Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]3)=[O:12])[CH2:7][CH2:6]1.Cl.[CH3:31][NH2:32].Cl.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:31][NH:32][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]3)=[O:12])[CH2:7][CH2:6]1
Reactant: O=C1CCc2cc(C(=O)N3CCN(CCC(Cl)c4ccccc4)CC3)ccc2N1
Reactant: CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CNC(CCN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 55.1 %

Procedure:
One gram of 6-[4-(3-chloro-3-phenylpropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril·hydrochloride, 0.17 g of methylamine·hydrochloride and 1.2 g of potassium carbonate were dispersed in 20 ml of acetonitrile and the dispersion was stirred at 60° C. for 4 hours. After the reaction was completed, the reaction mixture was poured into water then extracted with methylene chloride. The extract was dried with anhydrous sodium carbonate, then the solvent was removed by evaporation. Thus obtained residue was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol=20:1), then the desired product was converted into a citrate, and recrystallized from ethanol-water to yield 0.5 g of 6[-4-(3-methylamino-3-phenylpropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. dicitrate. White powdery substance. Melting point: 150°-156° C. (decomp.).
Reaction SMILES: Cl.C(OC1C=CC(S(Cl)(=O)=O)=CC=1[C:15]1[NH:20][C:19](=[O:21])[C:18]2=[C:22]([CH3:28])[N:23]=[C:24]([CH2:25][CH2:26][CH3:27])[N:17]2[N:16]=1)C>N1C=CC=CC=1.ClCCl>[CH3:28][C:22]1[N:23]=[C:24]([CH2:25][CH2:26][CH3:27])[N:17]2[C:18]=1[C:19](=[O:21])[NH:20][CH:15]=[N:16]2
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1nc(C)c2c(=O)[nH]cnn12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
110 mg (0.6 mmol) of 3-butylsydnoneimine hydrochoride are dissolved in 2.5 ml of pyridine and cooled to 0° C. 210 mg (0.5 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride are added, and the reaction mixture is stirred for 2 hours at 0° C. and overnight at room temperature. The mixture is diluted with dichloromethane, the organic phase is washed with water and dried over sodium sulphate and the solvent is removed under reduced pressure. Chromatography (dichloromethane/methanol) gives 16 mg (6%) of 2-[2-ethoxy-5-(3-butylsydnoneimine)-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H -imidazo[5,1-f][1,2,4]triazin-4-one. Rf=0.41 (dichloromethane/methanol=95:5)
Reaction SMILES: [OH:1][C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][NH:4]C(=O)OCCCC.S(=O)(=O)(O)O.[C:29](=O)(O)[O-].[Na+]>CO>[CH3:29][O:1][C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][NH2:4]
Reactant: CCCCOC(=O)NCC(O)(c1ccccc1)c1ccccc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(CN)(c1ccccc1)c1ccccc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of tent-butyl 2-hydroxy-2,2-diphenylethylcarbamate (0.42 g, 1.39 mmol) in methanol (10 mL) was treated with concentrated sulfuric acid (2 mL). The reaction was stirred at 23° C. for a week and then at 40° C. for 2 hours. Solid sodium bicarbonate was added to the reaction until the pH reached ˜6-7 and the methanol was evaporated. The residue was then taken into ethyl acetate/water and the aqueous phase was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified on preparative HPLC (ammonium acetate/acetonitrile/water) to give the title material (0.140 g, 46%). 1H NMR (400 MHz, CDCl3) δ: 3.11 (3H, s), 3.54 (2H, br s), 3.98 (2H, br s), 7.24-7.30 (2H, m), 7.31-7.36 (8H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@H:4]([CH3:6])[NH2:5].C(=O)C1C=CC=CC=1.CC(C)([O-])C.[K+].Cl.ClC[C:25]1[CH:37]=[C:36]2[C:28](=[N:29][C:30]3[C:35]2=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:27][N:26]=1>C1COCC1>[CH3:1][O:2][C:3](=[O:7])[C@:4]([C:25]1[N:26]=[CH:27][C:28]2[NH:29][C:30]3[C:35]([C:36]=2[CH:37]=1)=[CH:34][CH:33]=[CH:32][CH:31]=3)([CH3:6])[NH2:5]
