Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].NC1C=CN=CC=1Cl.C1COCC1.[N:32]12[CH2:40][CH2:39][CH2:38][C@H:37]1[CH2:36][NH:35][CH2:34][CH2:33]2>C(N(CC)CC)C>[CH2:36]1[N:35]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:34][CH2:33][N:32]2[CH2:40][CH2:39][CH2:38][C@@H:37]12
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: C1C[C@H]2CNCCN2C1
Agent: Nc1ccncc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)N3CCN4CCC[C@H]4C3)s2)noc1C(F)(F)F
Yield: 85 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-amino-3-chloropyridine by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and (S)-1,4-diazabicyclo[4.3.0]nonane. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a saturated aqueous NaHCO3 solution followed by water to afford product as a yellow colored solid (82 mg, 85%). 1H NMR (CDCl3) 1.34-1.48 (m, 1H), 1.70-1.90 (m, 3H), 1.92-2.20 (m, 1H), 2.10-2.26 (m, 2H), 2.32 (d, J=1.3, 3H), 2.80 (br s, 1H), 3.03-3.11 (m, 2H), 3.20 (obs br s, 1H), 4.40 (br s, 2H), 7.29 (d, J=4.0, 1H), 7.41 (d, J=3.5, 1H). 13C NMR 7.9, 21.3, 27.5, 30.0, ˜48 (br), 51.8, 53.5, 62.8, 114.7, 118.7 (q, J=271), 128.0, 129.3, 131.2, 140.2, 155.2 (q, J=40), 157.9, 162.9. 19F NMR −63.1. LC/MS 4.34 min, [M+1]+ 386.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([C:22](O)=[O:23])[C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:14][CH:15]=2)[CH:6]=[C:7]([CH3:9])[CH:8]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:30][NH2:31].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C)C=O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:30][NH:31][C:22]([C:12]1[C:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][CH:15]=[C:10]([C:5]2[CH:4]=[C:3]([CH3:2])[CH:8]=[C:7]([CH3:9])[CH:6]=2)[CH:11]=1)=[O:23]
Reactant: Cc1cc(C)cc(-c2cnc(-c3cccnc3)c(C(=O)O)c2)c1
Reactant: COc1ccc(CN)cc1OC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc(CNC(=O)c2cc(-c3cc(C)cc(C)c3)cnc2-c2cccnc2)cc1OC
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 5-chloro-2,3′-bipyridine-3-carboxylate (1-2, 0.3 g, 1.20 mmol) in dioxane (6 mL) was added 3,5-dimethylphenyl boronic acid (0.452 g, 3.01 mmol), cesium carbonate (1.17 g, 3.61 mmol), tricyclohexylphosphine (0.101 g, 0.362 mmol), and tris(dibenzylideneacetone)-dipalladium (0.166 g, 0.181 mmol), and stirred at 95° C. overnight. The reaction was then cooled to room temperature, and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and filtered, concentrated and purified via normal phase chromatography (0->5% MeOH in DCM) afforded methyl 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylate as a yellow foam. ESI+ MS [MH]+ C20H18N2O2=319.25. To a solution of methyl 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylate (0.385 g, 1.20 mmol) in tetrahydrofuran (3 mL) and methanol (3 mL) was added potassium hydroxide (0.122 g, 2.17 mmol) and water (1.25 mL) and the system was stirred at room temperature overnight. The reaction mixture was then neutralized with 6N HCl to a pH of 2.0 and then concentrated in vacuo to afford 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylic acid as a bone powder in the form of a bis HCl salt. ESI+ MS [MH]+ C19H16N2O2=305.0. To a solution of the bis HCl salt form of 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylic acid (0.390 g, 1.03 mmol) and 3,4-dimethoxybenzylamine (0.173 g, 1.03 mmol) in dimethylformamide (5 mL) was added EDC (0.029 g, 0.191 mmol), HOBt (0.317 g, 2.06 mmol) and triethylamine (0.720 mL, 5.16 mmol) and the system was stirred in the microwave at 100° C. for 15 minutes. The system was cooled to room temperature, extracted with EtOAc, washed with water and dried over magnesium sulfate. The crude reaction mixture was purified using normal phase chromatography (0->10% MeOH in DCM) to afford the title compound (1-3) as a white powder. 1H NMR (500 MHz, CDCl3) δ 8.98-9.00 (m, 2H), 8.65-8.66 (m, 1H), 8.17 (d, J=2 Hz, 1H), 7.98-8.00 (m, 1H), 7.28-7.30 (m, 3H), 7.11 (s, 1H), 6.78 (d, J=8 Hz, 1H), 6.41-6.67 (m, 2H), 5.72 (br s, 1H), 4.42 (d, J=6 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 2.43 (s, 6H). HRMS [M+H] C28H27N3O3 calc'd 454.2125, found 454.2107.
Reaction SMILES: [Cl:1][C:2]1[N:3]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH2:7][OH:8].C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[N:3]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][C:6]=1[CH:7]=[O:8]
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ccccc2)cc(CO)c1Cl
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.3 %

