Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[N:12]#[C:13][NH2:14].Cl.[N+:16]([O-:19])([OH:18])=[O:17]>C(O)(C)C>[N+:16]([O-:19])([OH:18])=[O:17].[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:13]([NH2:14])=[NH:12]
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: N#CN
Agent: Cl
Solvent: O=[N+]([O-])O
Solvent: CC(C)O
Product: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Temperature: 80 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
20 g of 2-Methyl-5-nitroaniline (0.131 mol; 1 eq.), 11.05 g of cyanamide (0.263 mol; 2 eq.) and 80 mL of isopropyl alcohol were placed in a reactor flask. The reaction mixture was heated to 80° C., and 18 mL of concentrated hydrochloric acid was slowly added dropwise within 80 minutes. The reaction mixture was stirred for 1 hour while maintaining the temperature at 80° C. Next, 6 mL of concentrated hydrochloric acid was added dropwise and the reaction mixture was kept at 80° C. for 2 hours. The reaction mixture was cooled down to 60° C. and 10 mL of 65% nitric acid (0.142 mol, 1.08 eq.) was added dropwise and the mixture was left with stirring until it was cooled down to room temperature. The solid product was filtered off, washed with 50 mL of isopropyl alcohol and dried in the air to afford 27.45 g (yield 81.1%) of 1-(2-methyl-5-nitrophenyl)guanidine nitrate, m.p. 203-206° C.; 1H NMR (DMSO-d6, 200 MHz): 2.32 (3H, s, CH3), 7.44 (4H, m, 4×NH), 7.64 (1H, d, J=8.2 Hz, 3-H), 8.09 (1H, d, J=2.5 Hz, 6-H), 8.15 (1H, dd, J=8.2 i 2.5 Hz, 4-H), 9.51 (1H, m, NH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]#[N:14])=[CH:10]2)=[CH:5][CH:4]=1.CS(C)=[O:17]>F[B-](F)(F)F.[Ag+]>[CH:2]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]#[N:14])=[CH:10]2)=[CH:5][CH:4]=1)=[O:17]
Reactant: N#Cc1ccc2ccc(CBr)cc2c1
Reactant: CS(C)=O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Product: N#Cc1ccc2ccc(C=O)cc2c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Silver tetrafluoroborate (1,168 mg) was suspended in 6 ml of dimethyl sulfoxide, 1,230 mg of 7-Bromomethyl-2-naphthalenecarbonitrile was added to the suspension, and the mixture was stirred at room temperature for 14 hours. The reaction solution was filtered, water was added to the mother liquid, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and then evaporated. The resulting residue was purified by silica gel column chromatography using a mixture of hexane and ethyl acetate as the eluent to give 543 mg of 7-formyl-2-naphthalenecarbonitrile in the form of white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[NH:8][CH2:7][CH2:6][CH2:5]2.[C:17]1([O:23][C:24](=O)[O:25]C2C=CC=CC=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:13][CH3:14])[O:15][CH3:16])[N:8]([C:24]([O:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:25])[CH2:7][CH2:6][CH2:5]2
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1Br)CCCN2C(=O)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 12, 2.28 g, 7.94 mmol) and diphenylcarbonate (2.13 g, 9.93 mmol) in THF (40 ml) at −17° C. was treated drop wise over 5 min with LHMDS (1M in THF, 8.34 ml, 8.34 mmol). The yellow reaction mixture was stirred for 30 min, quenched with sat. aq. NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by normal phase chromatography (80 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H) 7.37-7.45 (m, 2H) 7.19-7.28 (m, 3H) 5.46 (s, 1H) 3.80-3.87 (m, 2H) 3.29 (s, 6H) 2.84 (t, 2H) 1.90-2.00 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]2[CH:9](O)[CH2:8][S:7][C:6]=2[C:11]=1[Cl:12].B(F)(F)F.CCOCC.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:11]=1[Cl:12]
Reactant: COc1cc2c(c(Cl)c1Cl)SCC2O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1cc2ccsc2c(Cl)c1Cl
Yield: 100 %