Reactant: COC(=O)[C@H](C)N
Reactant: ClCC1=NCC2=Nc3ccccc3C2=C1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O=Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)[C@](C)(N)c1cc2c(cn1)[nH]c1ccccc12
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
In THF (85 mL) was dissolved the Schiffs' Base (2.45 g, 12.8 mmol), derivedfrom alanine methyl ester and benzaldehyde, and cooled to -40° C. Tothis was added potassium-t-butoxide (2.92 g, 26 mmol) and the orange solution stirred under nitrogen at -40° C. for 30 minutes. To this was added 3-(chloromethyl)-1H-β-carboline hydrochloride salt (3.24 g,12.8 mmol), the reaction mixture stirred for another 30 minutes at -40° C. and then slowly warmed to room temperature overnight. The black solution was evaporated in the vacuum and then partitioned between ethyl acetate (150 mL) and water (50 mL). To the organic layer was added 1N HCl (100 mL) and the mixture was stirred for 2 hours. Then the organic was separated, washed with Na2CO3 solution, dried over Na2SO4 and evaporated in the vacuum to give 2-(9H-β-carboline-3-yl)-alanine methyl ester (2.4 g, 50.5%) as a light tan foam.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=O)=[O:4].[N:13]1[NH:14][C:15]([NH2:18])=[CH:16][CH:17]=1>C(O)(=O)C>[N:13]1[N:14]2[C:15]([N:18]=[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]3=[C:3]2[OH:4])=[CH:16][CH:17]=1
Reactant: COC(=O)C1CCCCCC1=O
Reactant: Nc1ccn[nH]1
Solvent: CC(=O)O
Product: Oc1c2c(nc3ccnn13)CCCCC2
Yield: 83.7 %

Procedure:
A solution of 2-oxo-cycloheptanecarboxylic acid methyl ester (5 g, 29.4 mmol) and 2H-pyrazol-3-ylamine (2.44 g, 29.4 mmol) in acetic acid (5 mL) was heated at 100° C. for 1 hour and resulted in the formation of a colorless precipitate. The solid was collected via filtration and washed with ethanol and ethyl ether to give 6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]inden-10-ol (5 g, 85% yield). The product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.C([S:31][CH2:32][CH:33]([CH3:37])[C:34](O)=[O:35])(=O)C>ClCCl>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:34](=[O:35])[CH:33]([CH3:37])[CH2:32][SH:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CC(=O)SCC(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(CS)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
L-Proline tert-butyl ester (5.1 g) is dissolved in dichloromethane (40 ml) and the solution stirred and chilled in an ice bath. Dicyclohexylcarbodiimide (6.2 g) dissolved in dichloromethane (15 ml) is added followed immediately by a solution of 3-acetylthio-2-methylpropanoic acid (4.9 g) in dichloromethane (5 ml). After 15 minutes stirring in the ice bath and 16 hours at room temperature, the precipitate is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is dissolved in ethyl acetate and washed neutral. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo. The residue, N-(3-acetylthio-2-methylpropanoyl)-L-proline tert-butyl ester, is purified by column chromatography (silica gel, chloroform), yield 7.9 g. The named product is obtained by following the procedure of Example 29, step (b).
