Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1([CH3:21])[S:13][C@@H:12]2[C@H:14]([NH2:17])[C:15](=[O:16])[N:11]2[C@H:10]1[C:18]([OH:20])=[O:19].C[Si](C)(C)Cl.[C:27]1([O:33][C:34](=[O:45])[CH:35]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:36](O)=[O:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)(O)[O-].[Na+:50]>C(Cl)Cl>[Na+:50].[O:33]([C:34]([CH:35]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:36]([NH:17][CH:14]1[C:15](=[O:16])[N:11]2[CH:10]([C:18]([O-:20])=[O:19])[C:9]([CH3:21])([CH3:8])[S:13][C@H:12]12)=[O:37])=[O:45])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Reactant: O=C(O)C(C(=O)Oc1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)S[C@@H]2C(NC(=O)C(C(=O)Oc3ccccc3)c3ccccc3)C(=O)N2C1C(=O)[O-]
Temperature: 35 °C
Reaction time: 1 h

Procedure:
56 ml. (0.4 moles) of triethylamine are added to a suspension of 42 g. (0.2 moles) of 6-APA in 600 ml. of methylene chloride. Subsequently 430 g. (0.4 moles, 50 ml.) of trimethyl chlorosilane are added to the obtained solution at 10° C., and the mixture is stirred for 60 minutes. Thereafter the mixture is heated to 35° C., 104 g. (0.2 moles) of phenylmalonic acid phenylester pnetachlorophenyl ester are added, and subsequently 28 ml. (0.2 moles) of triethylamine are introduced dropwise into the mixture. The reaction mixture is stirred at room temperature for 3 hours, thereafter it is neutralized to pH=7 with 200 ml. of 8% aqueous sodium bicarbonate solution.
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]([O:12][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(Cl)c(O)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(Cl)c(OC2CCCCO2)c1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, to a solution of methyl 6-chloro-5-hydroxynicotinate (703 mg) in toluene (15 mL) were added 3,4-dihydro-2H-pyran (685 μL) and pyridinium p-toluenesulfonate (94 mg), and the mixture was stirred at room temperature for 2 hr and further at 60° C. for 1.5 hr. The reaction mixture was poured into water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (546 mg) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[N:17]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(Cl)Cl.CC(O)=O.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[N:17]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: Nc1nccc(COc2ccc([N+](=O)[O-])c3ccccc23)n1
Agent: [Pt]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1nccc(COc2ccc(N)c3ccccc23)n1
Yield: 91.1 %

Procedure:
A solution of the nitroarene (70) (1.10 g, 3.71 mmol) in a mixture of DCM (50 mL) and AcOH (40 mL) was passed through a Thales H-cube (1.0 mL·min−1, 55 mm, 10% Pt/C, 40° C., full hydrogen mode). LC-MS analysis of the resulting solution showed a mixture comprising of mainly starting material and ca. 20% product. The DCM was removed by evaporation in vacuo and the solution re-subjected to reduction using the same conditions at RT. The volatiles were evaporated in vacuo to give the title compound (71) (ca. 70% by LC-MS) as a purple solid (0.90 g, 64% yield): m/z 267 (M+H)+ (ES+).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5](/[CH:9]=[N:10]/[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:6]=[CH:7][CH:8]=1.C(N(CC)C(C)C)(C)C.[N+:29]([CH3:32])([O-:31])=[O:30]>C(OCC)(=O)C>[N+:29]([CH2:32][CH:9]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:18])([F:19])[F:1])[CH:4]=1)([O-:31])=[O:30]
Reactant: CC(C)(C)OC(=O)/N=C/c1cccc(C(F)(F)F)c1
Reactant: C[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(C[N+](=O)[O-])c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Of the compound from Example 11A, 3.6 g (13.17 mmol) were introduced in 26 ml of nitromethane and admixed with 0.69 ml (3.95 mmol) of N,N-diisopropylethylamine. The mixture was stirred at RT for 2 h. The reaction mixture was diluted with ethyl acetate and washed in succession twice each with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, and then with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated on a rotary evaporator. The residue (about 5 g) was dissolved in 15 ml of isopropanol at reflux. After cooling, the precipitated product was isolated by filtration, washed with a little isopropanol and sucked dry. After further drying in an HV, the title compound was obtained: 2.26 g (51% of theory).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH:12]=[CH2:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15].Cl[CH2:17][CH2:18][CH:19]([CH3:23])[C:20](=[O:22])[CH3:21]>>[O:22]=[C:20]([CH3:21])[CH:19]([CH3:23])[CH2:18][CH2:17][N:4]1[C:5](=[O:14])[C:6]2[N:7]([CH2:11][CH:12]=[CH2:13])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:15]
Reactant: CC(=O)C(C)CCCl
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2C
Product: C=CCn1cnc2c1c(=O)n(CCC(C)C(C)=O)c(=O)n2C