Procedure:
To a solution (50 mL) of [2-chloro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (830 mg) in acetonitrile were added tetra-n-propylammonium perruthenate (84 mg), N-methylmorpholine N-oxide (484 mg) and molecular sieves 4A powder (2.0 g), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→4:1) to give the title compound as a colorless oil (yield 440 mg, 53%).
Reaction SMILES: [OH:1][CH:2]([CH2:21][OH:22])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[OH-].[K+].[C:25]([O:42]C)(=O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>>[OH:1][CH:2]([CH2:21][OH:22])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:25](=[O:42])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCCCCCCCCNCC(O)CO
Reactant: CCCCCCCCCCCCCCCC(=O)OC
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCN(CC(O)CO)C(=O)CCCCCCCCCCCCCCC

Procedure:
N-(2,3-dihydroxypropyl)-N-hexadecylamine (0.40 g, 0.0013 mole) and potassium hydroxide (0.01 g, 0.18 mmole) were heated to 85° C. under vacuum. Methyl palmitate (0.343 g, 0.0013 mole) was heated to melt and added dropwise to the reaction. The reaction was heated under vacuum for 6 hours. A waxy off-white solid was obtained. The waxy solid was recrystalized from hot hexane (yield=0.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]2[N:6]=[C:7]([C:9]3[N:10](S(C4C=CC(C)=CC=4)(=O)=O)[C:11]4[C:16]([CH:17]=3)=[CH:15][C:14]([CH:18]=[O:19])=[CH:13][CH:12]=4)[NH:8][C:4]=2[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:42][O:43][CH2:44]Cl.O>CN(C)C=O>[Cl:32][C:31]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:42][O:43][CH3:44])[C:7]([C:9]3[NH:10][C:11]4[C:16]([CH:17]=3)=[CH:15][C:14]([CH:18]=[O:19])=[CH:13][CH:12]=4)=[N:6][C:5]=2[CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3nc4cc(Cl)c(Cl)cc4[nH]3)cc3cc(C=O)ccc32)cc1
Reactant: COCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCn1c(-c2cc3cc(C=O)ccc3[nH]2)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.1 %

Procedure:
To a solution of 5,6-dichloro-2-[5-formyl-1-(4-methylphenyl)sulfonylindol-2-yl]benzimidazole obtained in Example 45 (824 mg, 1.71 mmol) in dimethylformamide (10 mL) were added diisopropylethylamine (0.59 mL, 3.4 mmol) and chloromethyl methyl ether (0.16 mL, 2.1 mmol), and the mixture was stirred at room temperature for 15 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue were added methanol (80 mL) and 2 mol/L sodium hydroxide (5 mL), and the mixture was heated to reflux for 1 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was triturated with ether to afford 5,6-dichloro-2-[5-formylindol-2-yl]-1-(methoxymethyl)benzimidazole (570 mg, 89%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.[C:32]1([NH:38]N)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:38][C:32]3[C:37]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(I)c3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(I)c4)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenylhydrazine: ESMS m/e: 606.2 (M+H)+.
Reaction SMILES: Cl.[C:2]1([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]([CH2:21][NH2:22])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([N:25](CC)CC)[CH3:24]>C(O)C>[C:2]1([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]([CH2:21][NH:22][C:23](=[NH:25])[CH3:24])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCO
Product: CC(=N)NCC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 80 °C
Reaction time: 48 h