Reaction SMILES: N1(C2CCN(C3S[C:16]([NH:18][C:19]4[N:24]=[C:23]([NH:25][C:26]5[C:31]([O:32][CH3:33])=[N:30][C:29]([P:34]([CH3:37])([CH3:36])=[O:35])=[CH:28][N:27]=5)[C:22]([Cl:38])=[CH:21][N:20]=4)=NN=3)CC2)CCCCC1.[CH3:39][N:40]1[CH2:45][CH2:44][N:43]([C:46]2[O:50][C:49](CN)=[N:48][N:47]=2)[CH2:42][CH2:41]1>>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[C:31]([O:32][CH3:33])=[N:30][C:29]([P:34]([CH3:36])([CH3:37])=[O:35])=[CH:28][N:27]=2)=[N:24][C:19]([NH:18][CH2:16][C:49]2[O:50][C:46]([N:43]3[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]3)=[N:47][N:48]=2)=[N:20][CH:21]=1
Reactant: COc1nc(P(C)(C)=O)cnc1Nc1nc(Nc2nnc(N3CCC(N4CCCCC4)CC3)s2)ncc1Cl
Reactant: CN1CCN(c2nnc(CN)o2)CC1
Product: COc1nc(P(C)(C)=O)cnc1Nc1nc(NCc2nnc(N3CCN(C)CC3)o2)ncc1Cl

Procedure:
This compound can be prepared as in Example 32 by reacting 2,5-dichloro-N-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimidin-4-amine (as described in Example 51) with 1-[5-(4-methylpiperazin-1-yl)-1,3,4-oxadiazol-2-yl]methanamine.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[Mg+2].[Cl-].[Cl-].C(N(CC)CC)C.[CH2:31]=[O:32]>CC#N.CCOC(C)=O>[CH:31]([C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:7][C:2]=1[OH:1])=[O:32]
Reactant: C=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(O)n2)CC1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)c(O)n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
To a mixture of t-butyl 4-(6-hydroxypyridin-2-yl)piperazine-1-carboxylate (8.4 g, 30 mmol) and MgCl2 (5.8 g, 60 mmol) in CH3CN (100 mL) was added triethylamine (25.2 mL, 150 mmol). After the mixture was stirred for 10 minutes at ambient temperature, paraformaldehyde (9.0 g, 300 mmol) was added to the mixture. The mixture was stirred for 18 hours at 60° C., and then cooled to room temperature. The mixture was then diluted with EtOAc (500 mL) and washed with 1 M Rochelle salt solution (200 mL) and saturated NH4Cl solution (200 mL). The organic layer was concentrated under reduced pressure and purified by column chromatography (30%-50% EtOAc/hexanes) to yield 3.6 g (39%) of t-butyl 4-(5-formyl-6-hydroxypyridin-2-yl)piperazine-1-carboxylate as white solid. MS m/z 308.2 [M+H]+; 1H NMR (500 MHz, CDCl3) δ (ppm) 12.35 (1H, br), 9.55 (1H, s), 7.66 (1H, d, J=8.51 Hz), 6.26 (1H, d, J=8.83 Hz), 3.79 (4H, m), 3.56 (4H, m), 1.51 (9H, s).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][C:23]#[N:24])[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][C:23]#[N:24])[CH2:17][CH2:16]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: N#CCC[C@H]1CC[C@H](N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: N#CCC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 90 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.087 g, 0.41 mmol), 3-(trans-4-aminocyclohexyl)propanenitrile (0.080 g, 0.52 mmol) TFA salt and N,N-diisopropylethylamine (0.35 mL, 2.0 mmol) in isopropyl alcohol (0.89 mL) was heated at 90° C. for 2 h. The resulting mixture was concentrated and purified on silica gel (eluting with 0 to 20% EtOAc in dichloromethane) to give the desired product (63 mg, 47%). LCMS calculated for C16H19N4O2S (M+H)+: m/z=331.1. Found: 331.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][CH2:29][C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1.[ClH:33]>C(Cl)Cl.O1CCOCC1>[ClH:33].[ClH:33].[F:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:15][CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][CH2:29][C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCCN(C(=O)OC(C)(C)C)C4)c4cc(F)ccc43)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3C[C@@]4(CCCNC4)c4cc(F)ccc43)c21
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 5-fluoro-1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,3′-piperidine]-1′-carboxylate (0.110 g, 0.251 mmol) in DCM (3 mL) was added 4N HCl in dioxane (0.63 mL). The reaction mixture was stirred overnight and then filtered. Evaporation of the mother liquid gave (R)-4-((S)-5-fluorospiro[indoline-3,3′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochlorid. LCMS (APCI+) m/z 339 [M+H]+; Rt=2.29 min. The solid collected by filtration was suspended in 5:1 MeCN/MeOH (1 mL) and heated at reflux for about 5 minutes. After cooling, the precipitated solid was filtered and dried in air to give (R)-4-((R)-5-fluorospiro[indoline-3,3′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride. LCMS (APCI+) m/z 339 [M+H]+; Rt=2.31 min.
