Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([N:12]3[CH2:17][C@@H:16]4[CH2:18][C@H:13]3[CH2:14][N:15]4C(OC(C)(C)C)=O)[CH:9]=[N:10][CH:11]=2)=[CH:2]1.FC(F)(F)C(O)=O.[OH-].[Na+]>C1(OC)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([N:12]3[CH2:17][C@@H:16]4[CH2:18][C@H:13]3[CH2:14][NH:15]4)[CH:9]=[N:10][CH:11]=2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cncc(-c2ccsc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: c1cc(-c2cncc(N3C[C@@H]4C[C@H]3CN4)c2)cs1
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a stirred solution of (1S,4S)-5-(5-(3-thienyl)-3-pyridyl)-2-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptane (0.63 g, 1.4 mmol) in anisole (3.0 mL) at 0-5° C. under a nitrogen atmosphere, trifluoroacetic acid (2.0 mL, 26 mmol) was added dropwise over a 10 min period. After 0.5 h at 25° C., the solution was adjusted to pH 5 using 10% NaOH, followed by extraction with diethyl ether (1×15 mL) to remove the anisole. The aqueous portion was adjusted to pH 11 using 10% NaOH, followed by extraction with diethyl ether (3×25 mL). The combined diethyl ether extracts were dried (Na2SO4) filtered and concentrated under vacuum. Purification of the residue by column chromatography on silica gel, using chloroform:methanol:triethylamine (40:5:1) as eluent, gave a light yellow oil (124 mg, 34%).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:11]2[O:15][N:14]=[C:13]([CH3:16])[N:12]=2)[O:4]CC1.Cl>O1CCCC1>[CH3:16][C:13]1[N:12]=[C:11]([CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]2=[O:4])[O:15][N:14]=1
Reactant: Cc1noc(C2CCCCC23OCCO3)n1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1noc(C2CCCCC2=O)n1
Temperature: 60 °C
Reaction time: 13 h
Yield: 20.3 %

Procedure:
A mixture of 5-(1,4-dioxa-spiro[4.5]dec-6-yl)-3-methyl-[1,2,4]oxadiazole (0.67 g, 3.0 mmol), tetrahydrofuran (70 mL), and 3 N hydrochloric acid (35 mL) was stirred at 60° C. for 13 h. The mixture was cooled and extracted with ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate solution and with brine, dried over sodium sulfate, and evaporated under reduced pressure. The remaining solid was recrystallized from heptane to give the title compound (0.11 g, 20%) as an off-white solid. MS ISP (m/e): 181.1 [(M+H)+]. mp 74-76° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([S:15][CH:16]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([S:15][CH:16]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:17][C:18]([OH:20])=[O:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(SC(CCCCc2ccccc2)CC(=O)OC(C)(C)C)cc1OC1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(SC(CCCCc2ccccc2)CC(=O)O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
A stirred solution of (±)-t-butyl 3-(3-cyclopentyloxy-4-methoxyphenyl)sulfanyl-7-phenylheptanoate [0.5 g, Reference Example 1(a)] in dichloromethane (20 ml), at 0° C., was treated with trifluoroacetic acid (4 ml). The solution was allowed to warm to room temperature and then stirred for 18 hours. The reaction mixture was evaporated and the brown residue subjected to flash chromatography on silica eluting with a mixture of petroleum ether and ethyl acetate (1:1, v/v) to give the title compound (0.4 g) as a colourless oil. NMR (CDCl3): δ1.60 (m,8H), 1.90 (m,6H), 2.60 (m,4H), 3.28 (m,1H), 3.82 (s,3H), 4.74 (m,1H), 6.78 (d,1H), 7.00-7.38 (m,7H). Mass spectrum (FAB): m/z 428 M+.
Reaction SMILES: [C:1]([O:5][NH:6][C:7](=[O:44])[C@@H:8]([NH:26][C:27](=[O:43])[C@H:28]([CH:40]([CH3:42])[CH3:41])[NH:29]C(OCC1C=CC=CC=1)=O)[CH2:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])([CH3:4])([CH3:3])[CH3:2]>CO.C(O)C.[Pd]>[C:1]([O:5][NH:6][C:7](=[O:44])[C@@H:8]([NH:26][C:27](=[O:43])[C@H:28]([CH:40]([CH3:41])[CH3:42])[NH2:29])[CH2:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:15][CH:14]=1)(=[O:11])=[O:12])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NOC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CC(C)[C@H](N)C(=O)N[C@@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NOC(C)(C)C

