Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[C:13]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:13][O:9][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:4]([CH2:3][CH2:2][Cl:1])=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(CCCl)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCCl)cc1
Reaction time: 18 h

Procedure:
A solution of 4-(2-Chloro-ethyl)-benzoic acid (20 g, 108 mmol) in DMF (200 mL) is treated with K2CO3 (59.7 g, 432 mmol) and Mel (16.8 mL, 270 mmol) and stirred at 23 C for 18 h. The reaction mixture is diluted with EtOAc (450 mL) and washed with H2O (2×150 mL), saturated aqueous NaHCO3 (1×200 mL), brine (1×200 mL), dried (MgSO4), and concentrated to afford the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])=O.O.[NH2:23][NH2:24]>C(O)C>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:6]2[C:8]3[N:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:11])[NH:24][N:23]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1cccnc1C(=O)c1cccc(C(F)(F)F)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2cccc(C(F)(F)F)c2)c2ncccc12

Procedure:
A mixture of 2-(3-trifluoromethylbenzoyl)nicotinic acid (1.5 g) and hydrazine hydrate (0.4 g) in ethanol was heated at the reflux temperature for 5 hours. On cooling and reduction of the volume of solvent by evaporation, a precipitate formed which was collected by filtration, to give the title compound as a white solid, 1.08 g, m.p. 210°-215° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:31][CH3:32])=[C:16]([CH:22]4[CH2:25][N:24]([C@H:26]([CH3:30])[C:27]([OH:29])=O)[CH2:23]4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:51]([CH3:53])[CH3:52])C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CNC>CN(C=O)C.CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:31][CH3:32])=[C:16]([CH:22]4[CH2:25][N:24]([C@H:26]([CH3:30])[C:27]([N:51]([CH3:53])[CH3:52])=[O:29])[CH2:23]4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN([C@H](C)C(=O)O)C1
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN([C@H](C)C(=O)N(C)C)C1
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To a solution of (2R)-2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propanoic acid (4 mg, 0.009 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (4 mg, 0.009 mmol) in DMF (0.3 mL) at room temperature was added triethylamine (4 μL, 0.03 mmol) and dimethylamine hydrochloride (0.9 mg, 0.01 mmol). The reaction mixture was stirred for 1 h, then diluted with methanol and purified by preparative RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (2.7 mg, 63%). The product was isolated as a single diastereomer. LCMS calculated for C24H33ClN7O2 (M+H)+: m/z=486.2; Found: 486.1. 1H NMR (300 MHz, DMSO-d6): δ□ 8.09 (s, 1H), 7.23 (s, 1H), 6.18 (m, 1H), 3.78 (m, 3H), 3.50 (s, 3H), 3.01 (s, 3H), 3.0-2.9 (m, 3H), 2.77 (s, 3H), 2.54 (s, 3H), 2.06 (s, 3H), 1.67 (d, 3H), 0.98 (d, 3H) ppm.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH:25]=[O:26])[CH:23]=4)[N:18]([CH3:27])[N:17]=3)[N:14]=2)[N:9]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:8]=1)=[O:6])([CH3:3])[CH3:2].[CH3:36][Mg]Br>C1COCC1>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:26])[CH3:36])[CH:23]=4)[N:18]([CH3:27])[N:17]=3)[N:14]=2)[N:9]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(C=O)cc34)nc12
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(C(C)O)cc34)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
In a round-bottomed flask, 2-(5-formyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (111 mg, 0.225 mmol) was suspended in THF (3 ml). The pale yellow suspension was cooled to 0° C. and methylmagnesium bromide (3.0 M in diethyl ether, 0.23 ml, 0.69 mmol) was added dropwise. The dark red suspension was stirred at 0° C. for 1 h then quenched with saturated aqueous NH4Cl and extracted with dichloromethane (2×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 12 g silica gel with EtOAc/hexanes (gradient: 0-80% EtOAc) to afford 42 mg (37%) of 2-[5-(1-hydroxy-ethyl)-1-methyl-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as a light yellow solid.
Reaction SMILES: [I:1][C:2]1[C:3]2[C:4](=[CH:8][NH:9][N:10]=2)[N:5]=[CH:6][CH:7]=1.I[CH:12]([CH3:14])[CH3:13].[H-].[Na+]>CN(C=O)C.O.C(#N)C.O>[I:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([CH:12]([CH3:14])[CH3:13])[N:10]=2)[N:5]=[CH:6][CH:7]=1.[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][N:10]([CH:12]([CH3:14])[CH3:13])[C:3]=12
Reactant: Ic1ccnc2c[nH]nc12
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: CC(C)n1cc2nccc(I)c2n1
Product: CC(C)n1ncc2nccc(I)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %
Yield: 0.34 %

