Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][N:7](N)[C:6]=2[CH:15]=1.[C:16]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][N:7]3[C:6]=2[C:15]=1[C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=13
Reactant: CN1CCc2ccc(Cl)cc2N(N)CC1
Reactant: O=C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCCO
Product: CN1CCc2ccc(Cl)c3c4c(n(c23)CC1)CCCC4
Temperature: 25 °C
Yield: 48 %

Procedure:
To a solution of 9-chloro-4-methyl-3,4,5,6-tetrahydro-2H-benzo[e][1,4]diazocin-1-ylamine (4.9 g, 22.0 mmole) in 1-propanol (300 mL) was added cyclohexanone (25.0 ml, 240.0 mmole), followed by p-toluenesulfonic acid monohydrate (10.0 g, 50.0 mmole), and the resulting reaction mixture was refluxed for 30 hours. The reaction mixture was cooled to room temperature and solvent removed in vacuo to produce a brown residue. The residue was diluted with methylene chloride (300 mL) and washed with saturated aqueous sodium bicarbonate (200 mL), saturated aqueous sodium chloride (200 mL), dried (sodium sulfate) and concentrated in vacuo. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 1:1) provided 3.05 g of the title compound. 0.335 g of the free amine was treated with one equivalent of fumaric acid in ethanol to form a fumarate salt (0.544 g, mp 212-214° C.). MS (ES) m/z 289 ([M+H]+).
Reaction SMILES: N.C[N:3]([CH:5]=[O:6])C.[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:17]([CH3:32])=[C:18](C(O)=O)[CH:19]=[C:20]4[C:28]=3[C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=[CH:21]4)=[CH:15][C:10]=2[O:9][CH2:8]1>O>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:17]([CH3:32])=[C:18]([C:5]([NH2:3])=[O:6])[CH:19]=[C:20]4[C:28]=3[C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=[CH:21]4)=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: Cc1c(C(=O)O)cc2ccc3c(c2c1-c1ccc2c(c1)OCO2)OCO3
Reactant: CN(C)C=O
Agent: N
Solvent: O
Product: Cc1c(C(N)=O)cc2ccc3c(c2c1-c1ccc2c(c1)OCO2)OCO3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
WSC[1-Ethyl-3-(3-dimethylaminopropyl) carbodimide hydrochloride](33 mg) and ammonia (3N ethanol solution:0.14 ml) were added under ice-cooling to a DMF solution of 9-(1,3-benzodioxole-5yl)-8-methyl-naphtho[1,2-d]-1,3,-dioxole-7-carboxylic acid (50 mg) which was prepared in Reference Example 13. The mixture was stirred at room temperature for 2 hours, and the reaction was stopped with addition of water. The residue was purified with column chromatography (Silica-Gel 5 g, eluent:ethyl acetate-hexane=1:1) and recrystalized from methanol to yield the title compound (23 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH:12]=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C([O-])(=O)C.[Na+].Cl.[CH2:20]([O:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[CH3:1][O:2][C:3]([C:5]1([CH:12]=[N:28][O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:4]
Reactant: NOCc1ccccc1
Reactant: COC(=O)C1(C=O)CCCCCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(C=NOCc2ccccc2)CCCCCC1
Yield: 51 %

Procedure:
A mixture of 1-formyl-cycloheptanecarboxylic acid methyl ester from Preparation 34 (35.6 mmol theoretical), sodium acetate (5.84 g, 72 mmol) and O-benzylhydroxylamine hydrochloride (11.36 g, 72 mmol) were stirred in methanol (71 mL) for 2 h. The methanol was removed in vacuo and the residue partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc (50 mL×5). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo. Purifiaction by flash column chromatography using an eluting sytem of hexanes/EtOAc (99:1) provided the title compound as a clear colorless oil (5.22 g, 51%). MH+290.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[CH2:14])[CH2:9][C:10]([Cl:13])([Cl:12])[Cl:11])[CH:5]=[C:4]([O:15][CH3:16])[N:3]=1.BrC1C=C(C(=C)CC(Cl)(Cl)Cl)C=C([O:31]C)N=1.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2([CH2:9][C:10]([Cl:13])([Cl:12])[Cl:11])[CH2:14][O:31]2)[CH:5]=[C:4]([O:15][CH3:16])[N:3]=1
Reactant: C=C(CC(Cl)(Cl)Cl)c1cc(Cl)nc(OC)c1
Reactant: C=C(CC(Cl)(Cl)Cl)c1cc(Br)nc(OC)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1cc(C2(CC(Cl)(Cl)Cl)CO2)cc(Cl)n1