Procedure:
A solution of (R)-N-tert-butoxy-2-(CBZ-valinamido)-3-(4-phenoxyphenylsulfonyl)-propionamide (prepared above) in a mixture of methanol (300 ml) and ethanol (100 ml) was stirred under hydrogen at 1 atmosphere with palladium on carbon catalyst (10% Pd, 4 g) for 3 hours. The mixture was filtered, and the filtrate evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with 0-3% methanol in methylene chloride, to give (R)-N-tert-butoxy-2-valinamido-3-(4-phenoxyphenylsulfonyl)-propionamide (1.6 g).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=3)=[N:10][C:11]([S:15][CH3:16])=[N:12]2)=[C:7]([NH2:25])[C:6]=1[C:26]([NH2:28])=[O:27])([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)=[N:10][C:11]([S:15][CH3:16])=[N:12]2)=[C:7]([NH2:25])[C:6]=1[C:26]([NH2:28])=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(-c2nc(SC)nc3cc(C(C)(C)C)c(C(N)=O)c(N)c23)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CSc1nc(-c2cccc(O)c2)c2c(N)c(C(N)=O)c(C(C)(C)C)cc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyl 5-amino-2-methylthio-4-(3-methoxyphenyl)-quinazoline-6-carboxamide (example 25f, 1.5 g) in dry CH2Cl2 was cooled to 0° C. A solution of BBr3 (1.1 ml) in CH2Cl2 (25 ml) was added dropwise and after the addition was complete, the mixture was stirred for 3 h at room temperature. The mixture was diluted with CH2Cl2 and a saturated aqueous NaHCO3 solution (200 ml) was carefully added. The mixture was vigorously stirred for 1.5 h until all solids dissolved. The aqueous layer was extracted twice with CH2Cl2. The first organic layer was washed with sat. aq. NaHCO3 and brine. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The title compound was purified by chromatography on silica gel with hept/EtOAc=1/0 to 1/1 (v/v) as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[B:9]([OH:11])[OH:10].O[C:13]([C:16](O)([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[B:9]1[O:10][C:16]([CH3:18])([CH3:17])[C:13]([CH3:15])([CH3:14])[O:11]1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OB(O)c1cc(O)ccc1Cl
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2cc(O)ccc2Cl)OC1(C)C
Temperature: 120 °C
Yield: 82.9 %

Procedure:
2-chloro-5-hydroxyphenyl boronic acid (409 mg, 2.37 mmol), pinacol (336 mg, 2.85 mmol), toluene (20 ml) and 4 angstrom molecular sieves (400 mg) were combined and heated at 120° C. for 2 h. The reaction mixture was allowed to cool and was then partitioned between EtOAc (2×30 ml) and water (30 ml). The combined organics were washed with brine (20 ml), dried (Na2SO4) and evaporated in vacuo to afford the desired product as a white solid (500 mg, 83%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH:13][CH2:14][CH2:15][CH2:16][OH:17])([O-])=O>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1NCCCO
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc(N)c1NCCCO
Temperature: 25 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
Under hydrogen gas atmosphere, a mixture of 3-[(2,6-dinitrophenyl)amino]propan-1-ol (Reference Example 114; 17.7 g, 73.3 mmol), 10% palladium on carbon (50% wet, 3.5 g) and tetrahydrofuran (360 mL) was stirred at room temperature for 6 hr. The reaction mixture was filtered and concentrated in vacuo to give the title compound as an oil (12.1 g, 66.7 mmol, 91%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:17]4[CH2:23][CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32]>C(Cl)Cl>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:17]4[CH2:23][CH2:22][N:21]([C:34]([NH:33][CH2:31][CH3:32])=[O:35])[CH2:20][C:18]=4[N:19]=3)=[CH:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: CCN=C=O
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CCNC2
Solvent: ClCCl
Product: CCNC(=O)N1CCc2c(nc(-c3ccc(NC(=O)NC4CC4)cc3)nc2N2CCOC[C@@H]2C)C1
Reaction time: 5 h
Yield: 33.4 %