Procedure:
C-(7-Benzenesulfonyl-chroman-4-yl)-methylamine HCl salt (90 mg, 0.26 mmol) and methyl imidate (acetimidic acid methyl ester, 58 mg, 0.529 mmol) were dissolved in 3 mL of absolute ethanol and 0.362 mL of triethylamine (2.6 mmol) was added. The reaction mixture was stirred at 80° C. for 2 days. It was then cooled, partitioned between EtOAc and water, dried over MgSO4 concentrated and purified using column chromatography (silica gel, MeOH/CHCl3/NH4OH 10:89:1) After formation of the HCl salt, 9 mg (10%) of. N-(7-Benzenesulfonyl-chroman-4-ylmethyl)-acetamidine was collected. MS: 345 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([NH2:18])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:7]=1.CCN(C(C)C)C(C)C.[N:30]([C:33]1[CH:34]=[C:35]([C:39](=[O:41])[CH3:40])[CH:36]=[CH:37][CH:38]=1)=[C:31]=[O:32]>C(Cl)Cl>[C:39]([C:35]1[CH:34]=[C:33]([NH:30][C:31]([NH:18][C:5]2[N:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:14]([F:16])([F:17])[F:15])[N:7]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=2)=[O:32])[CH:38]=[CH:37][CH:36]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)c1cccc(N=C=O)c1
Reactant: Nc1cc(C(F)(F)F)nn1-c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cccc(NC(=O)Nc2cc(C(F)(F)F)nn2-c2ccccc2C(F)(F)F)c1
Yield: 26.3 %

Procedure:
To a solution of 5-trifluoromethyl-2-(2-trifluoromethyl-phenyl)-2H-pyrazol-3-ylamine (97 mg, 0.33 mmol) and DIEA (57 μL, 0.33 mmol) in DCM (2 mL) was added 3′-isocyanato-acetophenone (41 μL, 0.30 mmol). After 15 h the reaction mixture was concentrated and purified by chromatography (silica, EtOAc/Hex, 0:100 to 50:50) to yield the title compound (36 mg). 1H-NMR (DMSO-d6): δ 9.67 (1H, s), 8.24 (1H, m), 7.99 (1H, d), 7.94-7.80 (3H, m), 7.69 (1H, d), 7.62 (1H, d), 7.48 (1H, t), 6.31 (2H, s), 2.57 (3H, s); MS (ES): 457 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:47])=[C:8]([N:10]2[CH2:46][CH2:45][C:13]3[N:14]=[C:15]([C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[C:27]([CH3:44])=[CH:28][N:29]5[S:34]([C:37]4[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=4)(=[O:36])=[O:35])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][NH:21][C@H:20]([CH3:24])[CH2:19]4)[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2].[CH3:48][S:49](Cl)(=[O:51])=[O:50].CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:47])=[C:8]([N:10]2[CH2:46][CH2:45][C:13]3[N:14]=[C:15]([C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[C:27]([CH3:44])=[CH:28][N:29]5[S:34]([C:37]4[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=4)(=[O:35])=[O:36])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][N:21]([S:49]([CH3:48])(=[O:51])=[O:50])[C@H:20]([CH3:24])[CH2:19]4)[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCN[C@H](C)C6)n4)CN(c4cc(C(C)C)ccc4C)CC5)cccc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCN(S(C)(=O)=O)[C@H](C)C6)n4)CN(c4cc(C(C)C)ccc4C)CC5)cccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methylpiperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (52 mg, 0.080 mmol), prepared in a manner similar to that described in Example 25, methanesulfonyl chloride (0.01 mL, 0.096 mmol) and DIEA (0.042 mL, 0.240 mmol) in DCM (3 mL) was stirred at rt for 30 min. The reaction mixture was diluted with EtOAc, washed successively with sat NaHCO3, and brine, dried over Na2SO4 and concentrated. The resulting residue was purified via FCC (5-50% EtOAc/heptane) to provide (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methyl-4-(methylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 727.4 (M+H)+. To a solution of (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methyl-4-(methylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (40 mg, 0.055 mmol) in MeOH (4 mL), NH4OH (0.325 mL, 8.25 mmol) and KOH (27.8 mg, 0.495 mmol) was added. The mixture was heated in a microwave reactor 100° C. for 1 h. The mixture was then filtered and concentrated. The resulting residue was purified via FCC (0-45% EtOAc/heptane) to provide (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1H-indol-4-yl)-4-(3-methyl-4-(methylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.91 (d, J=2.02 Hz, 1 H) 7.40-7.43 (m, 1 H) 7.24 (dd, J=7.33, 1.01 Hz, 1 H) 7.09-7.16 (m, 3 H) 7.02 (d, J=1.26 Hz, 1 H) 6.87 (dd, J=7.83, 1.26 Hz, 1 H) 4.03-4.16 (m, 3 H) 3.70-3.84 (m, 2 H) 3.56 (d, J=12.88 Hz, 1 H) 3.33-3.42 (m, 2 H) 3.23-3.28 (m, 1 H) 3.14 (dd, J=12.88, 3.54 Hz, 1 H) 2.92-3.06 (m, 6 H) 2.79-2.90 (m, 1H) 2.22 (s, 3 H) 2.03 (s, 3 H) 1.32 (d, J=6.82 Hz, 3 H) 1.19 (dd, J=6.95, 1.89 Hz, 6 H); MS (ESI+) m/z 573.4 (M+H)+.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.[Br:10][C:11]1[CH:12]=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=[C:15]2[C:19]=1[NH:18][N:17]=[CH:16]2>C(OCC)(=O)C>[Br:10][C:11]1[C:19]2[C:15](=[CH:16][N:17]([CH3:6])[N:18]=2)[CH:14]=[C:13]([N+:20]([O-:22])=[O:21])[CH:12]=1
Reactant: C[O+](C)C
Reactant: O=[N+]([O-])c1cc(Br)c2[nH]ncc2c1
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: Cn1cc2cc([N+](=O)[O-])cc(Br)c2n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Trimethyloxonium tetrafluoroborate (1.5 g) was added to a solution of 7-bromo-5-nitro-1H-indazole (1.21 g) in ethyl acetate (12 mL), and the reaction solution was stirred at room temperature for 6 hours. After dilution with ethyl acetate, the reaction solution was washed successively with water and a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum, ethyl acetate and isopropyl ether were added to the resultant residue, and the deposited precipitate was filtrated to obtain 7-bromo-2-methyl-5-nitro-2H-indazole as a light yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH2:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:19]>>[C:21]([N:20]([CH2:18][CH3:19])[C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Reactant: CCNC(C)(C)C
Product: CCN(C(=O)c1cc(OCC2CC2)c(C2CC2)cn1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 23b, using 5-Cyclopropyl-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42c) and N-ethyl-2-methylpropan-2-amine (CAN 4432-77-3) as starting materials and isolated (9 mg, 4.5%) as colorless oil; MS (ESI, m/z): 317.6 (M+H+).
Reaction SMILES: N1C=CC=C2C(N)CCC=12.[CH2:11]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[N:22]O)[CH3:12]>>[CH2:11]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]1[NH2:22])[CH3:12]
Reactant: CCC1Cc2ccccc2C1=NO
Agent: NC1CCc2ncccc21
Product: CCC1Cc2ccccc2C1N

