Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:43])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]2C(=O)C3=CC=CC=C3C2=O)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].O.NN>C(O)C>[CH3:43][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:5]=1[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])=[O:22]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1
Agent: NN
Solvent: O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCCCN)C1c1cccc([N+](=O)[O-])c1
Yield: 48.1 %

Procedure:
A solution of 16 g of methyl 8-phthalimidooctyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 6.8 g of hydrazine monohydrate in 160 ml of ethanol was refluxed for 2 hours under heating. Precipitates (solid) thue formed was removed by filtration. The filtrate was concentrated under reduced pressure and after adding chloroform to the residue, precipitates again removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The product was eluted with chloroform-methanol (8:2 v/v), and crude crystals were recrystallized from ethanol-petroleum ether to provide 6 g of 8-aminooctyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[CH2:18][O:19][C:20]1[CH:52]=[CH:51][C:23]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[N:27](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:26]2=[O:50])=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[CH2:18][O:19][C:20]1[CH:52]=[CH:51][C:23]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[NH:27][C:26]2=[O:50])=[CH:22][CH:21]=1
Reactant: CN1c2ccccc2CC1COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1c2ccccc2CC1COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
3.1 ml of trifluoroacetic acid were added to a solution of 2.50 g of 5-[4-(1-methylindolin-2-ylmethoxy)benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 7) in 25 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was worked up following the procedure described in Example 1, to give 1.20 g of the title compound, melting at 46.1-48.9° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[I:10])=[O:4].[Li]>O1CCOCC1.O>[I:10][C:9]1[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1I
Agent: [Li]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1sc(-c2ccccc2)cc1I
Reaction time: 21.5 h
Yield: 97.6 %

Procedure:
A solution of 3-Iodo-5-phenyl-thiophene-2-carboxylic acid methyl ester (4.4 g, 12.78 mmol) in dioxane/water 4/1 (50 ml), at 21° C., under N2, was treated with lithium hydroxyde (2N, 19.3 ml, 38 mmol) and the solution left to stir for 21.5 h. The reaction mixture was evaporated to dryness and the residue partitioned between EtOAc (75 ml) and water (25 ml) and acidified with 2N HCl to pH 5.5. The aqueous phase was separated and extracted with EtOAc (3×50 ml). The combined organic extract were washed with brine, dried and evaporated to give 4.12 g (97%) of 3-Iodo-5-phenyl-thiophene-2-carboxylic acid as a pale yellow solid. NMR 1H (CD3OD, 400 MHz): 7.69-7.67 (m, 2H); 7.55 (s, 1H); 7.46-7.39 (m, 3H).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([CH3:36])[C:20]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:21][C:22]=3[C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)[C:17]2=[O:37])=[C:13]([CH3:38])[CH:12]=[C:11]([CH3:39])[N:10]=1)C1C=CC=CC=1>CO.[Pd]>[CH3:38][C:13]1[CH:12]=[C:11]([CH3:39])[NH:10][C:9](=[O:8])[C:14]=1[CH2:15][N:16]1[CH2:25][CH2:24][C:23]2[C:18](=[C:19]([CH3:36])[C:20]([O:32][CH:33]([CH3:34])[CH3:35])=[CH:21][C:22]=2[C:26]2[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=2)[C:17]1=[O:37]
Reactant: Cc1cc(C)c(CN2CCc3c(-c4cnn(C)c4)cc(OC(C)C)c(C)c3C2=O)c(OCc2ccccc2)n1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(CN2CCc3c(-c4cnn(C)c4)cc(OC(C)C)c(C)c3C2=O)c(=O)[nH]1
Yield: 57.5 %