Procedure:
To a solution of 11.8 g of 2-chloro-6-methoxy-4-(3,3,3-trichloro-1-methylenepropyl)pyridine containing the 2-bromo-6-methoxy-4-(3,3,3-trichloro-1-methylenepropyl)pyridine byproduct in 300 ml of chloroform was added 10.3 g of 85% m-chloro-perbenzoic acid. The solution was heated at reflux for 32 hours, cooled, and washed with 2N sodium hydroxide, water, and dried (Na2SO4). The solvent was removed in vacuo, leaving 12.5 g of crude product which was purified by high pressure liquid chromatography using 5% ethyl acetate in hexane as eluent. 5.4 g of pure product containing 16% of the bromo derivative was obtained. Analysis of the mixture was confirmed by gas-liquid chromatography, nuclear magnetic resonance spectroscopy, mass spectroscopy, and elemental analysis. Elemental analysis for the mixture:
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]2[O:15][N:14]=[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19](I)[CH:18]=3)[N:12]=2)[CH:5]=[CH:4][C:3]=1[C:24](=[O:26])[CH3:25].S([O-])(OCCCCCCCCCCCC)(=O)=O.[Na+].[C:45]([O-])([O-:47])=[O:46].[K+].[K+].[C]=O>C1(C)C=CC=CC=1.O.CC#N.CC#N.Cl[Pd]Cl.C(O)CCC>[C:24]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][C:11]2[O:15][N:14]=[C:13]([CH2:16][C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[C:45]([OH:47])=[O:46])[N:12]=2)=[C:7]([CH3:8])[C:2]=1[OH:1])(=[O:26])[CH3:25]
Reactant: CC(=O)c1ccc(OCc2nc(Cc3cccc(I)c3)no2)c(C)c1O
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [C]=O
Solvent: CC#N
Solvent: CCCCO
Solvent: O
Product: CC(=O)c1ccc(OCc2nc(Cc3cccc(C(=O)O)c3)no2)c(C)c1O
Yield: 64.6 %

Procedure:
Combine 1-{2-hydroxy-4-[3-(3-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone (150 mg, 0.32 mmol), sodium dodecyl sulfate (300 mg, 1.0 mmol), K2CO3 (45 mg, 0.32 mmol), 1-butanol (200 μL), and 1 drop of toluene in H2O (4 mL) in a pressure vessel, then degas with Ar for 5 min. Add PdCl2(MeCN)2 (18 mg, 0.07 mmol) to the reaction mixture. Exchange the atmosphere with carbon monoxide and heat the mixture to 70° C. under 20 psi of carbon monoxide. The reaction is heated until complete. Filter the black mixture through filter cell. Acidify the filtrate with 5 N hydrochloric acid to pH=1. A milky white mixture forms. Add a small amount of methanol to induce crystallization Collect the crystals by filtration to give the title compound (79 mg, 65%). 1H NMR (DMSO-d6) δ 12.99 (s, 1H), 12.79 (s, 1H), 7.86 (m, 1H), 7.79 (m, 2H), 7.52 (m, 1H), 7.42 (dd, 1H), 6.67 (d, 1H), 5.60 (s, 2H), 4.19 (s, 2H), 2.55 (s, 3H), 1.99 (s, 3H). LC-MS (m/e): 381 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([C:20](=[O:27])[CH:21]=[C:22]([OH:26])[C:23](O)=[O:24])[C:8](=[O:19])[N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:10]=1.Cl.[NH2:34][C@@H:35]1[CH2:39][CH2:38][CH2:37][C@H:36]1[OH:40]>CO>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([C:20](=[O:27])[CH:21]=[C:22]([OH:26])[C:23]([NH:34][C@@H:35]2[CH2:39][CH2:38][CH2:37][C@H:36]2[OH:40])=[O:24])[C:8](=[O:19])[N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:10]=1
Reactant: O=C(O)C(O)=CC(=O)c1cc(Cc2ccc(F)cc2F)cn(Cc2ccccc2F)c1=O
Reactant: N[C@@H]1CCC[C@H]1O
Agent: Cl
Solvent: CO
Product: O=C(N[C@@H]1CCC[C@H]1O)C(O)=CC(=O)c1cc(Cc2ccc(F)cc2F)cn(Cc2ccccc2F)c1=O