Reaction SMILES: CI.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:24])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:13]=2)=[CH:6][C:5]=1[NH:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:28]=1.[C:39](=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:24])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH:13]=2)=[CH:6][C:5]=1[NH:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([S:34]([CH3:37])(=[O:35])=[O:36])[CH3:39])[CH:28]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(NS(C)(=O)=O)c1
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(N(C)S(C)(=O)=O)c1
Temperature: 50 °C
Yield: 57.2 %

Procedure:
Methyl iodide (0.023 ml) was added to a mixture of N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-methanesulphonylaminobenzamide (0.17 g), caesium carbonate (0.121 g) and DMF (10 ml) and the resultant mixture was stirred and heated to 50° C. for 72 hours. The reaction mixture was poured into water (200 ml). The precipitate was isolated, washed in turn with water and diethyl ether and dried under vacuum at 60° C. There was thus obtained the title compound (0.1 g); m.p. 208-209° C.; NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 3.0 (s, 3H), 3.18 (t, 4H), 3.75 (t, 4H), 7.13 (m, 1H), 7.23 (d, 1H), 7.36 (m, 2H), 7.45 (d, 1H), 7.59 (m, 3H), 7.81 (d, 1H), 7.91 (d, 1H), 7.99 (d, 1H), 9.98 (s, 1H), 10.12 (s, 1H); Mass Spectrum: M+H+523.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClN1C(=[O:24])CCC1=O.CCOCC>C(O)(=O)C.P(=O)(O)(O)O.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10]2=[O:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Clc1cc(Cl)cc(-n2ccc3ccccc32)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=P(O)(O)O
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C1Cc2ccccc2N1c1cc(Cl)cc(Cl)c1
Yield: 70.9 %

Procedure:
To a solution of 7.8 g (29.9 mmol) of 1-(3,5-Dichlorophenyl)-1H-indole in 50 mL of acetic acid was added 4.0 g (30.1 mmol) of N-chlorosuccinimide. The mixture was warmed at reflux for 1hr, when TLC indicated the disappearance of starting material. The mixture was cooled and diluted with 16 mL of 70% aqueous phosphoric acid and 4 mL of water and warmed at reflux for 6 hr. The reaction was then cooled to afford a precipitate which was diluted with 50 mL of water and collected by filtration. The solid was partially dried by pulling vacuum through the filter cake and then dissolved in dichloromethane, dried (MgSO4), treated with carbon (Norit A), filtered through diatomaceous earth and concentrated to afford an orange solid. Trituration with ether gave 5.9 g (71%) of 1-(3,5-dichlorophenyl)-1,3-dihydro-indol-2-one which was used without further purification.