Procedure:
A mixture of 0.7 g of 6,7-dichloro-2,3-dihydro-3-hydroxy-5-methoxybenzo[b]thiophene, 1 ml of boron trifluoride etherate and 4 ml of glacial acetic acid is heated at 100° for 5 min. Ice is added and the mixture is basified with dilute sodium hydroxide solution. The off-white solid is collected on a filter, air-dried and recrystallized from ether-hexane to give 0.65 g of 6,7-dichloro-5-methoxybenzo[b]thiophene as prisms, mp 103°-104.5°.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@H:20]([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.[CH2:21]([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36](O)=[O:37])=[CH:30][CH:29]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:11][C@@H:10]2[C@@:2]3([CH3:1])[CH2:3][CH2:4][C@@H:5]4[C@@H:20]5[C:14](=[CH:15][C:16]([CH2:18][CH2:19]5)=[O:17])[CH2:13][CH2:12][C@H:6]4[C@@H:7]3[CH2:8][CH2:9]2)=[O:37])=[CH:30][CH:29]=1
Reactant: CCCCCCOc1ccc(CCC(=O)O)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCCCOc1ccc(CCC(=O)O[C@H]2CC[C@H]3[C@@H]4CCC5=CC(=O)CC[C@@H]5[C@H]4CC[C@]23C)cc1
Reaction time: 4 h
Yield: 92.8 %

Procedure:
To a stirred solution of 5.48 g 19-nortestosterone (20 mmol), 5.5 g 3-(4-hexyloxyphenyl)propionic acid (22 mmol), 0.24 g 4-dimethylaminopyridine (DMAP, 2 mmol) and 0.19 g p-toluenesulfonic acid (pTSA, 1 mmol) in 50 ml CH2Cl2 is slowly added at about 15° C. a solution of 5.2 g N,N'-dicyclohexylcarbodiimide (DCC, 25 mmol) in 30 ml CH2CL2. After 4 h at room temperature (no discolouration of the reaction mixture is seen) 1 ml of acetic acid is added to destroy the excess of DCC. Precipitated urea is then filtered off and the filtrate evaporated in vacuo. To the residue 50 ml ethyl acetate is added and, after stirring for 1 h, undissolved urea is filtered off and the filtrate evaporated in vacuo. The residue is crystallized from methanol/water. There is obtained 9.4 g of Anadur® (93% yield) as white crystals having a m.p. of 53°-55° C. and being pure in TLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]=[C:15]=[S:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[NH3:17]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([NH:14][C:15]([NH2:17])=[S:16])[CH:3]=1
Reactant: Fc1ccc(-c2ccccc2)c(N=C=S)c1
Reactant: N
Solvent: CCO
Product: NC(=S)Nc1cc(F)ccc1-c1ccccc1

Procedure:
Reaction of 4-fluoro-2-biphenylylisothiocyanate (12 g) in ethanol (10 ml) with 25% aqueous ammonia solution (40 ml) at ambient temperature for 8 hours gave N-(4-fluoro-2-biphenylyl)thiourea as a white solid (m.p. 185°-187° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][NH:13]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:13]1[CH2:14][CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCc3ccccc3C2)c(Cl)c1
Temperature: 80 °C
Yield: 99.9 %

Procedure:
A mixture of 3,4-dichloronitrobenzene (1.0 g, 5.2 mmol), 1,2,3,4-tetrahydroisoquinoline (0.97 g, 7.3 mmol), K2CO3 (3.6 g, 26 mmol), and DMSO (20 mL) was heated to 80° C. for 16 h with stirring. The mixture was allowed to cool to rt, and was then poured over ice. The resulting precipitate was collected by filtration and dried to provide the titled compound (1.5 g, 98%). MS (ESI): mass calcd. for C15H13ClN2O2, 288.7; m/z found, 289.1 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=1[C:38]1[C:42]([C:43](Cl)=[O:44])=[C:41]([CH3:46])[O:40][N:39]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=1[C:38]1[C:42]([C:43]([O:1][CH:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:13]=3)[CH2:10][CH2:11]2)=[O:44])=[C:41]([CH3:46])[O:40][N:39]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(O)c3ccccc3)CC2)c1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)OC(CCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(4-hydroxy-4-phenylbutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: Anal. Calcd for C36H39ClFN3O4+0.54CHCl3: C, 63.0; H, 5.72; N, 6.03. Found: C, 63.0; H, 5.54; N, 6.05; ESMS m/e: 632.2 (M+H)+.
Reaction SMILES: F[C:2]1[N:7]=[C:6]2[N:8]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:9]=[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>CN1C(=O)CCC1.O>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:8]2[C:6]3=[N:7][C:2]([NH:34][CH2:33][C:32]4[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=4)=[CH:3][CH:4]=[C:5]3[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:9]2)=[CH:20][CH:21]=1
Reactant: COc1ccc(CN)cc1
Reactant: COc1ccc(Cn2nc(C(=O)OC(C)(C)C)c3ccc(F)nc32)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(CNc2ccc3c(C(=O)OC(C)(C)C)nn(Cc4ccc(OC)cc4)c3n2)cc1
Temperature: 80 °C