Procedure:
To a solution of (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (example 15) (102 mg, 0.25 mmol) in DCM (3 mL) at room temperature (20° C.) was added ethyl isocyanate (32 uL, 0.27 mmol). The reaction mixture was stirred for 5 h. The solvent was removed in vacuo and the residue purified by prep HPLC (low pH) to afford an orange solid (40 mg, 33%).
Reaction SMILES: [CH2:1]([P:5](Cl)([CH2:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH:2]([CH3:4])[CH3:3].[CH2:12]([Mg]Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl>O1CCCC1>[CH2:1]([P:5](=[O:6])([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCCCC[Mg]Br
Reactant: CC(C)CP(=O)(Cl)CC(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCP(=O)(CC(C)C)CC(C)C
Temperature: 25 °C

Procedure:
A solution of di-isobutylphosphinyl chloride* (3.9g., 0.02 mole) in tetrahydrofuran (50 ml.) was added dropwise to a refluxing solution of n-heptylmagnesium bromide (prepared from magnesium turnings (1.2g., 0.05 mole), n-heptyl bromide (9.0g., 0.05 mole) and tetrahydrofuran (100 ml.)). The mixture was heated under reflux for 18 hours. After cooling to room temperature, the reaction mixture was poured onto ice and 2N HCl (300 ml.), and extracted with methylene dichloride (4 × 200 ml.). The combined extracts were washed with lithium hypochlorite solution, 2N NaOH solution and finally with water, then dried (MgSO4). The solvent was removed by distillation and the residual yellow oil (8g.) was eluted with chloroform down a silica gel column. The product (Rf = 0.1- 0.2 on silica t.l.c. (CHCl3)) was finally distilled to yield diisobutyl-n-heptyl-phosphine oxide as a colourless liquid, bp. 120°-2°/0.03 mm. (Found C 68.8; H 13.0; C15H33OP requires C 69.3; H, 12.7%.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH:22]1[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23]1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([N:22]3[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:23]3)[CH:3]=2)=[N:13][C:14]=1[O:20][CH3:21]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: COc1ccc(Nc2cc(Cl)nn3ccnc23)nc1OC
Product: COc1ccc(Nc2cc(N3CCC(NC(=O)OC(C)(C)C)C3)nn3ccnc23)nc1OC
Temperature: 160 °C
Yield: 8.1 %

Procedure:
A suspension of 6-chloro-N-(5,6-dimethoxypyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (1.5 g, 4.9 mmol) and tert-butyl pyrrolidin-3-ylcarbamate (3 g, 16 mmol) was heated to 160° C. for 2 h. The residue was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH=30:1) to give tert-butyl 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ylcarbamate (180 mg, 8%) as off-white solid. LC-MS: 456 [M+1]+, tR=1.396 min
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13]CC2)CCCCC1.CO.Cl[CH2:19]Cl>ClCCl>[CH3:19][N:7]([C:8]1[CH:13]=[CH:14][CH:15]=[CH:10][N:9]=1)[CH3:1]
Reactant: ClCCl
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Product: CN(C)c1ccccn1

Procedure:
Compound 23 was dissolved in dichloromethane (c. 3 mg/ml) and was treated with dicyclohexylcarbodiimide (5 equivalents), a catalytic amount of dimethylaminopyridine, and compound 11 to give after chromatography (silica, 10% methanol/dichloromethane) compound 24.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[C:23]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16](=[N:24]O)[C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:8][C:7]=2[CH:26]=1>[Ni].C(O)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[C:23]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH:16]([NH2:24])[C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:8][C:7]=2[CH:26]=1
Reactant: COc1ccc2nc(-c3cccc4c3-c3ccccc3C4=NO)[nH]c2c1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2nc(-c3cccc4c3-c3ccccc3C4N)[nH]c2c1
Yield: 73.1 %

