Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[C:11]1[N:19]=[CH:18][N:17]=[C:16]2[C:12]=1[NH:13][CH:14]=[N:15]2>C(O)(=O)C>[CH:2]1([CH2:8][O:9][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[NH:13][CH:14]=[N:15]3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: OCC1CCCCC1
Agent: [Na]
Solvent: CC(=O)O
Product: c1nc(OCC2CCCCC2)c2[nH]cnc2n1
Temperature: 100 °C
Reaction time: 120 h
Yield: 70 %

Procedure:
Sodium (0.4 g, 17.4 mmol) was added to stirred cyclohexylmethanol (10 ml) under nitrogen. The reaction was stirred at 100° C. until no sodium remained. 6-Chloropurine (500 mg, 3.24 mmol) was added, and the reaction was stirred under nitrogen at 100° C. for 5 days. After cooling to room temperature, the mixture was neutralised with glacal acetic acid and the solvent was removed in vacuo. Water (20 ml) was added and the product was extracted into dichloromethane (3×30 ml). The combined organic extracts were dried over MgSO4, and the volume of the solvent was doubled. After filtering hot and removal of the solvent, recrystallisation from ethyl acetate gave the title compound as a white crystalline solid (600 mg, 70%), m.p. 210-211° C.; (Found: C, 62.30; H, 6.93; N, 24.36. Calc. for C12H16N4O: C, 62.05; H, 6.94; N, 24.12%); νmax (cm−1) 3108, 3050,2930, 2849, 2801 (NH, C—H); δH (200 MHz, d6-DMSO) 8.479 (1H, s, C(2)H or C(8)H), 8.388 (1H, s, C(2)H or C(8)H), 4.348 (2H, d, J=6.2 Hz, OCH2), 1.854-1.692 (6H, m, cyclohexyl), 1.357-0.984 (5H, m, cyclohexyl); δC (50 MHz, d6-DMSO) 159.40, 155, 151.57, 142.88, 118, 71.41 (OCH2), 37.08, 29.40, 26.24, 25.47 (cyclohexyl); m/z 233 (MH+, 76%), 202 (33), 149 ([M—C6H11]+, 32%), 137 (100), 120 ([MH—C7H13O]+, 44%), 108 (30), 93 (27), 81 (65), 67 (62), 55 (88), 41 (89).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:15][C:16]1[CH:29]=[CH:28][C:19]([O:20][C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:15][C:16]1[CH:29]=[CH:28][C:19]([O:20][C:21]2[CH:27]=[CH:26][C:24]([NH:25][CH:2]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]3)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Oc3ccc(Cl)cc3)cc2)CC1
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
In a similar manner as described above in Paragraph A, a solution of 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (1 g, 4.5 mmol) and 4-(4-chlorophenoxy)aniline (1 g, 5 mmol) in dichloromethane was stirred as acetic acid (0.39 g, 6.5 mmol) was added. After 15 minutes, sodium triacetoxyborohydride (2 g, 9.4 mmol) was added and the reaction was stirred for 3 days. The reaction was treated with aqueous sodium bicarbonate. The organic layer was washed with water, dried, and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexane gave 1.3 g of 1,1-dimethylethyl 4-[[4-(4-chlorophenoxy)phenyl]amino]-1-piperidinecarboxylate.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[CH:25]>C(#N)C.CCOCC.[Cu]I>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[C:25][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C#CCCCCOCCCCCCBr
Reactant: Brc1ccc2ccccc2n1
Agent: [Cu]I
Solvent: CCOCC
Solvent: CC#N
Product: BrCCCCCCOCCCCC#Cc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.9 %

Procedure:
A mixture of 2-bromoquinoline (3.00 g), 6-[(6-bromohexyl)oxy]-1-hexyne (3.77 g), BTPC (90 mg), copper (I) iodide (11 mg) and dicyclohexyamine (2.79 g) in acetonitrile (35 ml) was stirred at room temperature under nitrogen for 20 h. The mixture was diluted with ether (90 ml), filtered and the filtrate evaporated in vacuo to give a brown oil. Purification by FCC eluting with hexane:ether (4:1→2:1) gave the title compound as a brown oil (4.25 g), t.l.c. (hexane:ether 2:1) Rf 0.22.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14]O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[BrH:22]>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][Br:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCCN(Cc2ccccc2)C1
Reactant: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: BrCC1CCCN(Cc2ccccc2)C1
Reaction time: 8 h