Procedure:
The titled compound was synthesized using the procedure described above using compound 8. The coupling compound, (1R,2R)-2-aminocyclopentanol hydrochloride, was synthesized by modification of the following procedure: Overman L. E.; Sugai, S., J. Org. Chem. 50, 4154-4155 (1985). The product was a yellow solid, mp 55-57° C., [α20D] −28.5 (c 0.1, MeOH), UV (MeOH) 396 nm (ε 14,100), 319 nm (ε 7444). 1H NMR (CDCl3, 500 MHZ): δ 15.41 (bs, 1H), 8.16 (s, 1H), 8.07 (s, 1H), 7.60-6.84 (m, 9H), 5.21 (s, 2H), 4.10-3.76 (m, 5H), 2.25-1.73 (m, 6H). 13C NMR (CDCl3, 125 MHZ): δ 181.1, 163.0, 162.1, 160.2, 159.0, 143.7, 141.4, 132.1, 132.1, 132.1, 131.2, 131.1, 131.1, 131.0, 130.5, 130.4, 124.7, 124.7, 122.5, 122.4, 122.3, 121.8, 116.9, 115.5, 115.3, 111.7, 111.7, 111.5, 111.5, 104.4, 104.2, 104.0, 98.1, 79.1, 60.2, 47.5, 32.5, 30.5, 30.4, 21.4. HRMS (M+H)+ calculated mass 527.1794 for C28H26F3N2O5. found 527.1804.
Reaction SMILES: CC(C)(O[CH2:6][CH2:7][CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[OH:10])CC.C1(C)C=CC(S(O)(=O)=O)=CC=1.CNC(C1(C2C=CC=CN=2)CCCO1)=S>C1(C)C=CC=CC=1>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:9]1[CH2:8][CH2:7][CH2:6][O:10]1
Reactant: CCC(C)(C)OCCCC(O)c1ccccn1
Agent: CNC(=S)C1(c2ccccn2)CCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1ccc(C2CCCO2)nc1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 33.9 %

