanol/H2O).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([NH:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)[CH2:20][CH2:19]2)=[O:14])=[C:6]([CH:12]=1)[O:7][CH2:8][C:9](O)=[O:10].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:45][CH:46]([CH3:49])[CH2:47][OH:48].O>CN(C)C=O.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([NH:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)[CH2:20][CH2:19]2)=[O:14])=[C:6]([O:7][CH2:8][C:9]([NH:45][CH:46]([CH3:49])[CH2:47][OH:48])=[O:10])[CH:12]=1
Reactant: O=C(O)COc1cc(Cl)ccc1C(=O)NCCN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: CC(N)CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CC(CO)NC(=O)COc1cc(Cl)ccc1C(=O)NCCN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 60 °C

Procedure:
The product of Example 2 (0.3 g) was dissolved in N,N-dimethylformamide (3 ml). 1,1′-Carbonyldiimidazole (0.1 g) and 2-amino-1-propanol (5 molar equivalents) were added, the solution heated at 60° C. for 1.5 hours and cooled. Water and ether were added, the organic phase separated and concentrated to a gum which was purified by chromatography (dichloromethane:methanol, 9:1) to give the product as a solid (0.15 g), m.p. 115-116° C.
Reaction SMILES: [ClH:1].C[O:3][C:4](=[O:31])[C@H:5]([CH2:14][C:15]1[N:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([CH3:30])[CH:22]=2)[CH:18]=[N:17][CH:16]=1)[NH:6]C(OC(C)(C)C)=O>>[ClH:1].[ClH:1].[CH3:30][C:23]1[CH:22]=[C:21]([CH2:20][N:19]2[C:15]([CH2:14][C@@H:5]([C:4]([OH:31])=[O:3])[NH2:6])=[CH:16][N:17]=[CH:18]2)[CH:26]=[CH:25][C:24]=1[N+:27]([O-:29])=[O:28]
Reactant: COC(=O)[C@H](Cc1cncn1Cc1ccc([N+](=O)[O-])c(C)c1)NC(=O)OC(C)(C)C
Agent: Cl
Product: Cc1cc(Cn2cncc2C[C@H](N)C(=O)O)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 92.9 %

Procedure:
A 6N hydrochloric acid solution (54.5 ml) was added to 3-(3-methyl-4-nitrophenyl)methyl-N-t-butoxycarbonyl-L-histidine methyl ester (IX-2) (1.3626 g, 0.00326 mol), and the mixture was refluxed under heating on a 120° C. oil bath for 2.5 hours. The resulting solution was cooled and then concentrated to obtain the objective compound (VIII-2) (1.1406 g; yield: 92.9%) as a light-brown oily material.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:7]=2)=[N:2]1.Cl[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[O:51][CH3:52].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:52][O:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[CH2:44][N:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[CH:7]=2)=[N:2]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc[nH]n3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1Cn1ccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)n1
Temperature: 75 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
(S)-2-(1-((5-(1H-Pyrazol-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (2.0 ml). 1-(Chloromethyl)-2-methoxybenzene (43 ml, 0.27 mmol) and cesium carbonate (200 mg, 0.61 mmol) were added and the mixture was stirred at 75° C. during 2 h. The reaction was poured into ice-water mixture, basified to pH 10 with sodium carbonate and extracted twice with ethyl acetate. The organics were combined and washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 30%, hexane-ethyl acetate) to give 86 mg (83% yield, 93% purity) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:32](Cl)=[O:33])=[CH:31][C:26]=2[O:25][CH2:24]1>C(OCC)(=O)C.CCCCCC>[CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH:20][C:32]([C:30]3[CH:29]=[CH:28][C:27]4[O:23][CH2:24][O:25][C:26]=4[CH:31]=3)=[O:33])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(C2c3c(C)c(NC(=O)c4ccc5c(c4)OCO5)c(C)c(C)c3OC2(C)C)cc1
Yield: 65 %