Procedure:
Carry out the procedure as in Example 6, starting from 900 mg of 4-(6-methoxy-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the preceding stage, and 1.55 mg of Raney Nickel in 50 ml of ethanol and 50 ml of tetrahydrofuran for 16 hours at 60° C. under a hydrogen pressure of 1 bar. After purification by making a paste in diisopropyl ether, we obtain 631 mg of 4-(6-methoxy-1H-benzimidazol-2-yl)-9H-fluoren-9(R,S)-ylamine, in the form of a brown powder, with the following characteristics:
Reaction SMILES: [CH3:1][N:2]([C@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])[C:3]1[C:4](OS(C(F)(F)F)(=O)=O)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=2.CC1(C)C(C)(C)OB([C:41]2[CH:42]=[C:43]3[C:47](=[CH:48][CH:49]=2)[N:46](C(OC(C)(C)C)=O)[N:45]=[CH:44]3)O1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[NH:46]1[C:47]2[C:43](=[CH:42][C:41]([C:4]3[C:3]([N:2]([CH3:1])[C@H:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH3:26])=[N:12][C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=4)[N:5]=3)=[CH:49][CH:48]=2)[CH:44]=[N:45]1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)[C@@H](C)c3ccccc3)nc2c1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N(C)[C@@H](C)c3ccccc3)nc2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of (S)-methyl 3-(methyl(1-phenylethyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (432 mg, crude) in ethylene glycol dimethyl ether (5 mL) was added tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate (201 mg, 0.58 mmol), K2CO3 (55 mg, 0.40 mmol), Pd(PPh3)4 (392 mg, 0.34 mmol) and water (1.5 mL) with stirring overnight at 90° C. in an oil bath. The resulting mixture was concentrated under vacuum, dissolved in water (100 mL), extracted with ethyl acetate (3×30 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified via silica gel chromatography (10% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(1H-indazol-5-yl)-3-(methyl(1-phenylethyl)amino)quinoxaline-6-carboxylate as a yellow solid (144 mg).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]1[CH:13]=[C:12]([CH3:14])[N:11]([CH:15]([C:17]2[C:18]3[CH2:41][NH:40][CH2:39][CH2:38][C:19]=3[N:20]=[C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]4)=[C:26]([O:36][CH3:37])[CH:25]=3)[N:22]=2)[CH3:16])[N:10]=1>C(Cl)Cl>[CH3:8][C:9]1[CH:13]=[C:12]([CH3:14])[N:11]([CH:15]([C:17]2[C:18]3[CH2:41][N:40]([C:1](=[O:3])[CH3:2])[CH2:39][CH2:38][C:19]=3[N:20]=[C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]4)=[C:26]([O:36][CH3:37])[CH:25]=3)[N:22]=2)[CH3:16])[N:10]=1
Reactant: COc1cc(Nc2nc3c(c(C(C)n4nc(C)cc4C)n2)CNCC3)ccc1-n1cnc(C)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1cc(Nc2nc3c(c(C(C)n4nc(C)cc4C)n2)CN(C(C)=O)CC3)ccc1-n1cnc(C)c1
Reaction time: 1 h
Yield: 16.03 %

Procedure:
Acetic anhydride (0.016 mL, 0.17 mmol) was added to a solution of 4-(1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine in DCM (1 mL) and stirred for one hour. The solvent was evaporated and the crude product was purified on prepHPLC yielding 1-(4-(1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (14.00 mg, 16.03%).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.[Cl-].[CH:30]1([CH2:33][Na])[CH2:32][CH2:31]1>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][CH2:33][CH:30]2[CH2:32][CH2:31]2)[N:10]=[CH:9]1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: [Na]CC1CC1
Agent: [Cl-]
Product: c1nc(CCCOCC2CC2)c[nH]1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 10 mmol of cyclopropylmethylsodium chloride are treated as described in Example 5. The title compound is crystallized in the form of hydrogen maleate from ethanol and diethyl ether.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:22])([C:17]3[N:18]=[CH:19][NH:20][CH:21]=3)[CH:14]([CH3:16])[CH3:15])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:23]([O:25]C)=O.[CH3:27][N:28]([CH3:30])[NH2:29]>>[CH3:27][N:28]([CH3:30])[N:29]1[CH2:2][C:3]2[C:12]3[CH:11]=[CH:10][C:9]([C:13]([OH:22])([C:17]4[N:18]=[CH:19][NH:20][CH:21]=4)[CH:14]([CH3:16])[CH3:15])=[CH:8][C:7]=3[CH:6]=[CH:5][C:4]=2[C:23]1=[O:25]
Reactant: CN(C)N
Reactant: COC(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1CBr
Product: CC(C)C(O)(c1ccc2c3c(ccc2c1)C(=O)N(N(C)C)C3)c1c[nH]cn1