Procedure:
A mixture of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-methyl-5-(1-methyl-1H-pyrazol-4-yl)-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (108k, 40 mg, 0.076 mmol) and 10% Pd/C (20 mg) in MeOH (10 mL) was hydrogenated under an H2 balloon at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by prep. TLC (EtOAc) to give the title compound (Example 108, 19 mg, 58%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 7.72 (s, 1H), 7.56 (s, 1H), 7.03 (s, 1H), 6.11 (s, 1H), 4.78 (s, 3H), 4.6-4.57 (m, 1H), 3.92 (s, 3H), 3.92 (s, 3H), 2.82-2.81 (m, 2H), 2.47 (s, 3H), 2.28-2.24 (m, 5H), 1.34-1.32 (d, 6H); MS 435.2 [M+H].
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:16](OC)=[O:17])=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1)#[N:2].Cl.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C.CN(C=O)C>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:16]([NH:28][CH:25]3[CH2:27][CH2:26]3)=[O:17])=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1)#[N:2]
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(C#N)nncc3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C#N)nncc2c1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To methyl 3-(1-cyanophthalazin-6-yl)-4-methylbenzoate (0.800 g, 2.6 mmol) was added 6N HCl (10.6 mL) and the reaction was heated in a microwave oven for 25 min at 120° C. The reaction was concentrated, dried in vacuo and DMF (5.3 mL) and cyclopropylamine (0.92 mL, 13 mmol) were added. HATU (2.0 g, 5.3 mmol) was added and the reaction mixture was stirred at RT for 1 h, then diluted with 75 mL ethyl acetate, partitioned with sodium bicarbonate (saturated, aqueous), and the organic layers were washed 2×20 mL with sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, concentrated in vacuo, and purified by HPLC to give the title compound. MS (ES+): 329(M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3].[CH2:24]([S:31](Cl)(=[O:33])=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:24]([S:31]([NH:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3])(=[O:33])=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Solvent: CN(C)C=O
Product: CC1C(=O)N(C(=O)[C@H](C)NS(=O)(=O)Cc2ccccc2)c2cccc(N)c2-c2ccccc21
Temperature: 25 °C
Reaction time: 84 h
Yield: 34.7 %

Procedure:
To 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7B) (0.2050 g, 0.66 mmol) in DMF (5 ml) was added benzylsulfonyl chloride (Aldrich) (0.0632 g, 0.33 mmol), stirred at RT for 3.5 days. The reaction mixture was evaporated to dryness. Water was added, extracted with CH2Cl2, washed with brine, dried over MgSO4. Evaporation and flash chromatography (silica, 5% MeOH /CH2Cl2), gave a residue, which was washed with Et2O /hexane (1:2, v/v) to give the title compound (0.0531 g, 35%) as a light yellow solid.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH:7]2[CH2:8][CH2:9][C:4]3([O:11][CH2:1][CH2:2][O:3]3)[CH2:5][CH2:6]2)[CH2:22][CH2:21]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccccc1N1CCN(C2CCC3(CC2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
A solution of 1,4-cyclohexanedione monoethylene ketal (4.68 g, 30 mmol), 1-(2-methoxy-phenyl)piperazine (5.8 g, 30 mmol), sodium triacetoxyborohydride (9 g, 42 mmol) and acetic acid (1.8 ml, 30 mmol) in 1,2-dichloroethane (8 ml) was allowed to stir at room temperature for 12 hours. The reaction was quenched with 1N sodium hydroxide (pH>9), and extracted with methylene chloride (3×100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) afforded 9.0 g (90%) of product as a semi-solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]1[C:24]([C:25](Cl)=[O:26])=[C:23]([CH3:28])[O:22][N:21]=1>>[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:25]([C:24]1[C:20]([C:14]2[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:13]=2[Cl:12])=[N:21][O:22][C:23]=1[CH3:28])=[O:26]
Reactant: COC(=O)CCCCCN
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Agent: Cl
Product: COC(=O)CCCCCNC(=O)c1c(-c2c(F)cccc2Cl)noc1C
Yield: 303.4 %