Procedure:
A solution of 4-(1,1-dimethylpropoxy)-1-(pyrid-2-yl)-butan-1-ol (122 g) and para-toluenesulphonic acid (107.4 g) in toluene (1000 cc) is kept at the boil for 28 hours so that the water formed is removed by azeotropic distillation. After cooling to a temperature of about 20° C., distilled water (250 cc) is added. The organic phase is decanted and washed with distilled water (50 cc); the aqueous phases are combined and neutralised by adding sodium bicarbonate (49 g). The mixture is extracted three times with ethyl acetate (1500 cc in total). The organic extracts are combined and filtered and the filtrate is concentrated under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. A first oily fraction (30.8 g) is thus obtained. The aqueous phase previously obtained is re-extracted five times with methylene chloride (2500 cc in total); the organic extracts are combined, dried over anhydrous sodium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 35° C. A second oily fraction (11.2 g) is thus obtained. The two fractions (30.8 g and 11.2 g) are combined and run into polyphosphoric acid (200 g) at 80° C., in the course of 30 minutes. After stirring for 10 minutes at the same temperature and then cooling to a temperature of about 20° C., the reaction mixture is poured into distilled water (400 cc). A 10 N aqueous solution of sodium hydroxide (450 cc) is then added, whilst keeping the temperature below 20° C. The resulting crystals are filtered off and washed with ethyl acetate (500 cc). After separation of the filtrate by decantation, the aqueous phase is extracted three times with ethyl acetate (1500 cc in total). The organic extracts are combined, dried over anhydrous sodium sulphate and filtered and the filtrate is concentrated under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. 2-(Pyrid-2-yl)-tetrahydrofuran (26 g) is thus obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]3[N:16]([C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]4)[N:19]=2)[CH:15]=[CH:14][S:13]3)[CH:7]=[CH:8][CH:9]=1.CCN(C(C)C)C(C)C.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>C(Cl)Cl>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([N:27]2[CH2:28][CH2:29][CH2:30][C@@H:25]([NH:24][C:20]3[N:19]=[C:18]([C:17]4[N:16]5[C:12]([S:13][CH:14]=[CH:15]5)=[N:11][C:10]=4[C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=4)[CH:23]=[CH:22][N:21]=3)[CH2:26]2)(=[O:49])=[O:48])=[CH:43][CH:42]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCNC3)n2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
The 4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine hydrochloride (6.81 g, 14.2 mmol) in methylene chloride (DCM) (60 ml) was cooled to 0° C. and was treated with Hunig's base (9.9 ml, 56.8 mmol). The mixture was kept at 0° C. for 30 minutes then the 4-chlorophenylsulfonyl chloride (3.3 g, 15.6 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride (100 ml) and was washed water (100 ml) and a saturated aqueous sodium chloride solution (100 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient (ethyl acetate/hexanes, 40-100%), affording 6.98 g (85%) of the title compound as a pale yellow solid. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.42 (br. s, 1H), 8.12 (d, J=5.1 Hz, 1H), 7.8-7.75 (m, 2H), 7.7-7.65 (m, 2H), 7.43-7.39 (m, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.18-7.1 (m, 2H), 7.05-6.98 (m, 1H), 6.42 (d, J=5.1 Hz, 1H), 4.0-3.9 (m, 1H), 3.78 (s, 3H), 3.74 (d, J=11.7 Hz, 1H), 3.48 (d, J=11.7 Hz, 1H), 2.5-2.4 (m, 1H), 2.33 (t, J=5.3 Hz, 1H), 1.95-1.8 (m, 2H), 1.65-1.5 (m, 1H), 1.45-1.4 (m, 1H). LCMS: 581 [M+H].
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]([C:14]1([C:28]([CH3:30])=[CH2:29])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]1=[O:27])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][CH2:5][CH:6]([C:14]1([C:28]([CH3:30])=[CH2:29])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]1=[O:27])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: C=C(C)C1(C(CCN=[N+]=[N-])C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)C1(C(CCN)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A solution of tert-butyl α-(2-azidoethyl)-2-oxo-1-(2-phenylethyl)-3-(propen-2-yl)-3-pyrrolidineacetate (2.12 g, 5.14 mmol) and triphenylphosphine (1.48 g, 5.65 mmol) in THF (15 mL) is stirred under N2 for 7 hours. Water (1 mL) is added and the solution stirred overnight at room temperature under N2. The solution is concentrated and purified by silica gel chromatography (75 g SG; EtOAc, 20% MeOH/EtOAc) to provide 1.94 g (97%) of the title compound as a yellow oil:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:36]=[N:35][N:34]([CH:37]([CH3:39])[CH3:38])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:26](=[O:33])[CH2:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]>CCO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:36]=[N:35][N:34]([CH:37]([CH3:39])[CH3:38])[C:16]=2[N:17]=[C:18]([CH:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:33])[CH2:27][CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])[CH2:22][CH2:21]2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)CCCN(C)C)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CCN(C(=O)CCCN(C)C)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 9.5 h