Procedure:
By a ring closure reaction, a detritylation reaction and purification in the same manner as in Example 1 using methyl 1-bromomethyl-6-[1-hydroxy-2-methyl-1-(1-H-imidazol-4-yl)propyl]-2-naphthoate (0.66 g) and 1,1-dimethylhydrazine (1.0 ml), the title compound (0.18 g) was obtained as a colorless amorphous solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:25][CH3:26])=[C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=2[N+:22]([O-])=O)[CH:9]=1)([CH3:3])[CH3:2]>O1CCCC1.CO.[C].[Pd]>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:25][CH3:26])=[C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([C:18]([F:19])([F:21])[F:20])=[CH:12][C:11]=2[NH2:22])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1-c1cc(OC)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(C)C)cc1-c1cc(OC)c(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.1 %

Procedure:
5′-Isopropyl-5,2′-dimethoxy-2-nitro-4-trifluoromethyl-biphenyl (2.35 g) is dissolved in a mixed solvent of tetrahydrofuran (20 ml) and methanol (30 ml), and thereto is added 10% palladium-carbon (500 mg) and the mixture is stirred under hydrogen atmosphere at room temperature for 1 day. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give 5′-isopropyl-5,2′-dimethoxy-4-trifluoromethyl-biphenyl-2-ylamine (1.88 g). MS (m/z): 340 [M+H]+
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4](=[NH:16])[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1Br)[CH3:2].[NH2:19]N>C(O)CCC>[CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[C:5]2[C:6](=[CH:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=2)[NH:19][N:16]=1)[CH3:2]
Reactant: NN
Reactant: CCN(CC)C(=N)c1cc(C(F)(F)F)ccc1Br
Solvent: CCCCO
Product: CCN(CC)c1n[nH]c2ccc(C(F)(F)F)cc12

Procedure:
A mixture of 5.0 g. of N,N-diethyl-2-bromo-5-trifluoromethylbenzamidine and 2.0 ml. of 95% hydrazine are refluxed in butanol for 12 hours. Evaporating the solution, treating the residue with ether and filtering gives 3-diethylamino-5-trifluoromethylindazole.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>>[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5]/[C:4](=[C:12]3/[C:13]([CH3:18])=[N:14][NH:15][C:16]/3=[O:17])/[CH:3]=2)=[CH:22][CH:21]=1
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Reactant: Nc1ccc(S)cc1
Product: CC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and 4-aminothiophenol using the procedure described in Example 6. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.97 (s, 3H) 6.77-6.79 (m, 3H) 7.33 (d, J=8.34 Hz, 2H) 7.64 (t, J=7.45 Hz, 1H) 7.88 (t, J=7.83 Hz, 1H) 7.96 (d, J=8.59 Hz, 1H) 8.14 (d, J=8.08 Hz, 1H); ESI-MS: m/z calc'd for C19H16N4OS 348.10. found 349.2 (M+H)+.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[NH:48]1[CH2:54][CH2:53][C:52](=[O:55])[NH:51][CH2:50][CH2:49]1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([N:48]4[CH2:54][CH2:53][C:52](=[O:55])[NH:51][CH2:50][CH2:49]4)=[O:44])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:3])([CH3:5])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: O=C1CCNCCN1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCNC(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with [1,4]diazepan-5-one (Oakwood Products) to give the title compound. HR-MS (ES, m/z) calculated for C40H50Cl2N7O4 [(M+H)+] 762.3296, observed 762.3297.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:22])=[N:12][CH:13]=[C:14]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:15]=1.CCN(CC)CC.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:22])=[N:12][CH:13]=[C:14]([N:16]2[CH2:17][CH2:18][N:19]([S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH2:20][CH2:21]2)[N:15]=1
Reactant: Nc1ncc(N2CCNCC2)nc1-c1nc2ccccc2[nH]1
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3nc4ccccc4[nH]3)n2)CC1
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
3-(1H-benzo[d]imidazol-2-yl)-5-(piperazin-1-yl)pyrazin-2-amine (50 mg, 0.169 mmol) was dissolved in DCM (3 mL) and Et3N (70.0 μL, 0.507 mmol) followed by ethanesulfonyl chloride (17.6 μL, 0.186 mmol) were added. The reaction was allowed to stir for 30 mins and then diluted with dichloromethane and washed with water. The aqueous layer was extracted further with dichloromethane and the organics washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo. The resultant residue was purified on silica gel by flash column chromatography (0-5% MeOH/DCM) to afford the title compound (42.6 mg, 65% Yield). MS (ES+) 388.0