Procedure:
To a solution of tert-butyl 6-fluoro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (2.55 g, 7.14 mmol) in NMP (30 mL) was added 4-methoxybenzylamine (2.80 mL, 21.41 mmol). The resulting mixture was then heated to 80° C. for 2 hours, after which the mixture was diluted with water (200 mL) and extracted with EtOAc (2×200 mL). The combined extracts were washed with water (100 mL), dried with MgSO4, filtered, absorbed onto silica gel (17 g) and removed the solvent in vacuo. This solid was purified on silica gel (80 g) column (0-100% EtOAc/CH2Cl2 to give the title compound. LRMS (M+1)=474.0
Reaction SMILES: [C:1](=O)([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)[O:2]C1C=CC=CC=1.[NH2:21][NH2:22]>CO>[C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)(=[O:2])[NH:21][NH2:22]
Reactant: NN
Reactant: CC1(C)CC(OC(=O)Oc2ccccc2)CC(C)(C)N1
Solvent: CO
Product: CC1(C)CC(OC(=O)NN)CC(C)(C)N1
Reaction time: 3 h

Procedure:
Into a 300 ml 3-neck flask were added 16.9 grams (0,061 mole) of phenyl 2,2,6,6-tetramethyl-4-piperidinyl carbonate and 100 ml of methanol. The flask was equipped with a magnetic stirrer, thermometer, reflux condenser and dropping funnel containing 3.4 grams (0.067 mole) of 64% aqueous hydrazine. The hydrazine was added slowly to the stirring methanol solution at room temperature. There was a slight exotherm. The reaction mixture was stirred for 3 hours and then allowed to stand overnight (i.e. for 20 hours) at room temperature. The next day, the methanol was stripped off on a rotating evaporator and the liquid residue dissolved in 150 ml of MtBE and washed with 50 ml of 10% NaOH which was saturated with salt. The MtBE solution was dried over anhydrous MgSO4, filtered and the MtBE stripped off on a rotating evaporator under reduced pressure. The residue, a very viscous liquid, was slurried in 20 ml of hexane until a solid formed. The solid was filtered off and air dried. The product weighed 6.4 grams (49% crude yield), had a melting point of 93°-94° C. and gas chromatography indicated it was about 95% pure. The infrared scan contained a strong carbonyl peak at 1710 cm-1 and a moderate carbonyl peak at 1625 cm-1. An additional 5.26 grams of crude product was recovered by extracting the aqueous wash with methylene chloride and stripping off the solvent.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21]C1C=CC=CC=1B(O)O>>[Cl:21][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[C:7]1[NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=1[C:14]=23
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1ccccc1Cl
Product: O=C1NCCc2c(-c3ccccc3Cl)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (210 mg, 0.79 mmol) and 2-chlorophenylboronic acid (136 mg, 0.87 mmol) were coupled to yield 2-(2-chlorophenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 78 mg (33%), as a shiny white solid. mp 275° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 2.76 (m, 2H), 3.38 (m, 2H), 7.23 (app t, 1H, J=7.8 Hz), 7.56 (m, 5H), 7.71 (dd, 1H, J=7.5, 0.9 Hz), 8.07 (br t, 1H), 11.53 (br s, 1H); MS (FAB, MH+) 297; Anal. (C17H13N2OCl.0.15 H2O) C, H, N.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:23])[CH2:16][CH:17]([OH:22])[CH2:18][C:19]([OH:21])=[O:20])=[C:11]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:3].[OH-].[Na+:32]>C1CCCCC1.CO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:23])[CH2:16][CH:17]([OH:22])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:32]
Reactant: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)O)c(-c2ccc(F)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCCCC1
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21