Reaction SMILES: [O:1]1[C:12]2[CH:4]([CH2:5][C:6](=[CH:10][CH:11]=2)[CH2:7][CH:8]=[CH2:9])[O:3][CH2:2]1.[C:13]([O:16][C:17](=O)C)(=[O:15])[CH3:14].C=O.S(=O)(=O)(O)O>CCCCCC.C(O)(=O)C.O>[C:13]([O:16][CH2:17][C:10]1[CH:11]=[C:12]2[O:1][CH2:2][O:3][C:4]2=[CH:5][C:6]=1[CH2:7][CH2:8][CH3:9])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCC1=CC=C2OCOC2C1
Agent: C=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCCc1cc2c(cc1COC(C)=O)OCO2
Temperature: 20 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
Dihydrosafrole (20 g), acetic acid (100 g) and water (10 g) were added to a mixture of acetic acid (250 ml), hexane (200 ml), acetic anhydride (40 g) and paraformaldehyde (40 g) to which 1.7 g of 40% sulphuric acid had been added. The reaction mixture was held at 60° C. for 5 hours and was then cooled to 20° C. and excess paraformaldehyde removed by filtration. Saturated brine (200 ml) was then added followed by ether (100 ml). The mixture was ether extracted (3 times) and combined extracts washed with brine (3 times). Following removal of solvent under reduced pressure the material was distilled under vacuum to give 4,5-methylenedioxy-2-propylbenzyl acetate (8) as a colourless oil (b.pt 154°-165° C. at 2.0 mm Hg) . . . Yield 59%.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])[N:8]=1)=[O:5].[CH:27](=O)[CH2:28][CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CO.ClCCl>[F:26][C:21]1[CH:22]=[C:23]([F:25])[CH:24]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:16][CH2:17][N:18]([CH2:27][CH2:28][CH3:29])[CH2:19][CH2:20]2)=[O:14])[N:8]=1)=[O:5]
Reactant: O=C(Nc1cccc(C(=O)C2CCNCC2)n1)c1c(F)cc(F)cc1F
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCCN1CCC(C(=O)c2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Reaction time: 1.5 h

Procedure:
Mix 2,4,6-trifluoro-N-[6-(piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide (50 mg), propionaldehyde (80 mg), sodium triacetoxyborohydride (38 mg) and acetic acid (21 mg) with dichloromethane (5 mL) and stir for 1.5 hrs. Dilute with methanol and load on a SCX column (10 g), wash with methanol, elute the product with 2M NH3-methanol. Purify the product on a silica gel column (10 g, dichloromethane/2M NH3 in methanol, gradient) to obtain the title compound as a free base (26 mg). Mass spectrum (electrospray) m/z=406 (M+1); 1H NMR (CDCl3): 8.52 (d, 1H), 8.38 (br, 1H), 7.92 (t, 1H), 7.82 (dd, 1H), 6.82 (m, 2H), 3.61 (br, 1H), 3.00 (m, 2H), 2.34 (m, 2H), 2.11 (m, 2H), 1.87 (m, 3H), 1.60 (m, 5H), 0.90 (t, J=7.3 Hz, 3H).
Reaction SMILES: C(S[C:4]1[N:5]=[C:6]([OH:13])[C:7]2[S:12][CH:11]=[CH:10][C:8]=2[N:9]=1)C.[NH2:14][C:15]1[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1>C(OCC)C>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][C:4]1[N:5]=[C:6]([OH:13])[C:7]2[S:12][CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: CCSc1nc(O)c2sccc2n1
Reactant: Cc1ccccc1N
Solvent: CCOCC
Product: Cc1ccccc1Nc1nc(O)c2sccc2n1

Procedure:
2-Ethylmercapto-4-hydroxythieno[3,2-d]pyrimidine 10 g, 0.047I mol) and o-toluidine (30 g, 0.0279 mol) were heated in an oil bath at 210° for 20 hours. The reaction mixture was poured into diethyl ether and the solid obtained was collected by filtration and dried. The mother liquor was extracted with 2N sodium hydroxide (3×100 ml). The aqueous extracts were combined, acidified with glacial acetic acid and extracted with chloroform (3×100 ml). The chloroform extracts were combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a solid. Recrystallization from methanol gave a pure sample, (5.32 g), m.p. 243°-245°.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:6]([NH2:7])=[CH:5][C:4]=1F)#[N:2].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH:23]([CH3:27])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[OH-].[Na+]>CS(C)=O.C(N(C(C)C)CC)(C)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:4]2[C:3]([C:1]#[N:2])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:6]([CH:5]=2)[NH2:7])[CH:23]([CH3:27])[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: N#Cc1cc([N+](=O)[O-])c(N)cc1F