Procedure:
Methyl-6-aminohexanoate hydrochloride (349 mg, 1.92 mmol) and 3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-oyl chloride (527 mg, 1.92 mmol) were converted to 2.23 g of the title compound by the procedure of Preparation 10. (100%). EA calculated for: C18H20N2O4ClF: C, 56.48; H, 5.27; N, 7.32. Found: C, 56.66; H, 5.20; N, 7.07. MS(FD) m/z 382.2 (M+).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].[C:17](OC)(=[O:22])[C:18]([O:20][CH3:21])=[O:19]>C1COCC1>[C:1]1(/[CH:7]=[CH:8]\[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(=O)OC
Reactant: Brc1ccccc1C=Cc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccccc1/C=C\c1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A solution of the Grignard agent prepared from part of the mixture of isomers of 1-phenyl-2-(2-bromophenyl)ethylene described above (5.58 g) and magnesium (0.63 g) in dry THF (20 ml) was added dropwise over 30 mins. to a stirred solution of dimethyl oxalate (5.06 g) in dry THF (40 ml) cooled to -15° C. The resulting mixture was stirred at about -15° C. for 30 minutes, then at room temperature for 1 hour, then poured into dilute hydrochlorice acid and extracted with ether. The extracts were washed with water, dried, concentrated under reduced pressure, then chromatographed twice [(i) 30% ether in petrol; (ii) 20% hexane in dichloromethane] to give isomerically pure Z-methyl 2-(2'-phenylethenyl)phenylglyoxalate (1.76 g, 31% yield) as a yellow oil, 1H nmr (CDCl3): delta 3.87 (3H, s), 6.78 centre of 2 doublets, each 1 H, J 12 Hz) p.p.m.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CN1CCOCC1>CN1CCCC1=O>[N:17]1[CH:18]=[CH:19][C:14]([N:1]2[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]2)=[CH:15][CH:16]=1
Reactant: Clc1ccncc1
Reactant: CCOC(=O)C1CCNCC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CCN(c2ccncc2)CC1

Procedure:
Ethyl isonipecotate (6.0 g, 38.66 mmol), 4-chloropyridine hydrochloride (5.9 g, 38.66 mmol) and N-methylmorpholine (9.3 mL, 85.0 mmol) were dissolved in N-methylpyrrolidinone (50 mL) and the resulting solution heated at 100° for 48 h. The solution was concentrated in vacuo and the residue dissolved in ethyl acetate (200 mL), washed with water and brine (2×100 mL), then dried (Na2SO4) and evaporated. The resulting residue was purified by flash chromatography (5%MeOH/CH2Cl2) to afford 21-1 as a crystalline solid.
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[CH3:17][C:18]([CH3:20])=[O:19]>C1COCC1>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:18]([OH:19])([CH3:20])[CH3:17])=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC(C)=O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC(C)(O)c1ccc(C(F)(F)F)cc1
Reaction time: 0.75 h

Procedure:
To magnesium turnings (30.2 g, 1.24 mol) in THF (30 mL) is added 1,2-dibromoethane (0.7 mL) followed by dropwise addition, over 1 h, of 4-bromotrifluoromethylbenzene (200 g, 0.89 mol) dissolved in THF (700 mL). The reaction is heated occasionally to maintain a gentle reflux and is stirred 45 min after the addition is complete. The dark reaction mixture is then cooled in an ice bath and acetone (103 g, 1.78 mol) added dropwise. After stirring an additional 1.5 h the reaction is carefully quenched with aqueous saturated NaHSO4, ethyl acetate added, the organics dried over MgSO4, concentrated and purified by silica gel chromatography (9:1 to 3:2, hexane to ethyl acetate) to give 4-trifluoromethyl-α,α-dimethylbenzyl alcohol of sufficient purity to carry to the next step; yield: 114 g (63%).
Reaction SMILES: [OH:1][C@@H:2]([CH2:22][OH:23])[C@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>CN(C=O)C>[Si:29]([O:23][CH2:22][C@H:2]([OH:1])[C@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N[C@H](c1ccc(C(F)(F)F)cc1)[C@@H](O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](c1ccc(C(F)(F)F)cc1)[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
tert-Butyl (1R,2R)-2,3-dihydroxy-1-(4-(trifluoromethyl)phenyl)-propylcarbamate (11 g, 32.8 mol) in 100 mL DMF was cooled in an ice-water bath. 1H-imidazole (8.2 mL, 72 mol) was added in one portion, and the mixture was stirred for 10 minutes under nitrogen. tert-Butyldimethylsilylchloride (5.43 g, 36.0 mmol) in 20 mL DMF was then added via syringe. The reaction was monitored by TLC. After 16 hours, DMF was evaporated under high vacuum. Distilled water (150 mL) was added, and the resulting mixture was extracted into diethyl ether (2×200 mL). The ether layer was washed with saturated aqueous ammonia chloride and dried over sodium sulfate. After removing the solvent, the product was obtained as a white solid (14.0 g, yield=95%). 1H NMR (400 MHz, CD3OD) δ ppm 0.08-0.12 (m, 6 H) 0.97 (s, 9 H) 1.43 (s, 9 H) 3.50 (s, 1H) 3.63 (s, 1H) 3.85 (s, 1H) 4.81 (s, 1H) 7.53-7.58 (m, 2H) 7.60-7.66 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6](=N)[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[S:20])[N:3]1[CH2:21][CH2:22][O:23][CH3:24].C(Cl)Cl.CC(C)=[O:31]>>[CH3:1][C:2]1([CH3:25])[C:6](=[O:31])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:18])([F:17])[F:19])[CH:9]=2)[C:4](=[S:20])[N:3]1[CH2:21][CH2:22][O:23][CH3:24]
Reactant: COCCN1C(=S)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=N)C1(C)C
Reactant: CC(C)=O
Solvent: ClCCl
Product: COCCN1C(=S)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(C)C