Procedure:
By using 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine and 1,3-benzodioxol-5-carbonyl chloride, the title compound was synthesized according to Example 1b. Yield: 65%. Melting point: 164-165° C. (Ethyl acetate-hexane).
Reaction SMILES: [C:1]([Si:18](C)([CH3:25])[O:19][N-:20][C:21]([CH3:24])([CH3:23])[CH3:22])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[NH:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30].C(#N)C.N1CCCCC1.C(Cl)Cl>CO>[C:21]([N-:20][O:19][SiH:18]([CH3:25])[CH3:1])([CH3:24])([CH3:23])[CH3:22].[NH:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30]
Reactant: CC(C)(C)[N-]O[Si](C)(C)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C(O)[C@@H]1CCCN1
Solvent: C1CCNCC1
Solvent: CO
Solvent: ClCCl
Product: C[SiH](C)O[N-]C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To the thus-obtained Fmoc-t-butyl-dimethyl siloxy amide-L-proline (Compound 18) (1.18 g, 2.5 mmol), anhydrous acetonitrile (5 ml) and piperidine (2.4 ml) were added, and this was stirred for 1 hour at room temperature. After the completion of the reaction, acetonitrile (50 ml) was added to the mixture, and insoluble matters were removed by filtration. The solvent in the filtrate obtained was removed by evaporation under reduced pressure. The residual substance obtained was applied to silica gel column chromatography (the eluent: CH2Cl2: CH3OH=9:1). Thus, Compound 19 in the form of colorless syrup was obtained (0.61 g, yield: 90%). The result of NMR analysis with respect to this compound is shown below.
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:12]2[N:13]=[CH:14][N:15]=[CH:16][C:11]=2[C:10]([C:17](=[O:19])[CH3:18])=[CH:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:17]([C:10]1[C:11]2[CH:16]=[N:15][CH:14]=[N:13][C:12]=2[N:8]([CH2:7][C:6]([OH:20])=[O:5])[CH:9]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)c1cn(CC(=O)OC(C)(C)C)c2ncncc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cn(CC(=O)O)c2ncncc12

Procedure:
A solution of (5-acetyl-pyrrolo[2,3-d]pyrimidin-7-yl)-acetic acid tert-butyl ester (146 mg, 0.53 mmol) and TFA (0.814 mL, 10.62 mmol) in CH2Cl2 (2.5 mL) was stirred at RT for 24 h. Solvents were removed under reduced pressure and the material thus obtained was used without further purification in the next step. 1H-NMR (400 MHz, DMSO): δ (ppm): 9.45 (s, 1H), 9.0 (s, 1H), 8.68 (s, 1H), 7.66-7.56 (m, 2H), 5.16 (s, 2H), 2.53 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]=2[Se:4][NH:3]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([N:3]1[C:2]([CH3:14])([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]=2[Se:4]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)N[Se]c2c([N+](=O)[O-])cccc21
Solvent: c1ccncc1
Product: CC(=O)N1[Se]c2c([N+](=O)[O-])cccc2C1(C)C
Yield: 93 %

Procedure:
The 3,3-dimethyl-7-nitrobenzisoselenazoline described in Example 1 (130 mg, 0.5 mmol) is treated with 1 ml of acetic anhydride and 1 ml of pyridine at 60° C. for 1.5 hours. The mixture is then evaporated to dryness. The residue is triturated with a mixture of ethyl acetate and cyclohexane (1:2). The red solid is filtered and rinsed to provide the expected amide (140 mg, 93%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([OH:15])=O)=[N:5][CH:4]=1)=[O:2].[NH2:16][C@@H:17]([CH3:38])[C:18]([NH:20][C@@H:21]([CH3:37])[C:22]([NH:24][C@@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:26]([NH2:28])=[O:27])=[O:23])=[O:19].C(O)(C(F)(F)F)=O.ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C.CO>[NH2:28][C:26](=[O:27])[C@@H:25]([NH:24][C:22](=[O:23])[C@@H:21]([NH:20][C:18](=[O:19])[C@@H:17]([NH:16][C:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][N:5]=1)=[O:15])[CH3:38])[CH3:37])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1
Reactant: O=Cc1cnc(N2CCC[C@H]2C(=O)O)s1
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Agent: On1nnc2cccnc21
Solvent: CO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1c1ncc(C=O)s1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 63 %