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(1-(4-(dimethylamino)butanoyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) in EtOH, 10% Pd/C in catalytic amount was added and stirred it at room temperature under hydrogen pressure (bladder pressure) for 3-16 h hr. On completion of reaction, reaction mass was filtered through celite bed, then filtrate was concentrated under reduced pressure to give the desired product. LCMS: 536.40 (M+1)+; HPLC: 83.00% (@ 254 nm) (Rt: 4.917); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (s, 1H), 8.75 (t, 1H), 8.27 (s, 1H), 7.52 (s, 1H), 5.89 (s, 1H), 5.20-5.17 (m, 1H), 4.57-4.54 (m, 1H), 4.36 (d, 2H, J=4.8 Hz), 4.01-3.98 (m, 1H), 3.32 (1H merged with DMSO peak), 3.19-305 (m, 2H), 2.72-2.67 (m, 2H), 2.40 (m, 2H), 2.40 (s, 6H) 2.20 (s, 3H), 2.12 (s, 3H), 2.04-1.91 (m, 2H), 1.79-1.63 (m, 4H), 1.48 (d, 6H, J=6.4 Hz).
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC(C)([O-])C.[Na+].O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Brc1ccccc1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc([C@@H]2C[C@H]2NCC2CCN(c3ccccc3)CC2)cc1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 11.7 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (200 mg, 0.429 mmol) in toluene (10 mL) was added bromobenzene (0.045 mL, 0.429 mmol) followed by sodium tert-butoxide (82 mg, 0.858 mmol), Pd2(dba)3 (7.86 mg, 8.58 μmol) and Q_Phos (12.18 mg, 0.017 mmol). The reaction mixture was heated in a sealable tube to 80° C. for 4 hours. Water (5 mL) was added and the layers were separated. The organic layer was washed with brine and dried over MgSO4, filtered and evaporated. The resulting oil was purified by preparatory HPLC (5 to 40% AcCN: H2O with 0.1% formic acid modifier). The fractions were collected and evaporated. The isolated oil was dissolved in 6 ml of EtOH and 3 ml of 1 M NaOH. The reaction mixture was stirred for 20 minutes and then concentrated. The resulting solution was then partitioned between 2 ml of water and 5 mL of EtOAc. The organic layer was separated and evaporated. The resulting oil was dissolved in 3 mL of acetonitrile. 0.5 mL of 4 M HCl/dioxane was added. After 5 minutes, 10 mL of diethyl ether was added dropwise. The white solid was filtered. trans-2-Phenyl-N-((1-phenylpiperidin-4-yl)methyl)cyclopropanamine (20 mg, 0.050 mmol, 11.68% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.75 (d, J=7.58 Hz, 2H), 7.51-7.69 (m, 3H), 7.31-7.40 (m, 2H), 7.12-7.31 (m, 3H), 3.65-3.88 (m, 4H), 3.31 (s, 1H), 3.08 (dt, J=4.07, 7.77 Hz, 1H), 2.62 (ddd, J=3.66, 6.63, 10.42 Hz, 1H), 2.36 (ddd, J=4.29, 7.45, 11.24 Hz, 1H), 2.26 (dd, J=2.53, 14.65 Hz, 2H), 1.88-2.06 (m, 2H), 1.63 (ddd, J=4.29, 6.63, 10.55 Hz, 1H), 1.37-1.52 (m, 1H); LC-MS Rt=0.59 min; MS (ESI): 307.3 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([NH:9][NH:10][C:11]([NH:13][CH3:14])=[O:12])=O)=[CH:3][CH:2]=1.ClC1C=CC(C(NNC(NCC)=O)=O)=CC=1>>[CH3:14][N:13]1[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:9][NH:10][C:11]1=[O:12]
Reactant: CNC(=O)NNC(=O)c1ccncc1
Agent: CCNC(=O)NNC(=O)c1ccc(Cl)cc1
Product: Cn1c(-c2ccncc2)n[nH]c1=O

Procedure:
When, in the procedure of Example 4, 1-(4-pyridoyl)-4-methylsemicarbazide is substituted for 1-(4-chlorobenzoyl)-4-ethylsemicarbazide, the title compound is obtained. Mp 249°-251° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[CH3:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](=[O:43])[C:29]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)([CH3:34])[CH2:30][S:31]2)=[CH:26][CH:25]=1>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:28]1([OH:43])[C:27]2[C:32](=[CH:33][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[S:31][CH2:30][C:29]1([C:35]1[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)[CH3:34])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2=O)cc1
Reactant: C#CCCCCCCO[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2(O)C#CCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 870.1 %