Procedure:
7-Iodo-2H-pyrazolo[4,3-b]pyridine (100 mg, 0.408 mmol), 2-iodopropane (0.049 ml, 0.490 mmol) and sodium hydride (19.59 mg, 0.816 mmol) were combined in DMF (5 mL). The mixture was stirred at room temperature for 1 hour then quenched by the addition of ice. The reaction mixture was purified by preparative HPLC eluting with a gradient of 20-90% 10 mmol NH4HCO3 in 20/80 (v/v) water/acetonitrile in 10 mmol NH4HCO3 in water using a Phenomenex Gemini Prep 5 μm C18, 75×30 mm column to give 7-iodo-2-isopropyl-2H-pyrazolo[4,3-b]pyridine (35 mg, 29.9% yield) and 7-iodo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine (25 mg, 0.34% yield). MS [M+H] found 288.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:14])[CH2:12]Cl)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][NH2:26])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:14])[CH2:12][NH:26][CH2:25][C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([O:16][CH3:15])[CH:18]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(NC(=O)CCl)c1
Reactant: COc1ccc(CN)cc1OC
Product: COc1cc(Br)cc(NC(=O)CNCc2ccc(OC)c(OC)c2)c1

Procedure:
In a manner similar to Preparation 12, react N-(3-bromo-5-methoxyphenyl)-2-chloroacetamide with 3,4-dimethoxybenzenemethanamine to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:11].C(N(CC)CC)C.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:22])[C@@H:4]1[CH2:8][C@@H:7]([O:9][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)=[O:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc(OC)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
trans-1-(p-Methoxybenzyloxycarbonyl)-4-hydroxy-L-proline methyl ester (5.18 g), 3.79 g of triethylamine and 3.77 g of t-butyldimethylsilyl chloride were dissolved in 52 ml of dry dimethylformamide. The resulting mixture was stirred at room temperature for 3 hours, diluted with water, extracted with ethyl acetate, washed successively with water, dilute hydrochloric acid and water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography to obtain trans-1-(p-methoxybenzyloxycarbonyl)-4-t-butyldimethylsilyloxy-L-proline methyl ester.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:10](=[O:13])[CH:11]=[CH2:12])=[N:7][CH:8]=1.[OH:21][CH:22]([C:27]1[CH:28]=[CH:29][C:30]([CH:33]=[O:34])=[N:31][CH:32]=1)[C:23]([OH:26])([CH3:25])[CH3:24].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[OH:21][CH:22]([C:27]1[CH:28]=[CH:29][C:30]([C:33](=[O:34])[CH2:12][CH2:11][C:10](=[O:13])[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][N:7]=2)[CH2:14][CH:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[N:31][CH:32]=1)[C:23]([OH:26])([CH3:24])[CH3:25]
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(SC)cn1
Reactant: CC(C)(O)C(O)c1ccc(C=O)nc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccc(C(O)C(C)(C)O)cn2)nc1
Yield: 63.9 %