Procedure:
55.1 g (0.268 mol) of N-benzyl-3-(hydroxymethyl)-piperidine are added to 400 ml of 48% hydrobromic acid with vigorous stirring and the mixture is refluxed for 1 hour. Then hydrogen bromide is introduced to saturation point (about 1 hour), the mixture is refluxed for another hour and left to stand overnight. It is then neutralized with solid potassium carbonate whilst cooling with ice and then extracted with methylene chloride. The organic phase is dried over magnesium sulphate and concentrated by evaporation in vacuo. Yield: 52.0 g (72.2% of theory), Rf value: 0.85 (aluminium oxide neutral, eluant: methylene chloride).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH2:22][CH2:23][CH3:24])[N:15]=2)[CH:3]=1.[NH3:25]>CO>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:25])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH2:22][CH2:23][CH3:24])[N:15]=2)[CH:3]=1
Reactant: N
Reactant: CCCc1nc(Nc2cc(Cl)nnc2C(=O)OCC)ccc1OC
Solvent: CO
Product: CCCc1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1OC
Temperature: 50 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a mixture of ethyl 6-chloro-4-(5-methoxy-6-propylpyridin-2-ylamino)pyridazine-3-carboxylate (1.22 g, 3.48 mmol) in methanol (10 mL) was added 7 N ammonia in methanol (23.6 g, 30 mL, 210 mmol) and the mixture stirred at 50° C. in a sealed tube for 16 h. The mixture was concentrated in vacuo to give 6-chloro-4-(5-methoxy-6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (1.113 g, 3.46 mmol, 100%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.72 (s, 1H), 8.89 (s, 1H), 8.77 (s, 1H), 8.13 (s, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.01 (d, J=8.6 Hz, 1H), 3.81 (s, 3H), 2.74 (t, J=7.3 Hz, 2H), 1.75 (m, 2H), 0.97 (t, J=7.3 Hz, 3H); MS (EI/CI) m/z: 321.9 [M+H].
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[NH:7][C:8]([C:10]([O:12]CC)=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1.[OH-].[Li+].C(O)C>C1COCC1>[CH3:1][CH:2]1[C:6]2[NH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cc2c([nH]1)C(C)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1CCc2cc(C(=O)O)[nH]c21
Yield: 9.9 %

Procedure:
The title compound was synthesized from ethyl 6-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.0208 g, 0.11 mmol, 1 equiv) and lithium hydroxide (0.12 mL, 1 M aqueous, 0.12 mmol, 1.1 equiv), according to General Procedure 7. A 1:1 mixture of ethanol (EtOH) and THF (2 mL) was used. The resulting product was purified by preparative HPLC using the Chromeleon purification system. A 0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 40% methanol and increasing to 100% over 7 minutes) afforded the title compound (1.8 mg) with purity by HPLC of 100% (UV). LCMS m/e 164.2 (M−H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.23 (d, J=6.83 Hz, 3H), 1.81-2.04 (m, 1H), 2.42-2.71 (m, 3H), 3.10 (dd, J=6.69, 1.88 Hz, 1H), 6.55 (s, 1H), 8.48 (br. s, 1H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH:14]3[CH:12]([C:13]3([C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[CH3:16])[CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH:14]3[CH:12]([C:13]3([C:17]3[CH:18]=[C:19]([NH:23][S:31]([CH3:30])(=[O:33])=[O:32])[CH:20]=[CH:21][CH:22]=3)[CH3:16])[CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(c2cccc(N)c2)C2CN(CCCC3CCCCC3)CC21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCCC3CCCCC3)CC21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.6 %

Procedure:
To a solution of 3-[3-(3-cyclohexylpropyl)-6-methyl-3-azabicyclo[3.1.0]-hex-6-yl]phenylamine (Preparation 10, 25 mg, 0.08 mmol) in dichloromethane (2 ml) at 0° C. under nitrogen was added pyridine (20 μl, 0.24 mmol) then dropwise over 5 minutes methanesulfonylchloride (25 μl, 37 mg, 0.32 mmol). The mixture was allowed to warm to room temperature and was stirred for 90 minutes. Further methanesulfonylchloride (10 μl, 15 mg, 0.13 mmol) was added and the mixture was stirred for 1 hour. The mixture was concentrated in vacuo and the residue was purified by silica (5 g) column chromatography eluting with 80:20:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (18 mg, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[O:13].C(CN)O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[C:17]1[NH:11][C:12](=[O:13])[NH:14][C:15]1=[O:16]
Reactant: COc1cccc(C=O)c1
Reactant: O=C1CNC(=O)N1
Solvent: O
Solvent: NCCO
Product: COc1cccc(C=C2NC(=O)NC2=O)c1
Yield: 79.9 %

Procedure:
A mixture of m-methoxybenzaldehyde (2.00 g., 14.7 mmoles) and hydantoin (1.47 g.) in water (12 ml) was heated to 70°; monoethanolamine (1.35 g., 1.5 molar ratio) was then added and the mixture was heated in an oil bath at 90°-92° for 4 hours with magnetic stirring. Isolation in the usual manner gave the title compound as a beige solid (2.56 g.), m.p. 229°-231° .
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].Cl[C:7]1[S:8][C:9]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=1>C(#N)C>[CH2:1]([NH:5][C:7]1[S:8][C:9]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[C:10]([C:12]([F:14])([F:13])[F:15])[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: O=C(OCc1ccccc1)c1sc(Cl)nc1C(F)(F)F
Solvent: CC#N
Product: CCCCNc1nc(C(F)(F)F)c(C(=O)OCc2ccccc2)s1
Yield: 36.3 %

Procedure:
By the procedure of Example 39, a stirred mixture of 20 ml acetonitrile, 3.65 g (49.8 mmol) of n-butylamine, and 8 g (24.9 mmol) of benzyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate (prepared as described in U.S. Pat. No. 4,199,506), was heated at reflux for 24 hours. The product was separated and then recrystallized from hexane to yield 3.24 g of a yellow solid product (m.p.=77°-79° C.) identified in Table I.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.[Cl:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=1)[O:12][C@@H:13]1[CH2:18][CH2:17][N:16](C)[CH2:15][C@H:14]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=1)[O:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:15][C@H:14]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN1CC[C@@H](Oc2cccc(Cl)c2)[C@H](c2ccccc2)C1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)N1CC[C@@H](Oc2cccc(Cl)c2)[C@H](c2ccccc2)C1
Reaction time: 18 h

Procedure:
2.01 g of ethyl chloroformate are added to a mixture of 3.7 g of the free base of trans-4-(3-chlorophenoxy)-1-methyl-3-phenylpiperidine of Example 32, 2.56 g of anhydrous potassium carbonate, and 28 ml of dry benzene. The mixture is then refluxed for 18 hours under nitrogen. An additional 0.67 g of ethyl chloroformate is added, and, after 4 more hours of reflux, the mixture is cooled and partitioned between water and ether. The phases are separated and the aqueous phase is extracted with ether. The combined organic phases are washed with saturated aqueous NaCl solution, stirred for 18 hours with anhydrous MgSO4, filtered and concentrated in vacuo to an oil comprising trans-4-(3-chlorophenoxy)-1-ethoxycarbonyl-3-phenylpiperidine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[CH3:28])=[C:10]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:9]=2)[C:5](I)=[CH:4][N:3]=1.[C:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])#[CH:36].C(N(CC)CC)C.CN(C)CCN(C)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[CH3:28])=[C:10]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:9]=2)[C:5]([C:36]#[C:35][Si:37]([CH3:40])([CH3:39])[CH3:38])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cc(-c2nc(N)ncc2I)n(COCC[Si](C)(C)C)c1-c1cc(Cl)ccc1C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CN(C)CCN(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cc(-c2nc(N)ncc2C#C[Si](C)(C)C)n(COCC[Si](C)(C)C)c1-c1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
In a sealed tube filled with argon, a mixture of ethyl 5-(2-amino-5-iodopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate (612 mg, 1.0 mmol), Pd(PPh3)2Cl2 (70 mg, 0.1 mmol), CuI (19 mg, 0.1 mmol), ethynyl(trimethyl)silane (0.415 mL, 3 mmol) and triethylamine (10 mmol) in degassed ACN (10 mL) was stirred at room temperature overnight. To the reaction mixture was added N,N,N′,N′-tetramethylethylenediamine (0.3 mL, 2 mmol) and the reaction mixture stirred at the same temperature for 15 min. The solvent was evaporated under vacuum and the residue purified by flash chromatography (hexane/EtOAc 8/2) to obtain the title compound (495 mg, 85%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(OCC)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(C(=O)c2ccc(N3CCCCC3)cc2)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture consisting of 3.73 g of 1-acetyl-4-(4-fluorobenzoyl)piperidine and 3.0 ml of piperidine was stirred at 100° C. for 24 hours and the reaction mixture was then dissolved in 100 ml of ethyl acetate. The solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order and the organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed and the residue was recrystallized from ethyl acetatehexane to give 3.7 g of the title compound as colorless crystals melting at 122°-125° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]2)=[O:10])[CH2:4][CH2:3]1.[C:17](OC(=O)NC1CCNCC1)(C)(C)C>>[NH2:1][CH:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:17]2)=[O:10])[CH2:6][CH2:7]1
Reactant: NC1CCC(NC(=O)N2CC[C@@H](N)C2)CC1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: NC1CCC(NC(=O)N2CCC(N)CC2)CC1

Procedure:
4-Amino-piperidine-1-carboxylic acid (4-amino-cyclohexyl)-amide is prepared analogously to (R)-3-amino-pyrrolidine-1-carboxylic acid (4-amino-cyclohexyl)-amide (Intermediate IF) by replacing (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester with piperidin-4-yl-carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:12]([CH:13]=O)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][S:9][C:4]=2[CH:3]=1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]3)=[N:24]2)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:12]([CH2:13][NH:36][CH:33]2[CH2:32][CH2:31][N:30]([CH2:29][CH2:28][S:27][C:23]3[CH:22]=[N:21][C:20]4[C:25](=[CH:26][C:17]([O:16][CH3:15])=[CH:18][CH:19]=4)[N:24]=3)[CH2:35][CH2:34]2)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][S:9][C:4]=2[CH:3]=1
Reactant: O=Cc1cc2c(cc1Cl)SCC(=O)N2
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Product: COc1ccc2ncc(SCCN3CCC(NCc4cc5c(cc4Cl)SCC(=O)N5)CC3)nc2c1

Procedure:
The title compound is prepared as a yellow solid (24 mg, 35% yield) following Scheme 3 and in analogy to Example 40 using 7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde (30 mg, 0.12 mmol 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (40 mg, 0.12 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@H:17]([OH:37])[C@@H:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:22]=2)[NH:19][CH3:20])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][O:39][CH:40]([O:43][CH3:44])[CH2:41]Br.C(=O)([O-])O.[Na+]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@H:17]([OH:37])[C@@H:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:22]=2)[N:19]([CH2:41][CH:40]([O:43][CH3:44])[O:39][CH3:38])[CH3:20])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN[C@H](c1ccc(OC)c(OCc2ccccc2)c1)[C@@H](O)c1ccc(OC)c(OCc2ccccc2)c1
Reactant: COC(CBr)OC
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc([C@H]([C@@H](O)c2ccc(OC)c(OCc3ccccc3)c2)N(C)CC(OC)OC)cc1OCc1ccccc1

Procedure:
Mixture: 1.40 g 2.8 mmol) of rel-(1S,2R)-1,2-bis(3'-benzyloxy-4'-methoxyphenyl)-2-methylaminoethanol, 0.43 ml (0.61 g, 3.6 mmol) of bromoacetaldehyde dimethyl acetal, 0.71 g (8.4 mmol) of sodium hydrogen carbonate.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18]>C1C=CC=CC=1>[C:16]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:19])[CH:17]=[CH2:18]
Reactant: OCCCCCCBr
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CC(=O)OCCCCCCBr
Yield: 65.2 %

Procedure:
Into a reactor, 30 g of 6-bromo-1-hexanol, 18.4 g of triethylamine, and 500 ml of benzene were charged, to which a solution of 16.5 g of acryloyl chloride in 200 ml of benzene was added dropwise, while stirring and cooling with ice, and stirred for 3 hours to give a reaction solution. The reaction solution was washed with a 3N-HCl and then with water, dried over sodium sulfate anhydride, and thereafter the solvent was evaporated and the residue was purified by the silica gel column chromatography (eluent; toluene) to give 25.4 g (Y., 65.1%) of 6-bromohexyl acrylate.
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH3:18])=[CH:12][CH:11]=2.CN([CH:22]=[O:23])C>C1COCC1>[F:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[CH:22]=[O:23])=[CH:14][C:13]([O:17][CH3:18])=[CH:12][CH:11]=2
Reactant: COc1ccc2ncc(F)cc2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2ncc(F)c(C=O)c2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 52 %

Procedure:
To a solution of DIPA (15.5 mL) in THF (300 mL), cooled to −78° C., was added n-BuLi (2.35N in hexanes, 44 mL). The reaction mixture was stirred 5 min at this temperature before warming to 0° C. The reaction mixture was stirred 15 min before cooling to −78° C. 3-fluoro-6-methoxy-quinoline (15 g, 84.7 mmol; see WO 2006/058700) in THF (50 mL+10 mL rinse) was added and the mixture was stirred 3 h at −78° C. DMF (3 mL, 1.2 eq.) was added quickly (within one min). After 45 min, the reaction mixture was quenched by adding 1-propanol (8 mL). The mixture was warmed to rt and extracted twice with EA. The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue triturated in Hept to give the title intermediate as an orange solid (9.0 g, 52% yield).
Reaction SMILES: Cl.Cl.[O:3]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[NH:21][C:22]([NH2:25])=[N:23][N:24]=2)[CH2:16][CH2:15]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[Br:28][CH:29]([CH:32]=O)[CH:30]=O>O>[Br:28][C:29]1[CH:30]=[N:25][C:22]2[N:23]([N:24]=[C:20]([N:17]3[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][CH2:11][CH2:10][O:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:19][CH2:18]3)[N:21]=2)[CH:32]=1
Reactant: O=CC(Br)C=O
Reactant: Nc1nnc(N2CCN(CCCCOc3ccccc3)CC2)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Brc1cnc2nc(N3CCN(CCCCOc4ccccc4)CC3)nn2c1

Procedure:
A 10.0 g (0.03 mole) amount of 5-[4-(4-phenoxybutyl)-1-piperazinyl]-4H-1,2,4-triazol-3-amine, dihydrochloride was partially dissolved in 20 ml of water, then 5N sodium hydroxide was added to adjust the pH to just greater than pH 7, resulting in formation of a solid. The solid was collected by filtration and washed with water. The colorless crystals, were transfered into a 125 ml round bottom flask and dissolved in 50 ml of ethanol. Then 7.5 g (0.05 moles) of bromomalonaldehyde was added and the mixture was heated at reflux for 7 hours. The reaction mixture was cooled and filtered. The filter was washed with ethanol/ether, then ether. The filtrate was evaporated in vacuo, combined with the filter cake, extracted with hot chloroform and filtered. The filtrate was passed through a pad of magnesium silicate and the pad was washed with chloroform. The combined chloroform filtrate and wash was evaporated to a syrup. Crystallization from ethanol gave 2.2 g of the desired product as pale yellow crystals, mp 122°-123° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:23](=O)[CH3:24].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:14]([CH2:23][CH3:24])[CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:21][CH:20]=1
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN(Cc1ccc(Cl)cc1)C1CCNCC1
Reaction time: 10 h
Yield: 40 %

Procedure:
4-(4-Chloro-benzylamino)-piperidine-1-carboxylic acid tert-butyl ester was dissolved in CH2Cl2 and acetaldehyde (0.678 g, 3.2 mmol), Na(OAc)3BH (0.163 g, 3.7 mmol) and 1 drop of AcOH was added. The solution was stirred in a sealed vessel for 10 h. The reaction mixture was washed with 1N NaOH, brine and dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (15% ethyl acetate/85% hexane) to yield the title compound (0.350 g, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:19]([O-])=O)[C:5]2[NH:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH:7]([CH3:17])[C:6]=2[CH:18]=1.NN>CO.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[C:5]2[NH:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: CC(C)=CCN1CCNc2c(cc(Cl)cc2[N+](=O)[O-])C1C
Agent: [Ni]
Agent: NN
Solvent: CO
Product: CC(C)=CCN1CCNc2c(N)cc(Cl)cc2C1C
Yield: 100 %

Procedure:
To a solution of 1.34 parts of 7-chloro-2,3,4,5-tetrahydro-5-methyl-4-(3-methyl-2-butenyl)-9-nitro-1H-1,4-benzodiazepine (prepared as intermediate 11) in methanol there were added 0.49 parts of Raney nickel. To the resulting suspension there was added dropwise a solution of 1.09 parts of hydrazine in a small amount of methanol, at reflux temperature and under an Argon atmosphere. Refluxing was continued for 11/2 hour. After cooling, the catalyst was filtered off and the filtrate was evaporated, yielding 1.3 parts (100%) of 7-chloro-2,3,4,5-tetrahydro-5-methyl-4-(3-methyl-2-butenyl)-1H-1,4-benzodiazepin-9-amine (interm. 19).