Procedure:
To a solution of material from Example 80 (25 mg, 0.110 mmol), (S)-2-amino-N-((S)-1-((S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-ylamino)-1-oxopropan-2-yl)propanamide, TFA (25 mg, 0.057 mmol), and 1-hydroxy-7-azabenzotriazole (4 mg, 0.029 mmol) in anhydrous DMF (2 mL) is added sequentially EDC (12 mg, 0.063 mmol), followed by N-methylmorpholine (40 μl, 0.364 mmol). The resulting solution is stirred at room temp for 45 min, diluted with MeOH (5 mL) and purified by preparative HPLC (Condition A) using a PHENOMENEX® Luna Axia 30×100 mm S10 column from 15% Solvent B to 85% Solvent B over 11 min, ret. T=5.9 min. The fractions containing the desired product were evaporated to dryness to give 23 mg (63%) of the title compound as a white solid as a TFA salt. LC/MS (Condition A): ret. T=2.04 min, (M+H)+ 531.27.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]1[C:11]([CH2:12]Br)=[CH:10][CH:9]=[CH:8][C:7]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22].O>CS(C)=O>[CH3:4][O:5][C:6]1[C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:8][CH:9]=[CH:10][C:11]=1[CH2:12][C:1]#[N:2]
Reactant: COc1ccccc1Oc1cccc(CBr)c1OC
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1Oc1cccc(CC#N)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
Powdered Potassium cyanide (2.50 g) was added to a solution of 2-methoxyphenyl 2-methoxy-3-bromomethylphenyl ether (12.0 g) in dimethylsulfoxide (100 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and then evaporated. The resultant oily residue (9.80 g) was subjected to column chromatography on silica gel and eluted with a mixture of benzene and hexane (1:1). The eluate was evaporated to give oily 2-[2-methoxy-3-(2-methoxyphenoxy)phenyl]acetonitrile (6.20 g).
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16](B(O)O)=[CH:17][CH:18]=[CH:19][CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:15]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=1[C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: Cc1cccc2cc(CO)c(Cl)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cccc2cc(CO)c(-c3ccccc3-c3ccccc3)nc12
Temperature: 120 °C
Yield: 27 %

Procedure:
A mixture of (2-chloro-8-methylquinolin-3-yl)methanol (342 mg, 1.65 mmol), 2-biphenylboronic acid (392 mg, 1.98 mmol) and K3PO4 (399 mg, 1.88 mmol) in DME (4 mL) and water (1 mL) was degassed. Pd(PPh3)4 (95 mg, 0.08 mmol) was added, the mixture was degassed and heated in the microwave at 120° C. for 1 h. The reaction mixture was allowed to cool and extracted with EtOAc (150 mL). The organic layer was washed with water (50 mL), separated, dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (SiO2, 0-100% EtOAc in heptane) gave the title compound (145 mg, 27%) as a white crystalline solid. δH (MeOD-d4) 8.19 (s, 1H), 7.71 (d, J 8.1 Hz, 1H), 7.40-7.66 (m, 6H), 7.15-7.20 (m, 2H), 7.08-7.12 (m, 3H), 4.30-4.40 (br m, 1H), 4.11-4.22 (br m, 1H), 2.70 (s, 3H). LCMS (ES+) 326.3 (M+H)+, RT 3.98 minutes (Method 3).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:14]=2[NH:13][C:12]([C:15](=[S:17])[NH2:16])=[CH:11]3)[CH2:3][CH2:2]1.Br[CH:27]([CH:30]=O)[CH:28]=[O:29].CN(C)C(=O)C>O>[CH:1]1([CH2:4][N:5]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:14]=2[NH:13][C:12]([C:15]2[S:17][C:27]([CH2:28][OH:29])=[CH:30][N:16]=2)=[CH:11]3)[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:20])[CH2:3][CH2:2]1
Reactant: NC(=S)c1cc2cccc(N(CC3CC3)S(=O)(=O)c3cccs3)c2[nH]1
Reactant: O=CC(Br)C=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=S(=O)(c1cccs1)N(CC1CC1)c1cccc2cc(-c3ncc(CO)s3)[nH]c12
Temperature: 90 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
A mixture of 7-[(cyclopropylmethyl)(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (225 mg), bromomalonaldehyde (182 mg) and N,N-dimethylacetamide (3 mL) was stirred at 90° C. for 1 hr. Water was added and the obtained precipitate was washed with water, and then with hexane. The solid was dissolved in a mixture of tetrahydrofuran (5 mL) and methanol (5 mL), and the mixture was cooled in an ice bath. Sodium borohydride (20 mg) was added and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated, and the residue was diluted with a mixture of tetrahydrofuran-ethyl acetate (1:1) and washed with saturated brine and aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtrated, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography and eluted with a mixture of ethyl acetate-hexane. The obtained solid was washed with a mixture of hexane-ether to give the title compound (100 mg, yield 50%) as crystals. melting point 174° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][C:16]=3[O:30][CH3:31])=[O:13])=[N:8][NH:9]2)=[CH:5][CH:4]=1.Br[C:33]1[N:34]=[C:35]([C@H:43]2[CH2:48][CH2:47][C@H:46]([N:49]3[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]3)[CH2:45][CH2:44]2)[N:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[C:37]=12>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:33]4[N:34]=[C:35]([C@H:43]5[CH2:44][CH2:45][C@H:46]([N:49]6[CH2:50][CH2:51][N:52]([CH3:55])[CH2:53][CH2:54]6)[CH2:47][CH2:48]5)[N:36]5[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[C:37]=45)=[CH:17][C:16]=3[O:30][CH3:31])=[O:13])=[N:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Reactant: COc1ccc2c(C(=O)Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3OC)n[nH]c2c1
Product: COc1ccc2c(C(=O)Nc3ccc(-c4nc([C@H]5CC[C@H](N6CCN(C)CC6)CC5)n5ccnc(C)c45)cc3OC)n[nH]c2c1