Procedure:
Following the procedure for the preparation of 6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine but substituting 2-ethyl-2,3-dihydro-1H-inden-1-one oxime and making non-critical variations provided the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6]C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19](Cl)=[O:20]>>[NH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][C:14]=1[C:19]([C:18]1[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:17]=1[Cl:16])=[O:20]
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1
Product: Nc1ccc(Cl)cc1C(=O)c1c(F)cccc1Cl
Yield: 42 %

Procedure:
In a manner similar to that described above for compound 1aa, 4-Chloro-N-Boc-aniline and 2-chloro-6-fluoro-benzoyl chloride were converted to 1ab (42% yield) MS m/z=284 (M+H).
Reaction SMILES: Cl.C([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])(=O)C.N>CO>[Cl:25][C:21]1[C:20]([F:26])=[C:19]([CH:24]=[CH:23][CH:22]=1)[NH:18][C:9]1[C:8]2[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([OH:5])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC(C)=O
Agent: Cl
Agent: N
Solvent: CO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
6-Acetoxy-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline hydrochloride (Reference Example 1, 8.72 g, 21.9 mmol) was dissolved in methanol (200 ml). Concentrated aqueous ammonia (15 ml) was added, and the solution heated to 50° C. with stiffing for 2 hours, causing precipitation of a cream coloured solid. The solid was collected by filtration, washed with diethyl ether (3×200 ml), and dried in vacuo at 60° C. over diphosphorous pentoxide, giving the product as an off white solid (5.40 g, 77%); 1H NMR: 3.95 (s, 3H), 7.19 (s, 1H), 7.23 (dd, 1H), 7.42 (dd, 1H), 7.50 (dd, 1H), 7.64 (s, 1H), 8.32 (s, 1H), 9.43 (s, 1H), 9.67 (br.s, 1H); Mass Spectrum: 320.4, 322.4.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].C(O)(=O)C.[C-:15]#[N:16].[K+].ClCCl>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]([OH:5])[C:15]#[N:16]
Reactant: [C-]#N
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: N#CC(O)c1c(Cl)cccc1Cl

