Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1.C(NCC)C.[ClH:29]>CO>[ClH:29].[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C@@H:9]([NH:15][C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: C[C@@H](NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1
Agent: Cl
Solvent: CCNCC
Solvent: CO
Product: C[C@@H](N[C@H]1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1

Procedure:
(1S)-6-bromo-N-[(1R)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt was prepared by separation of diastereomeric 6-bromo-N-[(1R)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine by SFC (Berger Amino, Chiral Technologies, 10% methanol, (2% diethyl amine/10% chloroform) 1500 psi, 50° C., 2 mL/min, retention time: 19.8 min.) The oil obtained was converted to the HCl salt to give a white solid. [α]25=−4.3 (c 0.23, MeOH); 1H-NMR (DMSO-d6): δ 11.6 (s, 1H), 10.08 (s, 1H), 9.64 (s, 1H), 7.86 (d, J=6.8 Hz, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.55-7.45 (m, 3H), 7.42 (d, J=8.6 Hz, 1H), 7.29 (dd, J=6.8 Hz, J=1.8 Hz, 1H), 4.75 (m, J=6.4 Hz, 1H), 4.57 (m, 1H), 3.47-3.37 (m, 2H), 2.70-2.64 (m, 2H), 2.13-2.07 (m, 2H), 1.65 (d, J=6.8 Hz, 3H); MS m/z 367, 369 (M−1); Anal. Calcd. For C20H22BrN2Cl: C, 59.20; H, 5.46; N, 6.90. Found: C, 59.29; H, 5.55; N, 6.92.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(N(CC)CC)C.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]([NH:11][S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(Br)c2cc[nH]c2c1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1cc(Br)c2cc[nH]c2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
4-Bromo-6-amino indole (100 mg, 0.47 mmol) and triethylamine (0.1 ml, 0.71 mmol) were stirred together in pyridine at 0° C. Benzene sulphonyl chloride (84 mg, 0.47 mmol) was then added and the mixture stirred for 1 hour, then allowed to warm to room temperature. The mixture was loaded directly onto an aminopropyl cartridge (10 g) and eluted with methanol. Solvent was evaporated to afford the title compound as an orange/brown gum (90 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].ClC1C=[C:37]([N:39](C)[CH3:40])C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([N:39]([CH3:40])[CH3:37])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCc1nc(-c2ccc(N(C)C)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(N(C)C)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-({5-[2-chloro-4-(dimethylamino)phenyl]-3,6-diethylpyrazin-2-yl}amino)-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a pale yellow amorphous solid. IR (diffuse reflectance) 2971, 2932, 2890, 2875, 1608, 1563, 1482, 1442, 1389, 1366, 1352, 1207, 1175, 1090, 961 cm−1; OAMS supporting ions at: ESI+ 465.2; MS (EI) m/z 464 (M+); HRMS (FAB) calcd for C27H33CLN4O+H1 465.2421, found 465.2406. Anal. Calcd for C27H33ClN4O: C, 69.74; H, 7.15; N, 12.05. Found: C, 69.68; H, 7.16; N, 11.99.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:3]=1[NH:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9]>C(O)(=O)C.[Fe]>[NH2:15][C:13]1[CH:12]=[CH:11][C:3]([NH:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])=[C:2]([Cl:1])[CH:14]=1
Reactant: CCCCC(=O)Nc1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Product: CCCCC(=O)Nc1ccc(N)cc1Cl

Procedure:
2'-Chloro-4'nitrovaleranilide (13.0 g.) is dissolved in warm glacial acetic acid (100 ml.) and iron powder (14 g.) is added portionwise to maintain gentle boiling. The resulting reaction mixture is refluxed for one-half hour and filtered. The filtrate is evaporated under reduced pressure and the residue is triturated with water. The solid that forms is collected (11.5 g.) and recrystallized from cyclohexane to yield 7.5 g., m.p. 96.5°-99° C.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH:16]=[CH:15][C:14]=2[CH:18]=1>CN(C=O)C.O>[CH:1]1([O:5][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH:16]=[CH:15][C:14]=3[CH:18]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: BrCc1ccc2occc2c1
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cc2cc(COC3CCC3)ccc2o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of cyclobutanol (1.0 mL, 14.0 mmol) and sodium hydride (0.5 g, 14.0 mmol) in DMF (20 mL) was stirred at 0° C. for 30 minutes. 5-(Bromomethyl)benzofuran (2.9 g, 14.0 mmol) was the added and resultant reaction mixture was slowly warmed to room temperature and left stirring over night. Reaction mixture was diluted to 100 mL with water. The solution was extracted with Et2O (20 mL×3); the combined extracts were washed with 1N NaOH solution, water and brine, dried, and concentrated under reduced pressure to yield the desired product after purification on silica (4/1 hexane/ethyl acetate). 1H NMR (400 MHz, CDCl3) δ 7.58 (d, 2H), 7.42 (d, 1H), 7.27 (d, 1H), 6.78 (s, 1H), 4.54 (s, 2H) 4.03 (m, 1H), 2.21 (m, 2H), 1.94 (m, 2H), 1.76 (m, 1H), 1.52 (m, 1H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[C:20]2[Cl:24]>N1C=CC=CC=1>[Cl:24][C:20]1[C:19]2[C:23](=[C:15]([NH:14][S:2]([C:5]3[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])[CH:16]=[CH:17][CH:18]=2)[NH:22][CH:21]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cccc2c(Cl)c[nH]c12
Solvent: c1ccncc1
Product: O=C(O)c1ccc(S(=O)(=O)Nc2cccc3c(Cl)c[nH]c23)cc1
Reaction time: 8 h
Yield: 77.8 %

Procedure:
2.82 g (12.8 mmol) of 4-(chlorosulfonyl)benzoic acid and 1.42 g (8.54 mmol) of 7-amino-3-chloro-1H-indole were reacted with each other in pyridine at room temperature under stirring overnight, to give 2.33 g of 4-[N-(3-chloro-1H-indole-7-yl)sulfamoyl]benzoic acid. To 303 mg (0.86 mmol) of the product were successively added 260 μl of dimethylformamide, 204 μl (0.95 mmol) of diphenylphosphorylazide, 132 μl (0.95 mmol) of triethylamine and 113 μl (0.94 mmol) of 2-(2-aminoethyl)pyridine, followed by stirring at room temperature overnight. After concentrating, ethyl acetate and an aqueous saturated sodium bicarbonate were added thereto. The organic layer was separated and washed with brine. After evaporating the solvent, the residue was purified by silica gel column chromatography, to give 175 mg of the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:11][S:12][C:13]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:19]=2)=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(O)(=O)C>[OH:8][CH2:9][C:10]1[S:11][S:12][C:13]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:19]=2)=[CH:14][CH:15]=1
Reactant: CN(C)c1cccc(OCC2=CC=C(CO[Si](C)(C)C(C)(C)C)SS2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)c1cccc(OCC2=CC=C(CO)SS2)c1
Reaction time: 3 h
Yield: 84 %

Procedure:
To a stirred solution of the 3-[(tert-butyldimethylsilyloxy)methyl]-6-[[3-(N,N-dimethylamino)-phenyloxy]methyl]-1,2-dithiin obtained above (100 mg, 0.24 mmol) in 2 mL THF was added a mixture of 2.4 mL of 1M tetrabutylammonium fluoride in THF and 1.4 mL of acetic acid. The reation mixture was stirred for 3 h until TLC analysis showed the reaction to be complete, then concentrated in vacuo. The residue was partitioned between 40 mL of water and 60 mL ethyl acetate. The organic phase was washed with dilute aqueous sodium bicarbonate, water, dried over sodium sulfate, and then evaporated to a small volume. The residue was chromatographed over silica gel column (ethyl acetate-hexane, 1:1) to yield 60.5 mg (84.0%) of the title compound. Further purification was accomplished by reverse-phase HPLC (PRP-1 column, acetonitrile-water, 2:3); 1H-NMR (CDCl3) δ7.3 (bs, 1 H), 7.1 (bs, 1 H), 6.64 (s, 1 H), 6.55 (d, J=7.2, 1 H), 6.46(d, J=5.6, 1 H), 6.41 (d, J=5.6, 1 H), 4.65 (s, 2 H), 4.30 (s, 2 H), 2.69 (s, 6 H).
Reaction SMILES: C(O[C:4](=[O:20])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[C:6]([O:8]CC)=O)C.C[O-].[Na+].[NH2:24][C:25]([NH2:27])=[O:26]>CO>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C:5]1[C:4]([OH:20])=[N:24][C:25]([OH:26])=[N:27][C:6]=1[OH:8]
Reactant: CCOC(=O)C(Oc1ccccc1OC)C(=O)OCC
Reactant: NC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1Oc1c(O)nc(O)nc1O
Temperature: 80 °C
Yield: 80.1 %

Procedure:
To a solution of (2-methoxyphenoxy)malonic acid diethyl ester (10.0 g) and a 28% solution of sodium methoxide (3.83 g) in methanol (100 ml) is added urea (2.33 g) under warming, and the mixture is refluxed at 80° C. for 16 hours. After the reaction is completed, the solution is concentrated, and acidified with 10% hydrochloric acid. The precipitated crystals are collected by filtration, washed, and dried to give 5-(2-methoxyphenoxy)-2,4,6-trihydroxy-pyrimidine (7.10 g) as a crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([O:11][CH3:12])=[C:6]([CH:8]([NH2:10])[CH3:9])[CH:7]=1.F[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[S:23]([CH3:26])(=[O:25])=[O:24].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([O:11][CH3:12])=[C:6]([CH:8]([NH:10][C:18]2[CH:19]=[C:20]([F:22])[CH:21]=[CH:16][C:17]=2[S:23]([CH3:26])(=[O:25])=[O:24])[CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)cc(C(C)N)c1OC
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(Cl)cc(C(C)Nc2cc(F)ccc2S(C)(=O)=O)c1OC
Yield: 30.6 %

Procedure:
A solution of 1-(5-chloro-2,3-dimethoxy-phenyl)-ethyl amine (1.27 g, 5.89 mmol), 2,4-difluoro-1-methanesulfonyl-benzene (1.25 g, 6.48 mmol) and N,N-diisopropylethylamine (2.1 mL, 11.78 mmol) in acetonitrile was stirred at 80° C. for 48 h. The solvent was concentrated in vacuo, the residue was taken up in dichloromethane and washed with water, dried, and concentrated under reduced pressure to the crude compound which was purified by silica gel column (20% ethyl acetate in hexanes) to afford [1-(5-chloro-2,3-dimethoxy-phenyl)-ethyl]-(5-fluoro-2-methanesulfonyl-phenyl)-amine (700 mg, 32%): 1H NMR (400 MHz, CDCl3): δ 7.74 (dd, 1H), 6.82 (m, 2H), 6.73 (dd, 1H), 6.42 (dd, 1H), 6.24 (dd, 1H), 4.82 (m, 1H), 3.95 (s 3 H), 3.88 (s, 3H), 3.27 (3, 3H), 1.58 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:16]=1[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:18]>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:14][C:15]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:16]=2[C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)=[O:18])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(NC(=O)c2cccc(OC)c2N)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: COc1ccc(NC(=O)c2cccc(OC)c2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 57 %

Procedure:
Using the procedure described in Example 93, Part A, 4-tert-butylbenzoyl chloride (0.81 mmol) and 2-amino-N-(4-methoxyphenyl)-3-methoxybenzamide (0.73 mmol) yielded 0.18 g (57%) of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH3:22])=[CH:16][CH:17]=4)[C:12](=[O:23])[CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:24](=O)([O:27]C)[O:25][CH3:26]>C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH3:22])=[CH:16][CH:17]=4)[C:12](=[O:23])[C@@H:11]3[C:24]([O:25][CH3:26])=[O:27])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)OC
Reactant: CCCOc1ccc2c(c1)C(=O)C[C@H]2c1ccc2c(c1)OCO2
Solvent: CC(=O)O
Product: CCCOc1ccc2c(c1)C(=O)[C@H](C(=O)OC)[C@H]2c1ccc2c(c1)OCO2
Temperature: 0 °C
Yield: 62 %

Procedure:
A 250 mL three-necked flask under nitrogen was charged with (S)-3-(1,3-Benzodioxol-5-yl)-2,3-dihydro-6-propoxy-1H-inden-1-one (6.6 g, 21.3 mmol, 90% e.e.) and dimethyl carbonate (70 mL). To the solution was added sodium t-amylate (4.7 g, 42.5 mmol) in four portions over 20 minutes to maintain the temperature below 35° C. Upon complete addition of base, stir the solution until the temperature drops to 20° C. (˜1.5 h). Cool the solution to 0° C. and add a 50% acetic acid solution (50 mL) over 15 minutes to keep the temperature below 5° C. Concentrate the solution to ¼ volume, add toluene (100 mL), wash the organic phase with water (2×100 mL), sat. NaHCO3 (100 mL), brine (100 mL), dry over MgSO4 and concentrate in vacuo. Slurry the crude solid in cold MeOH (25 mL, 0° C.), filter and air dry to afford (1S-trans)-Methyl 1-(1,3-benzodioxol-5-yl)-2,3-dihydro-3-oxo-5-propoxy-1H-indene-2-carboxylate as a pale yellow solid (4.8 g, 62%): mp 103.0-105.5° C.; 1H NMR δ7.15 (d, J=2.3 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.95 (dd, J=2.4, 8.3 Hz, 1H), 6.7 (m, 2H), 6.45 (d, J=1.2 Hz, 1H), 6.4 (m, 2H), 4.6 (s, 1H 3.9 (t, J=6.5 Hz, 2H), 3.7 (s, 3H), 1.8 (quintet, J=7.2 Hz, 2H), 1.05 (t, J=7.4 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10](Cl)([Cl:12])[Cl:11].[OH-].[Na+]>CN1CCCC1=O>[Cl:8][C:7]1[C:2]([CH:10]([Cl:12])[Cl:11])=[N:3][C:4]([Cl:9])=[CH:5][CH:6]=1
Reactant: ClC(Cl)Cl
Reactant: Clc1ccc(Cl)c(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Clc1ccc(Cl)c(C(Cl)Cl)n1
Reaction time: 8 h

Procedure:
2,3,6-Trichloropyridine (1.0 g, 0.0055 mole) was combined with 4 g N-methylpyrrolidone, 4 g (0.033 mole) of chloroform, and 1.0 g of 50 percent aqueous sodium hydroxide (0.013 mole). The resulting mixture was stirred and warmed mildly for about 1 hour at which time the product was found to be present in the reaction mixture by gas chromatography and mass spectrometry using an authentic sample of the product as a standard. After standing overnight at ambient temperature the title compound represented about 1.7 percent of the pyridines in the mixture.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3][CH2:2]1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:9]([N:1]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3][CH2:2]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a suspension of azepan-4-one (8.0 g, 53.47 mmol, 1.0 eq.) in methylene chloride (100 ml) was added TEA followed by benzaldehyde and reaction mixture was stirred at RT for 30 min. Na(OAc)3BH was added portionwise to the reaction mixture and it was then stirred at RT for another 4 h. The reaction mixture was quenched with NaOH (2 M, 80 ml) and extracted with methylene chloride (3×100 ml). The organic layer was dried over Na2SO4 and solvent was evaporated under reduced pressure to afford the crude product which was purified by column chromatography (silica gel, 20% EtOAc/hexanes) to yield the desired product as an oil. Yield: 78% (8.5 g, 41.87 mmol).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.[C:10]1([C:16](Cl)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[C:10]1([C:16]([NH:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O[C@H]1CC[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of trans-4-aminocyclohexanol hydrochloride (2.00 g; 13.19 mmol), triphenylmethyl chloride (4.41 g; 15.83 mmol) and triethylamine (6.44 ml; 46.17 mmol) in 40 ml CH2Cl2 is refluxed overnight. The solids are filtered off and the residue concentrated in vacuo. The resultant product is purified with CH2Cl2 CH2Cl2: ethylacetate (5:1) to obtain trans-4-triphenylmethylaminocyclo-hexanol which is used directly in the next step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:2]1.[C:15]([O:19][C:20](=O)[O:21]C(C)(C)C)([CH3:18])([CH3:17])[CH3:16]>CN(C1C=CN=CC=1)C.C(#N)C.C(OCC)(=O)C>[C:15]([O:19][C:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:2]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1c[nH]c2ccccc12
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2ccccc12
Yield: 105.9 %

Procedure:
A solution of 3.15 g of ethyl indole-3-carboxylate, 4.36 g of di-tert-butylcarbonate and 0.02 g of 4-DMAP in 30 ml of acetonitrile is stirred at room temperature for 15 min. The reaction mixture is then diluted with 200 ml of ethyl acetate. The organic phase is washed with dilute hydrochloric acid, water and saturated sodium chloride solution in succession, dried over sodium sulfate and concentrated. Purification by means of FC over 80 g of silica gel with a 15:1 mixture of hexane and ethyl acetate as the mobile phase gives 5.1 g of the title compound: Rf (G)=0.41.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC[N:32]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH2:32])=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)cc1OC
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2nc(-c3cccc(C(N)=O)c3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.6 %

Procedure:
To a mixture of 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (100 mg, 0.25 mmol), EDCI (70 mg, 0.37 mmol), HOBt (50 mg, 0.37 mmol) and Et3N (49 mg, 0.49 mmol) in DCM (20 mL) was bubbled ammonia until saturation. The mixture was stirred at room temperature for 3 h, then was filtered and the filtrate was concentrated to give residue which was purified by column chromatography (DCM:MeOH=50:1) to afford 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamide (22 mg, 14%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.13 (s, 1H), 9.37 (s, 1H), 8.88 (t, 1H, J=1.5 Hz), 8.51 (d, 1H, J=7.8 Hz), 8.10 (s, 1H), 7.98 (d, 1H, J=7.5 Hz), 7.86 (d, 1H, J=2.4 Hz), 7.58 (t, 1H, J=7.8 Hz), 7.49-7.44 (m, 2H), 7.99 (d, 1H, J=8.7 Hz), 3.82 (s, 3H), 3.77 (s, 3H). LC-MS: 408 [M+H]+, tR=1.39 min. HPLC: 97.78% at 214 nm, 97.42% at 254 nm, tR=1.39 min. LC-MS: 408 [M+H]+, tR=1.392 min. HPLC: 95.38% at 214 nm, 96.23% at 254 nm, tR=3.53 min.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].P(Br)(Br)[Br:16]>>[Br:16][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: BrP(Br)Br
Product: O=C1c2ccccc2C(=O)N1CCBr
Temperature: 0 °C

Procedure:
A mixture of 5.35 g (0.028 mol) of N-(2-hydroxyethyl)phthalimide and 7.7 g (0.028 mol) of phosphorus tribromide is warmed until solution is obtained. The reaction mixture is then cooled and poured into ice water. The resulting solid is collected by filtration and washed with water to give N-(2-bromoethyl)phthalimide.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:28])[F:27].O>CN(C)C=O>[F:27][C:26]([F:29])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH:7]2[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]2)=[N:11]1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Reactant: Fc1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(c2nn(-c3ccccc3C(F)(F)F)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
To a stirred suspension of 1.0 g of a 50% oil dispersion of sodium hydride in 20 ml of dimethylformamide was added, dropwise, 3.2 g of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 25 ml of hot dimethylformamide. After stirring for one hr at ambient temperature, 3.75 ml of 2-fluorobenzotrifluoride was added. The reaction mixture was heated to 90° C. and stirred for 17 hrs. The mixture was then poured into water, extracted with ether, dried over anhydrous magnesium sulfate and concentrated. The residue was purified using flash chromatography (silica gel, diethylamine-ethyl acetate, 1:9). The appropriate fractions were evaporated. The residue was recrystallized once from hexane, then combined with a previously prepared sample (1.1 g), and recrystallized from hexane to yield 2.17 g of (24%) of product, mp 110°-111° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:13])[N:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[CH:6][C:7]=1Cl.[CH2:14]([N:17]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][NH:27][CH3:28])=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16]>>[Cl:1][C:2]1[C:3](=[O:13])[N:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[CH:6][C:7]=1[N:27]([CH2:26][C:25]1[CH:29]=[CH:30][C:22]([CH2:21][N:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19][CH3:20])=[CH:23][CH:24]=1)[CH3:28]
Reactant: CCCN(CCC)Cc1ccc(CNC)cc1
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Product: CCCN(CCC)Cc1ccc(CN(C)c2cnn(C(C)(C)C)c(=O)c2Cl)cc1

Procedure:
The compounds as identified in Table 15 were prepared in the synthetic manner and after-treatment similar to those in Example 8 except that the 4,5-dichloro-2-alkyl- 3(2H)pyridazinones with R1 and R2 as identified in Table 15 were used instead of the starting 4,5-dichloro-2-t-butyl-3(2H)pyridazinone used in Example 8, and the N-alkylbenzylamines with R3, Y1, Y2 and Y3 as identified in Table 15 were used instead of the starting 4-di-n-propylaminomethyl-N-methylbenzylamine. In the NMR data, only the characteristic absorptions are given in Table 15.