Procedure:
Using the procedure of Example 71, the product of Example 78 was reacted to obtain the expected product melting at 98°-99° C. with a Rf=0.32 (eluant: methylene chloride--acetone (99-1))
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([Cl:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][N:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[C:24]([Cl:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=1
Reactant: NCc1ccccc1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3cnccn3)nc(NCc3ccccc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyrazin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-benzylamino-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[OH:11].[O:12]1[C:16]2[CH:17]=[CH:18]C=CC=2N=C1>>[O:12]1[CH2:16][CH:17]1[CH2:18][O:11][C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: Oc1cnc2ccccc2n1
Reactant: c1ccc2ocnc2c1
Product: c1ccc2nc(OCC3CO3)cnc2c1

Procedure:
Compound 71 was prepared in the manner of compound 6 substituting quinoxaline-2-ol for compound 8 in part C-5 of Example 1.
Reaction SMILES: [OH-:1].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[S:14][CH:13]=[CH:12][C:11]=3[C:6]=2S[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:4]([C:15]1[CH:16]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3](=[O:2])[N:7]2[C:6]=1[C:11]1[CH:12]=[CH:13][S:14][C:10]=1[CH2:9][CH2:8]2)(=[O:1])[CH3:3]
Reactant: Oc1c(-c2ccccc2)sc2[n+]1CCc1sccc1-2
Reactant: [OH-]
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1ccsc1CC2

Procedure:
A solution of 1 g of 5,6-dihydro-3-hydroxy-2-phenyl-thiazolo[3,2-a]thieno[3,2-c]pyridinium hydroxide (internal salt) and 0.23 g of 3-butyl-2-one in 10 ml of toluene was stirred at room temperature for 48 hours. The solution was evaporated in vacuo and the residue was chromatographed on silica gel with toluene/ethyl acetate (9:1). There was obtained pure 10-acetyl-4,5-dihydro-8-phenyl-7H-thieno-[3,2-a]quinolizin-7 one of m.p. 181°-182° (from ethyl acetate).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]=O)=[CH:14][C:13]=2[CH:19]=1>C(O)(C)C>[N:2]1([N:1]=[CH:17][C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([Cl:8])=[CH:19][C:13]=3[CH:14]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: O=Cc1cc2cc(Cl)ccc2o1
Reactant: NN1CCNCC1
Solvent: CC(C)O
Product: Clc1ccc2oc(C=NN3CCNCC3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
1-Aminopiperazine (29 g, 287 mmol) was dissolved in isopropyl alcohol (173 ml), to which 5-chlorobenzofuran-2-aldehyde (34.52 g, 191 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford piperazin-1-yl-(5-chlorobenzofuran-2-yl methylene)amine (49.49 g, yield 98%) as a yellow crystalline powder.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][N:9]=1.[O:15]1[CH2:20][CH2:19][CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH2:16]1>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:13]1[C:8]([C:17]2[CH2:16][O:15][CH2:20][CH2:19][CH:18]=2)=[N:9][CH:10]=[CH:11][N:12]=1
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Reactant: Clc1nccnc1Cl
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: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Clc1nccnc1C1=CCCOC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Sodium carbonate (6.48 mL, 12.95 mmol, 2.0 M in water) was added to a stirred mixture of 2,3-dichloropyrazine (1.28 mL, 8.63 mmol), 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.91 g, 4.32 mmol), and tetrakis(triphenylphosphine)palladium (0.50 g, 0.43 mmol) in dioxane (16 mL) under an argon atmosphere. The reaction mixture was stirred at 80° C. for 16 h before being cooled to room temperature and diluted with EtOAc. The mixture was washed with water, washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give 2-chloro-3-(5,6-dihydro-2H-pyran-3-yl)pyrazine. [M+1]=197.0.
Reaction SMILES: C([O:8][C:9]1[C:10]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:11]=2[C:12]2[CH:13]([CH2:25][Cl:26])[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:16]=2[CH:17]=1)C1C=CC=CC=1.N#N>CCOC(C)=O.C1COCC1.[Pd]>[C:21]([O:20][C:18]([N:15]1[C:16]2[CH:17]=[C:9]([OH:8])[C:10]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:11]=3[C:12]=2[CH:13]([CH2:25][Cl:26])[CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(OCc1ccccc1)c1ccc(C#N)cc21
Agent: [Pd]
Agent: N#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(O)c1ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.1 %