Procedure:
To a stirred and cooled (15° C.) solution of 350 parts of 2,6-dichlorobenzaldehyde and 1600 parts of acetic acid was added dropwise a solution of 162.8 parts of potassium cyanide in water during 30 minutes at 15°-20° C. After stirring for 16 hours at 20° C., 1300 parts of dichloromethane and 1000 parts of water were added. The separated aqueous layer was washed three times with dichloromethane. The combined organic layers were washed with water, dried, filtered and evaporated at 40° C., yielding 396 parts of 2,6-dichloro-α-hydroxybenzeneacetonitrile.
Reaction SMILES: O1CCCC1.COP([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(OC)=O.[H-].[Na+].[CH:22]([C:25]1[CH2:26][C@@H:27]2[C@H:30]([CH:31]=1)[C:29](=O)[CH2:28]2)([CH3:24])[CH3:23]>O>[CH:22]([C:25]1[CH2:31][C@@H:30]2[C@H:27]([CH:26]=1)[C:28](=[CH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:29]2)([CH3:24])[CH3:23]
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: CC(C)C1=C[C@@H]2C(=O)C[C@@H]2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A tetrahydrofuran (15 mL) solution of tert-butyl dimethylphosphonoacetate (3.70 g, 16.5 mmol) was added dropwise at 0° C. over 20 minutes to a tetrahydrofuran (15 mL) suspension of sodium hydride (0.68 g, 63%, 18.0 mmol), and the mixture was stirred at 0° C. for 20 minutes. To this solution, a tetrahydrofuran (15 mL) solution of (±)-(1S,5R)-3-isopropylbicyclo[3.2.0]hept-3-en-6-one (2.25 g, 15.0 mmol) was added dropwise at 0° C. over 15 minutes, and the mixture was stirred at room temperature for 2 hours. The mixture was treated with water, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a yellow oil substance (3.00 g, 81%).
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=2)=[C:6]([CH2:17][CH3:18])[CH:5]=1)([OH:3])=[O:2].[CH:19](O)([CH3:21])[CH3:20]>>[CH:19]([O:2][C:1]([C:4]1[C:13]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]([CH:14]([CH3:15])[CH3:16])[CH:12]=2)=[C:6]([CH2:17][CH3:18])[CH:5]=1)=[O:3])([CH3:21])[CH3:20]
Reactant: CCc1cc(C(=O)O)c2cc(C(C)C)cccc1-2
Reactant: CC(C)O
Product: CCc1cc(C(=O)OC(C)C)c2cc(C(C)C)cccc1-2

Procedure:
The acid chloride derivative (12) was produced in the same manner as in the synthesis of the above-mentioned 1-ethoxycarbonyl-3-ethyl-7-isoproylazulene (13) using 1-carboxy-3-ethyl-7-isopropylazulene (11) (1.21 g) as a starting material. Isopropanol was employed in place of the ethanol under the same reaction conditions and treatment as above to obtain the product (14) in a dark purple crystalline form, at a yield of 1.34 g (94.2%), having a melting point of 69° to 71° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:11][CH:12]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.Br>CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:11][CH:12]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2nc(-c3cccs3)c[nH]2)cc1Br
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(-c2nc(-c3cccs3)c[nH]2)cc1Br
Yield: 22 %

Procedure:
A mixture of 32 (5.7 g, 0.017 mole), glacial HOAc (30 ml), and 48% HBr (85 ml) was stirred and heated at reflux for 12 hours. The hydrobromide salt that precipitated on cooling was collected and shown to consist of a mixture of 32 and 33. The mixture was resuspended in glacial HOAc (30 ml)--48% HBr (85 ml) and again heated at reflux for 12 hours. The precipitated hydrobromide was collected, washed with HOAc and Et2O and then stirred with saturated NaHCO3 (100 ml) for 2 days. The solid was collected, chromatographed on silica gel and the product eluted with 70 toluene--30EtOAc to yield 1.2 g (22%) of 33, m.p 125°-130° C.