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1cc(N)c([N+](=O)[O-])cc1C#N
Temperature: 140 °C
Reaction time: 12 h
Yield: 76.4 %

Procedure:
To a solution of 8.00 g of 4-cyano-3-fluoro-6-nitroaniline (which was synthesized following J. Med. Chem. 1994, 37, 467) and 17.60 g of 1-tert-butoxycarbonyl-3-methylpiperazine in 25 ml of dimethylsulfoxide, 23 ml of diisopropylethylamine was added and stirred for 3 hours at 140° C. and 12 hours at room temperature. 1N aqueous sodium hydroxide solution was added to the reaction liquid which then was extracted with chloroform. The chloroform layer was dried on anhydrous magnesium sulfate and the solvent was distilled off. The residue was washed with chloroform-methanol, to provide 12.2 g of the title compound as a pale yellow solid.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.CN(C)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:15][S:16]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:18])=[O:17]
Reactant: On1nnc2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: CN(C)C
Solvent: c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)On1nnc2ccccc21
Reaction time: 8 h

Procedure:
1-Hydroxy-1,2,3-benzotriazole (6.5 g) and trimethylamine (7.0 ml) are dissolved in benzene (50 ml). To the solution is added dropwise methanesulfonyl chloride (3.9 ml) with stirring under ice-cooling and the mixture is stirred for 2 hours and then allowed to stand overnight. To the reaction mixture are added water and ethyl acetate. The ethyl acetate layer is washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off. The resulting crystals are washed with petroleum ether to give 1-methanesulfonyloxy-1,2,3-benzotriazole (9.2 g), melting point: 90°-92° C.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.CCCCCC.C([Li])CCC.[C:21](#[N:23])[CH3:22].[CH3:24][O:25][C:26]1[CH:34]=[C:33]2[C:29]([CH2:30][CH:31]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:32]2=O)=[CH:28][CH:27]=1>O1CCCC1.O>[CH3:24][O:25][C:26]1[CH:34]=[C:33]2[C:29]([CH2:30][CH:31]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)/[C:32]/2=[CH:22]\[C:21]#[N:23])=[CH:28][CH:27]=1
Reactant: CC#N
Reactant: COc1ccc2c(c1)C(=O)C(c1ccccc1)C2
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1ccc2c(c1)/C(=C/C#N)C(c1ccccc1)C2
Reaction time: 0.17 h
Yield: 15.9 %

Procedure:
To a solution of 1,1,1,3,3,3-hexamethyldisilazane (2.19 g, 13.6 mmol.) in tetrahydrofuran (80 ml) was gradually added dropwise, under argon atmosphere at -78° C., a normal butyl lithium hexane solution (1.56 M, 8.72 ml, 13.6 mmol.). The mixture was stirred for 10 minutes, to which was then added dropwise acetonitrile (0.65 ml, 12.4 mmol.). The mixture was stirred for further 20 minutes, to which was added dropwise a solution of 6-methoxy-2-phenyl-1-indanone (2.70 g, 11.3 mmol.) in tetrahydrofuran (10 ml), and the mixture was stirred for one hour. The temperature of the reaction mixture was gradually reverted to room temperature while pouring water thereto, and the organic substance was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was dissolved in toluene (100 ml), to which was added 10-camphor-sulfonic acid (0.5 g). The reaction mixture was heated for 2 hours under reflux. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate, and the organic substance was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue thus obtained was recrystallized to afford the titled compound (yield 0.47 g, yield 16%).