Procedure:
A mixture of 4-[5-(methylsulfanyl)pyridin-2-yl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (0.50 g), 5-(1,2-dihydroxy-2-methylpropyl)pyridine-2-carbaldehyde (0.32 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (43 mg), triethylamine (0.09 mL), tetrahydrofuran (6 mL) and ethanol (6 mL) was stirred with heating under reflux for 1 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and the title compound (0.51 g, yield 61%) was obtained as a colorless oil from a fraction eluted with ethyl acetate. MS: 524 (MH+).
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.B(F)(F)F.CCOCC.S(=O)(=O)(O)O.B(OC)(OC)OC>S1(CCCC1)(=O)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: FB(F)F
Agent: O=S(=O)(O)O
Solvent: O=S1(=O)CCCC1
Solvent: CCOCC
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 30 °C

Procedure:
To 20 ml of sulfolane were added 1.41 g of 7-ACA, 3.2 ml of boron trifluoride ethyl ether, 0.84 ml of concentrated sulfuric acid and 6.12 ml of trimethyl borate. The mixture was heated at 30° C. for 4 hours to advance a reaction. After completion of the reaction, substantially the same procedure as in Example 1 was repeated, to thereby obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.86 g. The yield of the desired product was 68%.
Reaction SMILES: C[N:2]1[CH2:21][CH2:20][N:5]2[CH2:6][C@@H:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]3[C:13]([C@@H:4]2[CH2:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[Na].[Cl:23]C(OC)=O>C(Cl)(Cl)Cl>[ClH:23].[ClH:23].[C:14]1([C@H:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C@@H:4]3[CH2:3][NH:2][CH2:21][CH2:20][N:5]3[CH2:6]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)Cl
Reactant: CN1CCN2C[C@@H](c3ccccc3)c3ccccc3[C@@H]2C1
Agent: [Na]
Solvent: ClC(Cl)Cl
Product: Cl
Product: c1ccc([C@@H]2CN3CCNC[C@H]3c3ccccc32)cc1
Yield: 48 %

Procedure:
To a stirred solution of cis-1,3,4,6,7,11b-hexahydro-2-methyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline (11.0 g, 0.039 m) in chloroform (1500 ml) was added sodium bicarbanate (83.1 g, 0.99 m) and methyl chloroformate (45.3 g, 0.48 m), and the mixture heated to reflux for 48 hours. The salts were removed by filtration and the organic phase washed with 5% HCl (3×300 ml) and water (300 ml) and dried over MgSO4. The solvent was evaporated and the oily residue treated with 95% hydrazine (250 ml) and refluxed for 24 hours. Water (500 ml) was added and the mixture evaporated to an oily residue. This was treated with water (500 ml) and a small amount of 50% NaOH to ensure pH 11, and the mixture extracted with chloroform (3×250 ml). The extracts were dried over MgSO4 and evaporated to a yellow oil. This was dissolved in methanol (50 ml) and isopropanol (50 ml) and acidified with HCl gas. Upon standing and cooling, a white solid crystallized, which was collected by filtration. Recrystallization from methanol/isopropanol/water and vacuum drying gave 6.4 g of cis-1,3,4,6,7,11b-hexahydro-7-phenyl-2H-pyrazino[2,1-a]isoquinoline dihydrochloride, m.p. 275°-277°. The product has an ad cyc H rating greater than 1×10-5M, a (3H)mepyramine rating greater than 1×10-6M and a (3H)QNB of 9.2×10-7M.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]1[CH:25]([CH:26](O)C#N)[CH2:24]1.C([BH3-])#N.[Na+].C(O)(=O)C.[OH-].[Na+]>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15]2[C:20]([NH:21][CH2:26][CH:25]3[CH2:23][CH2:24]3)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(c1ncccc1N)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N#CC(O)C1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CN(c1ncccc1NCC1CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h