Procedure:
In another preferred process, a lower alkyl ester of fluvastatin is suspended in cyclohexane. Then, about one molar equivalent of sodium hydroxide dissolved in a minimum of protic solvent like methanol, is added to the suspension. The addition should cause the suspension to clarify. Upon standing, fluvastatin sodium may precipitate from the solution in amorphous form. Otherwise, additional cyclohexane can be added to induce precipitation.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>CO.O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CCS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCS(=O)(=O)NCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
N-(4-Nitrobenzyl)ethanesulfonamide (776 mg, 3.18 mmol) was dissolved in methanol and tetrahydrofuran (1:1, 35 mL). 10% Pd/C (264 mg, 3 equiv) was added to it. The resulting mixture was stirred at room temperature for overnight under H2. TLC showed complete consumption of starting material. The mixture was filtered through celite bed and the filterate was concentrated under reduced pressure. The crude was purified by column chromatography to give N-(4-aminobenzyl)ethanesulfonamide (504 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:27]2[CH:28]=[N:29][C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=3)(O)[C@@H:9]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:28]=[N:29][C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[C:32]([C:37]([F:40])([F:38])[F:39])[CH:31]=3)[C@@H:9]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:24][CH:25]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCC[C@H](c1ccc(C(=O)OC(C)(C)C)cc1)C(O)(c1ccc(Cl)cc1)c1cnc2cc(C(F)(F)F)ccc2c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: CCC[C@H](c1ccc(C(=O)O)cc1)C(c1ccc(Cl)cc1)c1cnc2cc(C(F)(F)F)ccc2c1
Temperature: -78 °C

Procedure:
The product of step A (98 mg, 0.173 mmol) was dissolved in CH2Cl2 (15 mL) and triethylsilane (0.28 ml, 1.72 mmol) was added. The solution was cooled to −78° C., then BF3 gas was slowly bubbled through the solution until it was saturated (less than one minute, at the time fuming BF3 was observed from a small needle venting from the flask). The mixture was allowed to warm gradually to −20° C. When all starting material was consumed by LC/MS analysis, saturated NaHCO3 (aq) was added and the mixture was allowed to warm to room temperature. The mixture was extracted twice with EtOAc. The combined organic extracts were washed with water, dried over MgSO4, filtered, then concentrated. This afforded a mixture of diastereomers of the title compound, which was used in the next step without purification: LC1 2.39 min, (M+H) 498,
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5](Cl)[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[C-:17]#[N:18].[Na+]>CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:17]#[N:18])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: [C-]#N
Reactant: Clc1ccc2nc3ccccc3c(Cl)c2c1
Agent: [Na+]
Solvent: CO
Product: N#Cc1c2ccccc2nc2ccc(Cl)cc12
Yield: 55.1 %

Procedure:
A mixture of 1 gm of 2,9-dichloroacridine [obtained by the process of Bogucka, Roczniki, Chem. Vol. 40 (1966) p 677]230 mg of sodium cyanide and 20 cc of methanol was heated for 4 hours at 140°C in a sealed tube and after cooling, the mixture was filtered. The precipitate was washed with acetone and dried. The product was purified by sublimation in vacuo at 0.1 mm Hg to obtain 530 mg of 2-chloro-9-cyano-acridine melting at 208°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH:40]([F:42])[F:41])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([NH:34][CH2:35][CH2:36][C:37]#[N:38])[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.C=O.[C:45](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH:40]([F:41])[F:42])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:29][CH2:30][CH:31]([N:34]([CH2:35][CH2:36][C:37]#[N:38])[CH3:45])[CH2:32][CH2:33]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: N#CCCNC1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(CCC#N)C1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.5 %