Procedure:
A solution of 22 (71.5 mg, 0.159 mmol) and 10% Pd-C (40 mg) in anhydrous EtOAc (5 mL) was degassed with a stream of N2 for 30 s. The resulting mixture was placed under an atmosphere of H2 and stirred at 25° C. for 2.5 h. The mixture was diluted with THF (1 mL) and filtered through Celite (EtOAc wash). The solvent was removed in vacuo. Chromatography (SiO2, 1.5×6 cm, 20% EtOAc-hexane) afforded 23 (57.1 mg, 57.1 mg theoretical, 100%) as a white solid: 1H NMR (CDCl3, 400 MHz) δ8.25 (d, 1H, J=8.7 Hz, C6-H), 7.97 (s, 1H, C9-H), 7.87 (br s, 1H, C4-H), 7.42 (dd, 1H, J=1.5, 8.7 Hz, C7-H), 6.67 (br s, 1H, OH), 4.23 (d, 1H, J=11.4 Hz, C2-H), 4.14 (dd, 1H, J=8.8, 11.8 Hz, C2-H), 3.95 (m, 1H, C1-H), 3.82 (dd, 1H, J=3.2, 11.3 Hz, CHHCl), 3.46 (dd, 1H, J=9.8, 11.2 Hz, CHHCl), 1.59 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ154.2, 153.1, 142.9, 129.4, 127.8, 125.2, 123.2, 122.8, 119.3, 114.7, 111.0, 101.7, 82.5, 53.3, 46.3, 41.3, 28.4; IR (film) vmax 3315 (br), 2964, 2923, 2227, 1676, 1585, 1421, 1369, 1331, 1235, 1141, 729 cm-1 ; FABHRMS (NBA) m/z 358.1076 (M+ +H, C19H19ClN2O3 requires 358.1084).
Reaction SMILES: Cl.[N:2]1[C:10]2[CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:14]O>S(=O)(=O)(O)O>[CH3:14][O:12][C:11]([CH:8]1[CH2:9][C:10]2[N:2]=[CH:3][CH:4]=[CH:5][C:6]=2[CH2:7]1)=[O:13]
Reactant: CO
Reactant: O=C(O)C1Cc2cccnc2C1
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)C1Cc2cccnc2C1

Procedure:
A solution 6,7-dihydro-5H-[1]pyrindine-6-carboxylic acid hydrochloride (Example 88; 0.640 g, 3.21 mmol) and concentrated sulphuric acid (3 drops) in methanol (100 ml) is heated to reflux for 3 hours. The solvent is evaporated, the residue is treated with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic phases are washed with brine, dried (MgSO4) and evaporated to afford 6,7-dihydro-5H-[1]pyrindine-6-carboxylic acid methyl ester, MH+178.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16]C3C=CC=C4C(NC(=O)C=34)=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:29]N>C(O)C>[NH2:29][CH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][CH2:11]1
Reactant: NN
Reactant: O=C1NC(=O)c2c(CCCCN3CCC(c4ccccc4)CC3)cccc21
Solvent: CCO
Solvent: O
Product: NCCCCN1CCC(c2ccccc2)CC1

Procedure:
To a solution of 10.38 g (28.64 mM) of 4-(4-phenylpiperidin-1-yl)butan-1-ylphthalimide in ethanol (160 ml) was added 4.2 ml (86.58 mM) of hydrazine monohydrate at room temperature and the mixture was refluxed for 1.5 hours. The white solid that formed was filtered off and the solvent was distilled off under reduced pressure. The residue was diluted with aqueous solution of sodium hydroxide and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide the title compound.