Procedure:
1-tert-Butyloxycarbonyl-4-[N-methyl-N-(3-amino-2-pyridinyl)amino]piperidine (1.64 g, 5.37 mmol) is dissolved in methanol (0.2M) and cooled to 0°. Cyclopropylcarboxaldehyde (0.40 ml, 5.37 mmol) is added. After stirring 5 min, sodium cyanoborohydride (337 mg, 5.37 mmol) is added. The reaction is refluxed one hour, then stirred overnight at 20°-25°. Acetic acid (53.7 mmol) is added and the reaction refluxed 3 hr. After cooling to 20°-25°, cyclopropylcarboxaldehyde (820 mg, 2.68 mmol) and sodium cyanoborohydride (168 mg 2.68 mmol) are added and the reaction stirred 16 hr at 20°-25°. The mixture is diluted with water, adjusted to pH 9 with sodium hydroxide (1N) and extracted with chloroform. The extract is filtered and concentrated. The concentrate is chromatographed (silica gel; ethyl acetate/hexane (20/80) to give the title compound; NMR (300 MHz, CD3OD) 7.39, 6.79, 3.79, 3.07, 2.80, 2.63, 2.44, 1.52, 1.33, 1.27, 0.93, 0.35 and 0.05δ.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[N:32]=[C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:30]=[CH:29][CH:28]=1.[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:36]2[CH2:37][CH2:38][N:33]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[N:32]=3)[CH2:34][CH2:35]2)=[O:48])[C:44]=1[CH3:45]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: COc1cccc(N2CCNCC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cccc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)n1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(6-Methoxy-pyridin-2-yl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.45 (t, 1H), 6.34 (d,1H), 6.05 (d, 1H), 5.37 (s, 2H), 3.77 (s, 3H), 3.50 (m, 6H), 3.34 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected=418.1, found=418.0.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[F:13][C:14]([F:24])([F:23])[CH2:15][NH:16][C:17]([NH:19][C:20]([NH2:22])=[S:21])=[NH:18]>CCO>[F:24][C:14]([F:13])([F:23])[CH2:15][N:16]=[C:17]([NH2:18])[NH:19][C:20]1[S:21][CH:2]=[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:22]=1
Reactant: N=C(NCC(F)(F)F)NC(N)=S
Reactant: COC(=O)CCCCC(=O)CCl
Solvent: CCO
Product: COC(=O)CCCCc1csc(NC(N)=NCC(F)(F)F)n1

Procedure:
To a solution of methyl 7-chloro-6-oxoheptanoate (2.0 g.) in hot EtOH (20 ml.) was added a solution of 2,2,2-trifluoroethylamidinothiourea (2.1 g.) in hot EtOH (20 ml.). The resulting mixture was heated under reflux for 1 hour. The mixture was then evaporated to dryness and the residue partitioned between ether (20 ml.) and water (60 ml.). The aqueous layer was separated and basified with sodium bicarbonate and extracted with EtOAc. The EtOAc solution was evaporated to dryness and the residue crystallised from EtOAc/ether containing a small amount of acetone to give methyl 5-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]valerate which was used without further purification.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:7]=[N:6][CH:5]=[N:4]1.[OH-].[Na+].[Cl:15][C:16]1[C:17]2[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=2[S:19][C:20]=1[C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:15][C:16]1[C:17]2[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=2[S:19][C:20]=1[C:21]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)=[O:22]
Reactant: NCCCCn1cncn1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCCn1cncn1)c1sc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A mixture of about 2.13 g of 1H-1,2,4-triazole-1-butanamine, dihydrochloride, about 70 ml of methylene chloride, about 30 ml of 1N sodium hydroxide and about 2.3 g of 3-chlorobenzo[b]thiophene carbonyl chloride was stirred at room temperature overnight. About five ml of 1N sodium hydroxide and about 50 ml of methylene chloride were added. The organic layer was separated, washed twice with water, dried and concentrated to an oil. The oil was crystallized from ether, giving about 2.8 g of the desired product as a yellow solid, mp 103°-105° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.CO>[C].[Pd].O1CCCC1>[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([C:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[O:16])[CH2:22][CH2:21]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(OCc3ccccc3)cc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(O)cc2)CC1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A mixture of 1-{[4-(benzyloxy)phenyl]carbonyl}-4-(2-tert-butylphenyl)piperazine obtained in Example 17 (1.3 g), palladium carbon (contains 50% H2O, 300 mg), methanol (120 mL), and tetrahydrofuran (30 mL) was stirred at room temperature under hydrogen atmosphere (5 atm). The mixture was filtered and evaporated under reduced pressure to provide the title compound (1.03 g, quant.) as a solid.
Reaction SMILES: [C:1]1([Si:7]2([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[Si:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[Si:9]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[Si:8]2([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:53]1([Si:59]([Li])([CH3:61])[CH3:60])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.[CH3:63][Si:64]([CH3:67])([CH3:66])Cl.C(=O)(O)[O-].[Na+]>CCCCCC.O1CCCC1>[CH3:60][Si:59]([CH3:61])([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[Si:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[Si:8]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[Si:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[Si:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[Si:64]([CH3:67])([CH3:66])[CH3:63]
Reactant: [Li][Si](C)(C)c1ccccc1
Reactant: C[Si](C)(C)Cl
Reactant: c1ccc([Si]2(c3ccccc3)[Si](c3ccccc3)(c3ccccc3)[Si](c3ccccc3)(c3ccccc3)[Si]2(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)[Si](c1ccccc1)(c1ccccc1)[Si](c1ccccc1)(c1ccccc1)[Si](c1ccccc1)(c1ccccc1)[Si](c1ccccc1)(c1ccccc1)[Si](C)(C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
In an argon atmosphere, to a tetrahydrofuran solution (9 ml) of 109 mg (0.15 mmol) of octaphenylcyclotetrasilane was added 0.56 ml (0.15 mmol) of a tetrahydrofuran solution (0.27M) of phenyldimethylsilyllithium, and stirred at 0° C. for 15 minutes. Trimethylchlorosilane in an amount of 108 mg (1.0 mmol) was added, and reacted at room temperature for 3 hours. Hexane (2 ml) and saturated aqueous sodium bicarbonate solution (2 ml) were added, stirred, the hexane layer was separated, and dried with magnesium sulfate. The resulting crude product was purified by a silica gel column chromatography (hexane) to give 45 mg (32% yield) of 1,1,6,6,6-pentamethyl-1,2,2,3,3,4,4,5,5-nonaphenylhexasilane (3).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)[S:7][CH:8]=1)(=[O:3])[NH2:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C.CO>C(Cl)Cl>[C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:10][CH2:11][CH:12]([O:15][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:13][CH2:14]2)[S:7][CH:8]=1)(=[O:3])[NH2:2]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)c1csc(N2CCC(O)CC2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CS(=O)(=O)OC1CCN(c2nc(C(N)=O)cs2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.3 %

Procedure:
To a solution of 1-(4-carbamoyl-1,3-thiazol-2-yl)-4-hydroxypiperidine (1.93 g, 8.49 mmol) (obtained as described in Reference Example 15(2)) in methylene chloride (100 ml) were added methanesulfonyl chloride (10.0 ml, 129 mmol) and triethylamine (18.0 ml, 129 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 24 hours. After checking the completion of the reaction, methanol was added to the reaction mixture in an ice bath and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford 1-(4-carbamoyl-1,3-thiazol-2-yl)-4-methanesulfonyloxypiperidine (1.59 g, yield 61%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:14](#[N:18])/[CH:15]=[CH:16]/[CH3:17]>CO>[C:14]([CH2:15][CH:16]([N:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1)[CH3:17])#[N:18]
Reactant: C/C=C/C#N
Reactant: Fc1ccc(C2CCNCC2)cc1
Solvent: CO
Product: CC(CC#N)N1CCC(c2ccc(F)cc2)CC1

Procedure:
A solution of 4-(4-fluorophenyl)piperidine (360 mg, 2 mmol) and crotononitrile (0.33 mL, 4 mmol) in methanol (4 mL) was refluxed for five hours. The solvent was concentrated under vacuum and the residue triturated with hexane/diethyl ether to give the racemic title compound as a solid.