Procedure:
A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (3-(5-chloro-2-difluoromethoxy-phenyl)-1-{2-[4-(2-cyano-ethylamino)-piperidin-1-yl]-2-oxo-ethyl}-1H-pyrazol-4-yl)-amide (31.1 g, 52.0 mmol) in DCM (500 mL) was treated with 37% aqueous formaldehyde solution (21.3 mL, 286.2 mmol). On complete addition the reaction was cooled in an ice bath before the addition of sodium triacetoxyborohydride (44.1 g, 208.2 mmol) portionwise. The reaction mixture was warmed to room temperature and stirred for 1.5 hours, after which, the reaction was filtered and the filtrate diluted with methanol. The mixture was diluted with methanol and loaded onto a pad of Isolute® SCX-2 which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. The basic fractions were combined and evaporated. The resultant residue was purified by flash column chromatography on silica eluting with 0-10% 2M NH3/MeOH in DCM. Appropriate fractions were combined and evaporated. The resultant residue was recrystallized from ethyl acetate to afford the title compound as a pale brown solid (30.7 g, 96%). LCMS (Method 5) [M+H]+=612.2, RT=2.84 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=7.0, 1.6 Hz), 8.70-8.67 (m, 1H), 8.68 (s, 1H), 8.32 (s, 1H), 7.63 (dd, 1H, J=8.8, 2.7 Hz), 7.56 (d, 1H, J=2.7 Hz), 7.47 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=7.0, 4.2 Hz), 7.26 (t, 1H, J=73.4 Hz), 5.22-5.24 (m, 2H), 4.38 (d, 1H, J=12.9 Hz), 3.96 (d, 1H, J=13.5 Hz), 3.06 (t, 1H, J=12.7 Hz), 2.62-2.65 (m, 6H), 2.22 (s, 3H), 1.72 (d, 2H, J=11.9 Hz), 1.34-1.40 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[Cl:13][C:14]1[C:15](F)=[CH:16][C:17]([F:27])=[C:18]([CH:26]=1)[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:13][C:14]1[C:15]([O:12][C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:10])([F:11])[F:9])=[C:2]([Cl:1])[CH:3]=2)=[CH:16][C:17]([F:27])=[C:18]([CH:26]=1)[C:19]([NH:21][S:22]([CH3:25])(=[O:23])=[O:24])=[O:20]
Reactant: Oc1ccc(C(F)(F)F)c(Cl)c1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2ccc(C(F)(F)F)c(Cl)c2)cc1F
Temperature: 90 °C
Reaction time: 18 h
Yield: 4.9 %

Procedure:
To 3-chloro-4-(trifluoromethyl)phenol (Preparation 16, 110 mg, 0.56 mmol) and 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (Preparation 13, 150 mg, 0.56 mmol) dissolved in dimethylsulfoxide (5 ml) was added potassium carbonate (232 mg, 1.68 mmol) and the mixture stirred at 90° C. for 18 hours under nitrogen. The mixture was poured onto ammonium chloride (aq) and extracted with ethyl acetate (3×20 mL), washed with water (3×20 mL) and dried (MgSO4). Purification of the crude product by silica gel column chromatography using 80% Ethyl acetate in heptane furnished the title compound as white solid (12.2 mg, 4.9%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1([CH2:11]C(O)=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[N-:16]=[N+]=[N-].[N-]=C=O>>[NH2:16][CH2:11][C:5]1([CH2:4][C:3]([O:2][CH3:1])=[O:15])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CC1(CC(=O)O)CCCCC1
Agent: [N-]=C=O
Product: COC(=O)CC1(CN)CCCCC1

Procedure:
1,1-Cyclohexanediacetic acid monomethyl ester is converted via the corresponding acid chloride into the azide. The azide is degraded by the Curtius method to the isocyanate. The isocyanate is then hydrolyzed to give methyl 1-aminomethyl-1-cyclohexaneacetate. Heating this substance in alkaline methanol under reflux for three days affords 8-azaspiro[5,4]decan-9-one or gabapentin lactam. GBP-L was characterized by means of Thin Layer Chromatography, Infrared-Spectroscopy, [1H]-NMR and [13C]-NMR (Nuclear Magnetic Resonance Spectroscopy) and FAB-MS (Fast Atom Bombardment Mass Spectroscopy).