Procedure:
8-(t-Butyldimethylsilyloxy)-1-octyne (12 g, 49.9 mmol) was dissolved in dry tetrahydrofuran (150 ml) under argon atmosphere and then cooled to −78C. 2.5M n-Butyllithium (18 ml, 44.9 mmol) was added dropwise thereto, and the mixture was warmed to −10° C. and stirred for 1 hour and then cooled to −78° C. 7-Methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-one (860 mg,2.9 mmol) was added portionwise and then warmed to room temperature and stirred for 1.5 hour. The mixture was quenched by water. The reaction solvent was evaporated off, then the residue was dissolved in ethyl acetate, which was washed with water. The organic solvent was dried over anhydrous magnesium sulfate and removed by evaporation under vacuum. This product was purified by column chromatography on silica gel, eluting with 10% ethyl acetate in n-hexane. After removal of the solvent, 14 g of the title compound was obtained as colorless oil. (yield: 99.3%)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:18]=1.I[CH3:20].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:20])[C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:18]=1
Reactant: CI
Reactant: CC1CN(C2CCC2)c2nc(Cl)ncc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(C2CCC2)c2nc(Cl)ncc2N(C)C1=O
Reaction time: 2 h
Yield: 89 %

Procedure:
To a mixture of 0.94 g (0.00352 mole) of (rac)-2-chloro-9-cyclobutyl-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-52), 0.33 mL (0.00529 mole) of iodomethane and 15 mL of N,N-dimethylformamide at 0 degrees, was added 0.21 g (0.00529 mole) of 60% oil dispersion of sodium hydride. The mixture was stirred at 0 degrees for 2 hours and then partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes-ethyl acetate (100:0-60:40) to give 0.88 g of (rac)-2-chloro-9-cyclobutyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-52) as white powder. HRMS (ES+) m/z Calcd for C13H17CLN4O2+H [(M+H)+]: 281.1164. Found: 281.1163.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[Cl:10][S:11](O)(=[O:13])=[O:12].S(Cl)(Cl)(=O)=O>ClCCl>[F:1][C:2]([F:9])([F:8])[C:3]1[S:4][C:5]([S:11]([Cl:10])(=[O:13])=[O:12])=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cccs1
Reactant: O=S(=O)(O)Cl
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(C(F)(F)F)s1

Procedure:
5-trifluoromethyl-thiophene-2-sulfonylchloride was prepared from commercially available 2-trifluoromethyl-thiophene through reaction with chlorosulfonic acid in dichloromethane and subsequent silica gel chromatography (1H-NMR of the sulfonylchloride (CDCl3, 400 MHz): δ [ppm] 7.9 (1H, d), 7.5 (1H, d)).
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:9][C:10](=[O:12])[O-:11])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].[C:13]([Cl:23])(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCOCC>C(O)(C(F)(F)F)=O.CC(C)=O>[ClH:23].[C:13]([C:3]([CH2:9][C:10](=[O:11])[O-:12])([CH2:4][N+:5]([CH3:8])([CH3:6])[CH3:7])[OH:2])(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Solvent: CCOCC
Product: C[N+](C)(C)CC(O)(CC(=O)[O-])C(=O)C=Cc1ccccc1
Reaction time: 4.5 h
Yield: 70 %

Procedure:
4.55 g (0.023 moles) of carnitine hydrochloride are dissolved in 6.9 mls of CF3COOH, and to the solution an excess (16 mls) of cinnamoyl chloride is added. The mixture is kept under stirring at 40°-45° C. for 4-5 hours. At the end of this period of time, the mixture is diluted with 60 mls of acetone and some ether is slowly added till complete precipitation. The mixture is filtered and the precipitate which has the tendency to become hygroscopic is quickly washed with ether and dried under vacuum at a temperature not exceeding 50° C.; 5.3 g of a product are obtained (yield 70%) having the following characteristics: