Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[Br:7][C:8]1[CH:9]=[C:10]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:11]([O:20][CH3:21])=[C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[Br:7][C:8]1[CH:9]=[C:10]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:11]([O:20][CH3:21])=[C:12]([N:14]2[CH2:15][CH2:16][N:17]([C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH2:18][CH2:19]2)[CH:13]=1
Reactant: COCC(=O)Cl
Reactant: COc1c(N2CCNCC2)cc(Br)cc1C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCC(=O)N1CCN(c2cc(Br)cc(C(C)(C)C)c2OC)CC1
Reaction time: 1 h

Procedure:
Methoxyacetyl chloride (0.28 ml) was added to a solution of 1-[5-bromo-3-(tert-butyl)-2-methoxyphenyl]piperazine (850 mg) and triethylamine (0.73 ml) in methylene chloride (12 ml) while cooling on ice, the mixture was brought to room temperature and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate, the insoluble portion was filtered off, and the concentrated residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (730 mg) as light red crystals (70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][Cl:15])[CH:10]=[CH:11][C:5]=2[CH:4]=1>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)C=C2
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2

Procedure:
Next, the 1-(7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane (59.2 g, 0.2 mol) is hydrogenated in glacial acetic acid (500 ml) in the presence of 10% palladium/charcoal (5 g) for 6 hours at 50° C. under 5 bar. The catalyst is removed by suction filtering, the glacial acetic acid is distilled off in vacuo and the residue is neutralized with potassium carbonate after the addition of water. The precipitate is suction filtered, washed free from salts with water and dried.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.[O-:10][CH2:11][CH3:12].[Na+]>C(O)C>[NH2:1][C:2]1[C:7]([O:10][CH2:11][CH3:12])=[N:6][C:5]([Br:9])=[CH:4][N:3]=1
Reactant: CC[O-]
Reactant: Nc1ncc(Br)nc1Br
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(Br)cnc1N
Yield: 87.4 %

Procedure:
A solution of 2-amino-3,5-dibromopyrazine (obtained as described in Gazz. Chim. Ital., 1960, 90, 1807) (1.26 g) and sodium ethoxide (0.4 g) in ethanol (50 ml) was heated under reflux for 4 hours. Volatile material was removed by evaporation and the residue was partitioned between water (20 ml) and ethyl acetate (50 ml). The organic layer was separated and dried (MgSO4). Volatile material was removed by evaporation to give 2-amino-5-bromo-3-ethoxypyrazine (0.95 g); 1H NMR (d6 -DMSO): 1.4 (t, 3H), 4.3 (q, 2H), 6.4 (br s, 2H), 7.6 (s, 2H); mass spectrum (+ve CI): 218 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[N:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[N:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[C:21](=[O:24])[NH:22][N:23]=[C:4]2[C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44].O>CN(C=O)C>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([N:12]2[C:8]([C:7]3[C:2]([CH3:1])=[C:3]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)[C:4]4[N:5]([C:21](=[O:24])[N:22]([CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44])[N:23]=4)[CH:6]=3)=[CH:9][CH:10]=[N:11]2)=[CH:14][CH:15]=1)#[N:18]
Reactant: CN(C)C(=O)CCl
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2c(=O)[nH]nc2c1-c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2c(=O)n(CC(=O)N(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.6 %

Procedure:
To a solution of 4-{5-[7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 9, 55 mg. 0.12 mmol) in DMF (3 mL) was added cesium carbonate (58 mg, 0.18 mmol) followed by 2-chloro-N,N-dimethylacetamide (19 μL, 0.18 mmol). The reaction mixture was stirred at RT for 18 hrs then water was added and the reaction mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by preparative HPLC, eluting with a gradient of 20-70% MeCN in water (+0.1% formic acid) to give the title compound as a yellow solid (22 mg).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:37]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:37][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:16][CH:15]=3)[CH2:26][CH:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ccccn1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cc1)C1CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To a solution of 5-[4-(cyclopropylsulfonyl)phenyl]-1-(pyridin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (220 mg) in N,N-dimethylformamide (5 mL) was added ammonium acetate (190 mg), and the mixture was stirred at 100° C. for 1 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, from a fraction eluted with ethyl acetate-hexane (3:1, volume ratio) to give a crude product. The obtained crude product was subjected to basic silica gel column chromatography, and the title compound (95 mg, yield 45%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 437 (MH+).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([Br:28])[C:22]2[S:26][CH:25]=[N:24][C:23]=2[CH:27]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:29]I>C1COCC1>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([Br:28])[C:22]2[S:26][C:25]([CH3:29])=[N:24][C:23]=2[CH:27]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CI
Reactant: Brc1cc(OCc2ccccc2)cc2ncsc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc2cc(OCc3ccccc3)cc(Br)c2s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 1.0 M THF solution of LiHMDS (3.0 mL, 3.0 mmol) was diluted into THF (20 mL) under Ar, and the resulting solution was cooled to −78° C. 5-(benzyloxy)-7-bromobenzo[d]thiazole (4.03) (807 mg, 2.52 mmol) was added as a solution in THF (4 mL) over 2 min, washing with additional THF (3×2 mL). The resulting mixture was stirred 30 min, and MeI (0.47 mL, 7.6 mmol) was added in one portion. After stifling an additional 10 min, the mixture was removed from the cold bath and was allowed to warm to r.t. After 1.25 h at r.t., the reaction was diluted with saturated aqueous NH4Cl (50 mL), water (15 mL), and EtOAc (50 mL). The phases were separated, and the organic phase was dried over Na2SO4, filtered, and concentrated to afford a crude residue that was purified by silica gel chromatography (0-20% EtOAc in hexanes) to afford 5-(benzyloxy)-7-bromo-2-methylbenzo[d]thiazole 4.03D. LCMS-ESI+ (m/z): [M+H]+ calcd for C15H13BrNOS: 334.0. found: 334.0.
Reaction SMILES: N1C2C=CC=CC=2NC=1.[F:10][CH:11]([F:21])[C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.[NH2:22][C:23]1[C:31]([NH2:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]>>[F:10][CH:11]([F:21])[C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[C:14]1[NH:32][C:31]2[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([OH:27])=[O:26])[C:23]=2[N:22]=1
Reactant: O=Cc1ccc(F)cc1C(F)F
Reactant: Nc1cccc(C(=O)O)c1N
Agent: c1ccc2[nH]cnc2c1
Product: O=C(O)c1cccc2[nH]c(-c3ccc(F)cc3C(F)F)nc12

Procedure:
The same general procedure outlined above for the preparation of benzimidazole was used employing 2-(difluoromethyl)-4-fluorobenzaldehyde 45 and 2,3-diaminobenzoic acid 1 as the starting materials to afford 2-(2-(difluoromethyl)-4-fluorophenyl)-1H-benzo[d]imidazole-4-carboxylic acid 46. MS (ESI) calcd for C15H9F3N2O2: 306.6; found: 307 [M+H].
Reaction SMILES: O=[C:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=1[O:19][CH3:20])[CH2:3][CH2:4][C:5]([O:7]C)=O.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1>>[F:21][C:22]([F:32])([F:33])[O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[CH:2]([C:9]3[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=3[O:19][CH3:20])[CH2:3][CH2:4][C:5]2=[O:7])=[CH:26][CH:25]=1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)CCC(=O)c1c(OC)cc(OC)cc1OC
Product: COc1cc(OC)c(C2CCC(=O)N2Cc2ccc(OC(F)(F)F)cc2)c(OC)c1

Procedure:
Prepared according to the described general procedure 3 (GP3) by reaction of methyl 4-oxo-4-(2,4,6-trimethoxyphenyl)butanoate with commercially available (4-(trifluoromethoxy)phenyl)methanamine. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions D): tR=1.08 min.; [M+H]+: 425.72 g/mol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C)N1C=CC=CC1.[NH2:43][C:44](=[N:48]O)[C:45]([NH2:47])=[O:46]>CN(C)C=O>[NH2:48]/[C:44](=[N:43]\[O:10][C:9]([C@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])=[O:11])/[C:45]([NH2:47])=[O:46]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Reactant: NC(=O)C(N)=NO
Agent: CN(C)N1C=CC=CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O/N=C(\N)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
(R)-2-[2-(tert-Butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (3.47 g, 11.6 mmol) in dimethylformamide (21 ml) was treated with 1,1′-carbonyldiimidazole (1.97 g, 12.2 mmol) and the mixture was stirred at ambient temperature for 1 hour. N-Dimethylaminopyridine (1.43 g, 11.7 mmol) was then added in one portion, followed by the addition of 2-amino-2-(hydroxyimino)acetamide (1.25 g, 12.1 mmol, Helv.Chim.Acta; 47; 1964; 33-46). The resulting mixture was stirred at room temperature for 24 hours. The mixture was partitioned between ethyl acetate and a 10% solution of citric acid in demineralised water. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with demineralised water (×4) and brine, dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was crystallised from n-hexane, the precipitate was collected by filtration and dried in vacuo to afford the title compound as a colourless solid (3.30 g, 74% yield).
Reaction SMILES: [Cl:1][CH:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[NH:3]1.[C:21](OC)(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[NH2:24].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO.ClCCl.Cl.CO>[ClH:1].[CH:18]1([C:16]2[CH:17]=[C:13]([NH:12][C:10]3[C:9]4[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=4[N:3]4[C:21](=[O:29])[C:22]5[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=5[N:24]=[C:2]4[N:11]=3)[NH:14][N:15]=2)[CH2:20][CH2:19]1
Reactant: COC(=O)c1ccccc1N
Reactant: ClC1N=C(Nc2cc(C3CC3)n[nH]2)C2=C(CCCC2)N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=c1c2ccccc2nc2nc(Nc3cc(C4CC4)n[nH]3)c3c(n12)CCCC3
Yield: 7.1 %

Procedure:
(2-Chloro-1,2,5,6,7,8-hexahydro-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (150 mg, 0.518 mmol), in methyl anthranilate (0.1 ml, 0.777 mmol) was heated to 135° C. for 4 hours to give a brown gum. This was dissolved in methanol/dichloromethane and added to a mixture of ethyl acetate and aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the extracts dried over magnesium sulphate and concentrated. Purification by flash chromatography on silica gel eluting with 4% methanol/dichloromethane gave a pale yellow gum. This was dissolved in 0.5M HCl in methanol and crystallised by the dropwise addition of diethyl ether to give cream coloured crystals of 5-(5-cyclopropyl-2H-pyrazol-3-ylamino)-1,2,3,4-tetrahydro-quinazolino[3,2-a]quinazolin-12-one hydrochloride (15 mg, 7%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:32]3[CH2:37][CH2:36][C@@H:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[NH:18]C(=O)OC(C)(C)C)=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[NH2:18][CH:17]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@H:32]3[CH2:37][CH2:36][C@@H:35]([N:38]4[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]4)[CH2:34][CH2:33]3)[N:9]=2)=[CH:16][CH:15]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C(NC(=O)OC(C)(C)C)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C(N)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 0 °C
Yield: 93.6 %

Procedure:
Cis-tert-butyl N-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methyl]carbamate (2.05 g, 0.00344 mol) was triturated in anhydrous dichloromethane (50 mL) and the reaction mixture was cooled to 0° C. Trifluoroacetic acid (10 mL) was added dropwise and the resulting solution was warmed up to ambient temperature and stirred under an atmosphere of nitrogen for one and a half hour. The solvents were removed under reduced pressure, the residue suspended in water (50 mL) and basified with saturated aqueous sodium bicarbonate solution. It was extracted with dichloromethane (3×150 mL), the combined organic extracts were dried with magnesium sulfate and the solvent was removed under reduced pressure to yield cis-3-{4-[amino(phenyl)methyl]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.60 g, 0.00322 mol) as an off-white solid.
Reaction SMILES: [Cl-].[CH:2]1([CH2:7][NH2+:8][CH2:9][CH2:10]Cl)[CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[N:20]=[C:21]=[S:22]>>[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[N:20]=[C:21]1[N:8]([CH2:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:9][CH2:10][S:22]1
Reactant: ClCC[NH2+]CC1CCCC1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Agent: [Cl-]
Product: Clc1cccc(N=C2SCCN2CC2CCCC2)c1Cl

Procedure:
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopentylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3-(cyclopentylmethyl)-1,3-thiazolidine.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][C:3]=1[O:12][CH3:13].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:13][O:12][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[C:16]1[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=1)[CH:9]=[N:8][CH:7]=[CH:6]2
Reactant: COc1cc2ccncc2cc1Br
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ccncc2cc1-c1cccnc1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
7-Bromo-6-methoxyisoquinoline (100 mg), tetrakistriphenylphosphine palladium(0) (49 mg), and 3-pyridineboronic acid (155 mg) were suspended in a mixed solvent composed of N,N-dimethylformamide (1.5 ml) and a 2 N aqueous potassium carbonate solution (1.5 ml), and the mixture was stirred at 80° C. for 4.5 hr. The reaction was cooled to room temperature, the reaction solution was then filtered, and the solvent was removed from the filtrate by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with dichloromethane. The dichloromethane layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give 6-methoxy-7-pyridin-3-yl-isoquinoline (42 mg, yield 85%).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7][CH2:6]2.[I-].[Na+].Cl[CH2:17][CH2:18][CH2:19][C:20]([NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:21].[Na+].[Cl-]>CO>[CH:23]1([NH:22][C:20]([CH2:19][CH2:18][CH2:17][O:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8](=[O:13])[CH2:7][CH2:6]3)=[O:21])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: O=C(CCCCl)NC1CCCCC1
Agent: [Cl-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2cc(OCCCC(=O)NC3CCCCC3)ccc2N1
Yield: 47.8 %

Procedure:
0.5 Gram of metallic sodium is dissolved in 50 ml of methanol under ice cooling, and to this solution is added 3.2 g of 6-hydroxy-3,4-dihydrocarbostyril, 3.2 g of sodium iodide and 4.6 g of N-(4-chlorobutyryl)cyclohexylamine, followed by 5-hour refluxing under agitation. After the reaction, the reaction solution is poured into 400 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The resultant crude crystals are recrystallized from methanol to obtain 3.1 g of 6-[3-(N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with melting point of 220°-221° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[CH2:15]([C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26](=O)[C:27](OC)=[O:28])=[CH:22][NH:23]2)=[CH:19][CH:18]=1)[CH3:16].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH2:15]([C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]3[C:27](=[O:28])[NH:14][C:12](=[O:13])[C:11]=3[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:2]([CH3:1])[CH:3]=[CH:4]4)=[CH:22][NH:23]2)=[CH:19][CH:18]=1)[CH3:16]
Reactant: CCc1ccc2c(C(=O)C(=O)OC)c[nH]c2c1
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1ccc2c(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)c[nH]c2c1
Temperature: 50 °C
Reaction time: 7 h
Yield: 30 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (370 mg, 1.97 mmol) and methyl 2-(6-ethyl-1H-indol-3-yl)oxoacetate (446 mg, 1.93 mmol) in DMF (8.0 mL) at 4° C. under N2, was added a 1.0 M solution of potassium tert-butoxide in THF (6.0 mL, 6.0 mmol) dropwise over 20 min. The reaction was heated to 50° C. and stirred for 7 h at this temperature. The reaction mixture was then cooled to room temp and quenched with 1.0 N hydrochloric acid (5.0 mL), extracted with EtOAc (2×15 mL), washed with saturated NaHCO3 (30 mL), saturated NaCl (30 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 50% EtOAc/hexanes containing 1% TEA) gave the title compound (214 mg, 30%) as a red solid, mp 98–100° C. 1H NMR (DMSO-d6) δ 11.69 (s, 1H), 11.06 (s, 1H), 7.78 (m, 1H), 7.60 (m, 1H), 7.28 (m, 1H), 7.16 (s, 1H), 6.95 (m, 1H), 6.86 (m, 1H), 6.50 (m, 1H), 6.32 (m, 1H), 6.20 (m, 1H), 3.69 (s, 3H), 3.32 (m, 2H), 1.11 (m, 3H). MS (ESI, negative mode): m/z=368 [C23H19N3O2−H]−
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>CS(C)=O>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:7][CH:8]=1)=[O:1]
Reactant: NC(=O)c1cc(-c2ccc(CO)cc2)no1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cc(-c2ccc(C=O)cc2)no1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 50.3 %

Procedure:
To a solution of 3-(4-hydroxymethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 19; 100 mg, 0.46 mmol) in DMSO (1.5 mL) was added Dess-Martin periodinane (214 mg, 0.5 mmol). The mixture was stirred at room temperature for 2.5 h. Water (5 mL) was added and the mixture was filtered to give a white solid. The filtrate was extracted three times with EtOAc and the combined extracts were dried (Na2SO4), filtered and evaporated to give a residue. The white solid from the first filtration was triturated with MeOH and the mixture was filtered. The filtrate was evaporated to give a second residue. The two residues were combined and purified by chromatography (25% acetone/CH2Cl2) to give 3-(4-formyl-phenyl)-isoxazole-5-carboxylic acid amide (50 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[N:3]=1
Reactant: NCCCCCCCCN
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: NCCCCCCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[(8-aminooctyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 1,8-diaminooctane, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:5]([C:15]#[CH:16])[CH:4]=1.C(N(CC)CC)C.[Cl:24][C:25]1[N:30]=[CH:29][C:28]([O:31][CH2:32][C:33](O)=[O:34])=[CH:27][CH:26]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C1COCC1.CCOC(C)=O>[Cl:24][C:25]1[N:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([NH:1][CH2:2][C:3]2[CH:8]=[C:7]([F:9])[C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:5]([C:15]#[CH:16])[CH:4]=2)=[O:34])=[CH:27][CH:26]=1
Reactant: O=C(O)COc1ccc(Cl)nc1
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1cc(CNC(=O)COc2ccc(Cl)nc2)cc(F)c1NS(C)(=O)=O
Reaction time: 0.17 h
Yield: 22.8 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide (74.3 mg, 0.266 mmol) was suspended in THF and treated with triethylamine (27 mg, 0.266 mmol) and then the resulting mixture was stirred for 10 mins. (6-chloro-pyridin-3-yloxy)-acetic acid (50 mg, 0.266 mmol) was added to the reaction mixture followed by DMTMM (62.5 mg, 0.266 mmol) after 10 mins. The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, sat'd NaHCO3 (×3), and brine, and then dried over anh. MgSO4, filtered and concentrated under reduced pressure. The crude residue was recrystallized (CH2Cl2) to yield the title compound (25 mg, 25%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:7]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[S:5][CH:6]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[S:5][CH:6]=1
Reactant: Cc1csc(C2CCN(C(=O)OC(C)(C)C)C2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(C2CCNC2)n1
Yield: 96.1 %

Procedure:
To a solution of tert-butyl 3-(4-methylthiazol-2-yl)pyrrolidine-1-carboxylate (90 mg, 0.34 mmol) in TFA/CH2Cl2 (20%, 2 mL) was stirred at rt for 1 h and concentrated to give 4-methyl-2-(pyrrolidin-3-yl)thiazole (55 mg, 98%) as a yellow oil.