Procedure:
6-Methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indazole-3-carboxamide (28 mg) and 1-bromo-8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (26 mg) were reacted according to the procedure described in example 4 step 4c and purified by prep-HPLC (column Luna C18(2); gradient acetonitrile/water with constant 0.003M trifluoroacetic acid). Proper fractions were collected and made basic with aqueous sodium hydrogencarbonate, extracted with dichloromethane, organic layer dried (Na2SO4) and concentrated in vacuo to give 6-methoxy-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1H-indazole-3-carboxamide (7.5 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])[N:3]=1.N1C(C)=CC=CC=1C.[Cl:20][C:21]1[CH:22]=[C:23]([C@@H:31]([CH2:35][C@H:36]2[CH2:40][CH2:39][C:38](=[O:41])[CH2:37]2)[C:32](Cl)=[O:33])[CH:24]=[CH:25][C:26]=1[S:27]([CH3:30])(=[O:29])=[O:28]>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([C@@H:31]([CH2:35][C@H:36]2[CH2:40][CH2:39][C:38](=[O:41])[CH2:37]2)[C:32]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][C:8]([OH:10])([CH3:11])[CH3:9])[N:3]=2)=[O:33])[CH:24]=[CH:25][C:26]=1[S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)c1ccc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Cl)cc1Cl
Reactant: CC(C)(O)Cn1ccc(N)n1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
In a round bottom flask was placed 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 35 mg, 0.22 mmol), 2,6-lutidine (35 μL, 0.30 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionyl chloride in methylene chloride (˜0.10 M solution, 2 mL, 0.20 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 50% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-propionamide (88 mg, 91%) as a white foam: [α]30589=−79.0° (c=0.10, methylene chloride); ES-HRMS m/e calcd for C22H28N3O5SCl (M+H)+ 482.1511, observed 482.1511; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.50 (m, 1H, CH), 1.79-2.29 (m, 8H, 4×CH2), 3.34 (s, 3H, SO2CH3), 3.87 (s, 2H, NCH22), 3.96 (m, 1H, ArCHCO), 4.65 (s, 1H, OH), 6.45 (d, J=1.7 Hz, 1H, Ar), 7.51 (d, J=1.7 Hz, 1H, Ar), 7.62 (d, Jo=8.0 Hz, 1H, Ar), 7.73 (s, 1H, Ar), 8.02 (d, Jo=8.0 Hz, 1H, Ar), 10.85 (s, 1 H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]([N+:17]([O-:19])=[O:18])=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].[CH:20]1(N)[CH2:22][CH2:21]1.O>ClCCCl>[Cl:1][C:2]1[CH:13]=[C:12]([NH:14][CH:20]2[CH2:22][CH2:21]2)[C:11]([N+:17]([O-:19])=[O:18])=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(NC1CC1)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc1Cl
Reactant: NC1CC1
Solvent: O
Solvent: ClCCCl
Product: O=C(NC1CC1)c1cc([N+](=O)[O-])c(NC2CC2)cc1Cl

Procedure:
2.00 g (5.95 mmol) of 2-chloro-N-cyclopropyl-4,5-dinitrobenzamide (see Synthesis Example 4, Stage 1) were initially charged in 150 ml of 1,2-dichloroethane, 0.85 g (14.88 mmol) of cyclopropylamine was added and the mixture was heated under reflux for three hours. After cooling, water was added and the 2-chloro-N-cyclopropyl-4-(cyclopropylamino)-5-nitrobenzamide was filtered off with suction and dried. Yield 1.16 g (66% of theory)