Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[N:4]=[CH:5][S:6][C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[N:11]=1)=[CH2:2].B.C1C[O:25]CC1.OO.[OH-].[Na+]>C1COCC1.O>[OH:25][CH:1]([C:3]1[N:4]=[CH:5][S:6][C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[N:11]=1)[CH3:2]
Reactant: C1CCOC1
Reactant: C=Cc1ncsc1CSc1nc(O)cc(C(F)(F)F)n1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Product: CC(O)c1ncsc1CSc1nc(O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 2.2 %

Procedure:
To a solution of 2-{[(4-ethenyl-1,3-thiazol-5-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (see Example 167; 130 mg, 0.41 mmol) in anhydrous THF 5 mL was added borane-THF solution (1M in THF; 5.0 mL, 5.0 mmol). The mixture was stirred at room temperature for 24 hours. After cooling to 0° C., hydrogen peroxide (30%, 1.8 mL, 18 mmol) was added to the reaction mixture, followed by 10N NaOH (1.0 mL, 10 mmol). The reaction mixture was stirred for 1.5 hours, and water (25 mL) was added. The reaction mixture was extracted with ethyl acetate (3×25 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated to provide the crude product, which was purified by combiflash using 0 to 15% MeOH:CH2Cl2 to provide 2-({[4-(1-hydroxyethyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-6-(trifluoromethyl)pyrimidin-4-ol (3.0 mg). 1H NMR (500 MHz, DMSO-d6): δ 1.41 (d, 3H), 4.77 (q, 2H), 5.06 (m, 1H), 6.55 (s, 1H), 8.85 (s, 1H); M+338.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][N:10]=1.[NH:19]1[CH2:29][CH2:28][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20]1>C1COCC1>[CH2:26]([O:25][C:23]([CH:22]1[CH2:28][CH2:29][N:19]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH2:20][CH2:21]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ncnc2ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(c2ncnc3ccccc23)CC1
Yield: 92.1 %

Procedure:
Triethylamine (12.7 mL, 91.1 mmol) was added to a solution of 4-chloro-quinazoline (5.00 g, 30.4 mmol) and ethyl isonipecotate (4.78 g, 30.4 mmol) in THF (80 mL) at ambient temperature. After being refluxed for 12 hours, the mixture was concentrated in vacuo, and the resulting residue was partitioned between DCM and aqueous 0.1 M NaOH. The separated DCM layer was dried (Na2SO4), filtered, and concentrated in vacuo. The resulting solids were suspended in Et2O and filtered to give 1-quinazolin-4-yl-piperidine-4-carboxylic acid ethyl ester (8.0 g, 28.0 mmol). This material was dissolved in EtOH (50 mL) and THF (50 mL) followed by the addition of NaOH (3.73 g, 93.4 mmol) in H2O (50 mL). After being stirred for 12 hours, the mixture was neutralized with 1.0N HCl (93.5 mL) and concentrated in vacuo. After the volatile organics are removed, a white precipitate forms in the resulting aqueous solution. The solid was filtered off and air-dried to give 1-quinazolin-4-yl-piperidine-4-carboxylic acid (6.5 g). 1H NMR (DMSO-d6, 400 MHz) δ 12.28 (bs, 1H), 8.57 (s, 1H), 7.91 (m, 1H), 7.75 (m, 2H), 7.49 (m, 1H), 4.13 (m, 2H), 3.22 (m, 2H), 2.57 (m, 1H), 1.93 (m, 2H), 1.72 (m, 2H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)#[N:11].N1CCCCC1>CO>[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:14][CH:13]=1)#[N:11]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: COC(=O)CC(=O)OC
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)C(=Cc1ccc(C#N)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Dimethyl malonate (5.04 g, 38.13 mmol), 4-cyanobenzaldehyde (5.00 g, 38.13 mmol) and piperidine (0.097 g, 1.1 mmol) are dissolved in methanol (150 ml). The reaction mixture is stirred for two days (48 hours) at room temperature. The solvent is removed in vacuo to afford a viscous oil which is recrystallised from methanol.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:36][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:44]=1)[CH:40]=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:40][C:39]3[CH:42]=[C:43]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH:44]=[C:37]([O:36][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:38]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cc(OCc5ccccc5)cc(OCc5ccccc5)c4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 3,5-bis-benzyloxy benzaldehyde. MS (ESI) m/z 681.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C(O)C.[H][H]>[Pd]>[N:16]1([CH:12]2[CH2:13][CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH2:11]2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: O=[N+]([O-])c1ccc(N2CCCC(N3CCOCC3)C2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCCC(N3CCOCC3)C2)cc1
Yield: 99.5 %

Procedure:
4-[1-(4-Nitro-phenyl)-piperidin-3-yl]-morpholine (1.30 g, 4.46 mmol) was dissolved in Ethanol (35.0 mL, 599 mmol) and the solution was carefully added to 10% Palladium on Carbon (0.500 g, 37.5 mmol) under nitrogen. The mixture was then placed on a Parr hydrogenation apparatus and was allowed to shake at 55 psi until uptake of hydrogen ceased. The catalyst was then filtered to afford 1.16 g of 4-(3-Morpholin-4-yl-piperidin-1-yl)-phenylamine without further purification. (M+H)=262.7. 1H NMR (400 MHz, DMSO, d6) δ 6.67 (d, 2H, J=8.72 Hz), 6.47 (d, 2H, J=10.09 Hz), 4.54 (s, 2H), 3.55 (m, 4H), 3.41 (m, 1H), 3.22 (m, 1H), 2.51 (m, 4H), 2.40 (m, 3H), 1.86 (m, 1H), 1.76 (m, 1H), 1.56 (m, 1H), 1.18 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[CH:16]=1)([O-])=O>[Ni].C(O)C>[CH:6]1[C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[CH:16]=[C:4]([NH2:1])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)oc1ccccc12
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc2c(c1)oc1ccccc12
Reaction time: 18 h

Procedure:
Combine 3-nitrodibenzofuran (22.0 g, 0.1 mol) and Raney nickel (2.75 g), and ethanol (365 ml) and hydrogenate at room temperature and 40 psi (276 kPa). After 18 hours, filter and concentrate the filtrate to residue. Chromatograph the residue eluting with 9:1 hexane:EtOAc to give the title compound.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:12]2[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]2[CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)=[CH:21][CH:20]=1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: BrCc1ccc(Br)cc1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc(Br)cc1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 4-bromobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[O:22])[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:25][CH:24]=2)=[O:22])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2=C(C(=O)c3ccc(O)cc3)c3ccc(OC)cc3CC2)c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(C2=C(C(=O)c3ccc(OCCN4CCCCC4)cc3)c3ccc(OC)cc3CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[2-(3-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-hydroxyphenyl]methanone, (3.5 g, 9.0 mmol), anhydrous K2CO3 (6.25 g, 45 mmol), N-2-chloroethylpiperidine hydrochloride (1.75 g, 9.5 mmol, Aldrich Chem. Co.) 10 mg of KI, and anhydrous DMF (150 mL) were combined under a nitrogen atmosphere and the resulting mixture was stirred at room temperature for 16 hr. The DMF was removed under reduced pressure and the residue was distributed into water and ethyl acetate. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. After concentration to an oil, the product was purified by column chromatography over silica gel using a gradient from chloroform to 95:5 chloroform:methanol. The appropriate fractions gave, on evaporation of the solvent and vacuum drying of the residue at 80° C. overnight, an oil which weighed 3.1 g. (69%). 1H NMR (CDCl3) δ 7.80 (d, J=9.0 Hz, 2H), 7.10-7.00 (m, 1H), 6.90-6.70 (m, 6H), 6.70-6.68 (m, 2H), 4.09 (t, J=5.9 Hz, 2H), 3.78 (s, 3H), 3.65 (s, 3H), 3.02 (t, J=8.1 Hz, 2H), 2.90-2.70 (m, 4H), 2.60-2.40 (m, 3H), 1.70-1.50 (m, 5H), 1.50-1.01 (m, 2H); MS (FD) m/e 497 (M+); Anal. Calc′d. for C32H35NO4: C, 77.24; H, 7.09; N, 2.82. Found: C, 77.05; H, 7.19; N, 3.05.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:28][C:29]([CH3:31])=O>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][O:16][CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([CH:29]([CH3:31])[CH3:28])[CH2:22][CH2:23]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: CCCCC(COCC1CCNCC1)NC(=O)c1ccc2c(Cl)c[nH]c2c1
Reactant: CC(C)=O
Product: CCCCC(COCC1CCN(C(C)C)CC1)NC(=O)c1ccc2c(Cl)c[nH]c2c1

Procedure:
Using alkylation method A, 3-chloro-N-[1-butyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (0.18 mmol) and acetone (1 mL, 14 mmol) afforded, after SCX purification, 60 mg (70%) of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[OH:7])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[NH4+].[Cl-]>C1COCC1.O>[CH2:26]([C@H:8]([C@H:6]([OH:7])[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[O:15])[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)OC(=O)C[C@H](O)C(=O)OC(C)C
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)OC(=O)[C@@H](O)[C@@H](Cc1ccccc1)C(=O)OC(C)C
Temperature: 20 °C
Reaction time: 16 h
Yield: 42.5 %

Procedure:
To a cold (−78° C.) solution of diisopropyl-(S)-(−)-malate (4.72 mL, 22.9 mmol, 1 eq.) in anhydrous THF (8.50 mL) was added slowly a solution (1 M) of lithium bis(trimethylsilyl)amide (48.1 mL, 48.1 eq., 2.10 eq.) in tetrahydrofuran. The temperature was raised to 20° C. over 30 minutes, than lowered again to −78° C. Benzyl bromide (4.70 g; 27.5 mmol; 1.20 eq.) was added and the mixture stirred at RT for 16 hours. The reaction mixture was then cooled to 0° C. and a saturated solution of NH4Cl was added. The resulting mixture was diluted with water, extracted three times with EtOAc. The combined organic layers were washed with brine and dried over MgSO4, filtered and evaporated under reduced pressure. The residue was then purified by chromatography (SiO2, 20/80 EtOAc/c-hex) to give the product as a colourless oil (3.00 g, 42%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[O:34]1[CH2:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH2:36][CH2:35]1.O1CCOCC1>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.CO.O>[O:34]1[CH2:35][CH:36]=[C:37]([C:2]2[CH:3]=[C:4]3[C@:15]4([CH2:19][S:18][C:17]([NH2:20])=[N:16]4)[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:21]5[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=5)[CH:13]=4)[O:8][C:5]3=[N:6][CH:7]=2)[CH2:38][CH2:39]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1ncc(C3=CCOCC3)cc12
Temperature: 100 °C
Yield: 81.5 %

Procedure:
A microwave vessel was charged with (S)-3-bromo-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (0.12 g, 0.27 mmol), potassium carbonate (0.19 g, 1.35 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.11 g, 0.54 mmol), tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), dioxane (1.81 mL) and water (0.90 mL). The reaction was heated in a microwave at 100° C. for 45 min. After cooling to rt, the organic layer was separated with a separatory funnel, dried over sodium sulfate, filtered, and concentrated to afford a yellow oil which was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-100% EtOAc in 90/10 CH2Cl2:CH3OH to provide a white solid, (S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (0.1 g, 0.22 mmol, 83% yield). MS m/z=447.2 [M+H]+. Calc'd for C24H19FN4O2S: 446.5.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:15])(=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[S:25])=[CH:19][CH:18]=1>C1C=CC=CC=1.CCCCC>[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:14][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:25])=[CH:19][CH:18]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: CCCCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCCCC
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CCCCCCC(=N)NC(=S)Nc1ccc(F)cc1

Procedure:
Following a procedure similar to that described in Example 1 but using 1.6 g. sodium in 200 ml. dry acetone, 12.3 g. heptanamidine hydrochloride, and 11.6 g. 4-fluorophenyl isothiocyanate (b.p. 48° C./0.025 mm.; prepared from 4-fluoroaniline) in 50 ml. dry acetone there was obtained 1-(4-fluorophenyl)-3-(heptanimidoyl)-2-thiourea, m.p. 75°-76° C. (from benzene-n-pentane); hydrochloride (17.1 g.), m.p. 155° C. (from acetonitrile).
Reaction SMILES: CO[C:3](=[O:28])[CH:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:10][CH2:9]1)[CH2:5][CH2:6][OH:7].ClC1C=C(/C=C/[C:39]([N:41]2CCC(=O)N(C3CCOC3=O)C[CH2:42]2)=O)C=CC=1Cl.N1CCCCC1>CCO>[Cl:26][C:21]1[CH:20]=[C:19](/[CH:18]=[CH:17]/[C:16]([N:11]2[CH2:12][CH2:13][C:14](=[O:15])[N:8]([CH:4]([CH2:5][CH2:6][OH:7])[C:3]([N:41]([CH3:42])[CH3:39])=[O:28])[CH2:9][CH2:10]2)=[O:27])[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: COC(=O)C(CCO)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Reactant: O=C1OCCC1N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)C(=O)C(CCO)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Yield: 43 %

Procedure:
In analogy to the procedure described in example 3, treatment of (rac)-2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-4-hydroxy-butyric acid methyl ester (with 50% of the lactone, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(2-oxo-tetrahydro-furan-3-yl)-[1,4]diazepan-5-one) (intermediate 6) in EtOH with piperidine for 1.5 days at 60° C. and 2 days at RT gave 43% of the titled compound as light yellow foam. MS: 482.2 (MH+, 2Cl).
Reaction SMILES: [CH2:1]1[CH2:16][O:15][C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][C:4]2([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH3:9])[O:2]1.[H-].[Na+]>C1C=CC=CC=1>[CH2:9]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][C:4]1([CH3:9])[CH2:5][CH2:6][CH2:7][CH2:8][C:3]21[O:2][CH2:1][CH2:16][O:15]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:3]=1
Reactant: CC1(CCCCO)CCCCC12OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC1(CCCCOCc2ccccc2)CCCCC12OCCO2
Temperature: 25 °C

Procedure:
A solution of 1,1-ethylenedioxy-2-(4'-hydroxybutyl)-2-methylcyclohexane (26 g, 0.136 mol.) in benzene (100 ml) is added to a suspension of sodium hydride (6.53 g, 0.272 mol; 13.05 g of a 50% mineral oil dispersion freshly washed with pentane and benzene) in benzene (500 ml) in a nitrogen atmosphere. After 30 minutes benzylbromide (35 g, 020 mol) in benzene (100 ml) is added and the mixture is heated at reflux for 20 hours. The reaction mixture is cooled to room temperature and diluted with water (100 ml) and ether (500 ml). The organic layers are separated and washed with satd. NaCl (2×400 ml) and dried (MgSO4). The solvents are removed under reduced pressure and the crude product is chromatographed on SilicAR CC-7 (575 g) in hexane. Elution with 5% ethyl acetate/hexane gives 2-(4'-benzyloxybutyl)-1,1-ethylenedioxy-2-methylcyclohexane as a slightly yellowish oil (32.45 g, 90%): nmr (CDCl3)δ0.98 (s, 3H, CH3), 3.5 (t, 2H, --O--CH2 --CH2), 3.98 (s, 4H, ketal) 4.44 (s, 2H, O--CH2 --Ph), 7.3 (s, 5H, aromatic).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>C(OCC)C>[CH3:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:25]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=3)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(COc2cccnc2N)cc1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1ccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 2-amino-3-(4-methylbenzyloxy)pyridine (1.45 g, 0.0068 mol), 4chlorophenyl isothiocyanate (1.38 g, 0.008 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 1.8 g (70%), m.p. 145°-147 ° C.
Reaction SMILES: [ClH:1].[S:2]1[CH2:6][CH:5]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH:10]2[CH3:23])[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[CH3:28]OC1C(N2CCNC(C)C2)=NC=CC=1>>[ClH:1].[S:2]1[CH2:6][CH:5]([CH:7]([CH3:28])[CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH:10]2[CH3:23])[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2
Reactant: COc1cccnc1N1CCNC(C)C1
Reactant: COc1cccnc1N1CCN(CCC2CSc3ccccc32)C(C)C1
Agent: Cl
Product: COc1cccnc1N1CCN(CC(C)C2CSc3ccccc32)C(C)C1

Procedure:
The title compound was prepared (48%, mp 167°-170° C.) in a manner analogous to the preparation of 1-[2-(2,3-dihydrobenzo[b]thien-3-yl)ethyl]-4-(3-methoxy-2-pyridinyl)-2-methylpiperazine hydrochloride (Example 6) by the reaction of 2,3-dihydro-3-benzo[b]-thienepropanol tosylate with 1-(3-methoxy-2-pyridinyl)-3-methylpiperazine.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[C:21]([O:25][C:26]([NH:28][CH:29]1[CH:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:21]([O:25][C:26]([NH:28][CH:29]1[CH:33]([CH3:34])[CH2:32][N:31]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[CH:5][C:4]=2[F:19])[CH2:30]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CC1CNCC1NC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CC1NC(=O)OC(C)(C)C
Yield: 50 %

Procedure:
A mixture of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), 3-t-butoxycarbonylamino-4-methylpyrrolidine (0.5 g) and DBU (0.25 g) was refluxed for an hour. The reacting mixture was concentrated under reduced pressure, to the resulting residue was added acetonitrile-ether (1:1) to crystallize and the precipitate was collected by filtration. This precipitate was recrystallized from dichloromethane-methanol to give the title compound (0.4 g) as pale yellow powder, mp 213°-215° C.
Reaction SMILES: [C:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:11]3[NH:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:21](N1C=CN=C1)(N1C=CN=C1)=[S:22]>O1CCCC1>[C:1]1([C:7]2[N:12]3[C:11]4[N:10]([C:21](=[S:22])[NH:18][C:16](=[O:17])[C:15]=4[CH:14]=[N:13]3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1cnn2c1NCC=C2c1ccccc1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c(=S)n2c3c1cnn3C(c1ccccc1)=CC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
A mixture of 7.6 g of 4,5-dihydro-7-phenyl-pyrazolo(1,5-a)pyrimidine-3-carboxamide (prepared as described in Example 25 of commonly assigned U.S. Pat. No. 4,847,256) in 304 ml of dry tetrahydrofuran is stirred and cooled at -78° C., under nitrogen and 2.17 g of sodium hydride (60 percent dispersion in mineral oil) is added. The mixture is stirred at -78° C. for 30 minutes, then 4.84 g of 1,1'-thiocarbonyldiimidazole is added in one portion and the temperature is kept at -78° C. for 2 hours and then is allowed to rise slowly to room temperature. Stirring is continued for 48 hours, and then the reaction mixture is quenched with 500 ml of water and neutralized with 5 percent aqueous hydrochloric acid. A crystalline solid forms which is collected by filtration, triturated with ether, filtered and dried to give 3.2 g of the desired product as white crystals, mp 289-291° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:15]=1)[C:9](N(OC)C)=[O:10])[CH3:2].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:15]=[C:8]([CH:9]=[O:10])[CH:7]=[N:6][CH:5]=1)[CH3:2]
Reactant: CCOc1cncc(C(=O)N(C)OC)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CCOc1cncc(C=O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 15-3 (14.0 g, 66.5 mmol) and CH2Cl2 (200 mL) at -78° C. under argon was added DIBAL (1.0M hexanes, 90 ml) dropwise over 30 minutes. After 30 minutes, the solution was warmed to 0° C. for 1 hour. The reaction was quenched with 100 ml 1.0M Rochelle's salt, stirred for 1.0 hour and then extracted with Et2O. The organic layer was dried (MgSO4), and then concentrated to give the aldehyde 15-4 as a brown oil.