Procedure:
1-(4-Oxo-3-methylpentyl)-3-methyl-7-allylxanthine (melting point 73-74° C.) is prepared from 3-methyl-7-allylxanthine and 1-chloro-3-methylpentan-4-one.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([OH:10])(=[S:9])[CH3:8].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH2:20]Cl)[CH:13]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH:13]=1)[CH2:20][S:9][C:7](=[O:10])[CH3:8]
Reactant: COc1ccc(Cl)cc1CCl
Reactant: CC(O)=S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1CSC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of cesium carbonate (0.55 g, 1.70 mmol) in dimethylformamide (13 mL) was added thioacetic acid (0.24 g, 3.14 mmol) followed by addition of 4-chloro-2-chloromethyl-1-methoxybenzene (0.50 g, 2.62 mmol) in one portion. The reaction was stirred in the dark at ambient temperature overnight. The reaction was diluted with ethyl acetate, washed with water, 5% aqueous sodium hydrogen carbonate, and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.58 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].Br[CH2:13][CH2:14][CH3:15]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:13][CH2:14][CH3:15])[N:6]=[C:5]2[I:11]
Reactant: Clc1ccc2[nH]nc(I)c2c1
Reactant: CCCBr
Product: CCCn1nc(I)c2cc(Cl)ccc21
Yield: 75 %

Procedure:
The title compound was prepared in 75% yield from 5-chloro-3-iodo-indazole and 1-bromopropane according to the general procedure for Preparation 10A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 0.92 (3H, t, J=7.6 Hz), 1.91-1.97 (2H, m), 4.33 (2H, t, J=7.2 Hz), 7.31 (1H, d, J=8.8 Hz), 7.37 (1H, dd, J=2.0, 8.8 Hz), 7.46 (1H, d, J=1.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N@:11]1[CH2:13][CH:12]1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1)=[O:15])(=[O:10])=[O:9].[I-].[Na+].[CH:34]([N:37]=[C:38]=[O:39])([CH3:36])[CH3:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:13][CH:12]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[N:37]([CH:34]([CH3:36])[CH3:35])[C:38]1=[O:39])(=[O:9])=[O:10]
Reactant: CC(C)N=C=O
Reactant: O=C(C1C[N@@]1S(=O)(=O)c1ccccc1Cl)N1CCN(c2ncccc2C(F)(F)F)CC1
Agent: [I-]
Agent: [Na+]
Product: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2Cl)CC1C(=O)N1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
In analogy to example 2, [(S)-1-(2-chloro-benzenesulfonyl)-aziridin-2-yl]-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone (example 72, step 3) was reacted with sodium iodide and isopropylisocyanate to give the title compound as a colorless foam. MS: 560.2 ([M+H]+)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].Br.[Br:32][CH2:33][CH2:34][NH2:35].C(N(CC)CC)C>C1COCC1>[Br:32][CH2:33][CH2:34][NH:35][S:27]([C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:18](=[O:19])[CH2:17][CH2:16][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=2)=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: CC(C)(C)c1cc(CCC(=O)Nc2ccc(S(=O)(=O)Cl)cc2)cc(C(C)(C)C)c1O
Reactant: NCCBr
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(CCC(=O)Nc2ccc(S(=O)(=O)NCCBr)cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.6 %

Procedure:
To a stirred suspension of 4-[3-(3,5-di-tert-butyl-4-hydroxy-phenyl)-propionylamino]-benzenesulfonyl chloride (4.38 g, 0.0097 mol) and 2-bromoethylamine hydrobromide (2.11 g, 0.0103 mol) in THF (30 g) at 0-2° C. under nitrogen was added dropwise a solution of triethylamine (2.01 g, 0.0199 mol) in THF (9 g). When addition was complete, the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was filtered and the filtrate was spin evaporated in vacuo. The residue was chromatographed over silica (toluene/acetone 75:25) to give 2.7 g of N-[4-(2-bromoethylsulfamoyl)-phenyl]-3-(3,5-di-tert-butyl -4-hydroxy-phenyl)-propionamide as a white crystalline solid, mp 153-155° C.
Reaction SMILES: [CH:1]1([N:4]([CH2:11][CH2:12][OH:13])[S:5]([CH2:8][CH2:9][CH3:10])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH2:14]([S:17](Cl)(=[O:19])=[O:18])[CH2:15][CH3:16]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]1([N:4]([S:5]([CH2:8][CH2:9][CH3:10])(=[O:7])=[O:6])[CH2:11][CH2:12][O:13][S:17]([CH2:14][CH2:15][CH3:16])(=[O:19])=[O:18])[CH2:3][CH2:2]1
Reactant: CCCS(=O)(=O)Cl
Reactant: CCCS(=O)(=O)N(CCO)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)OCCN(C1CC1)S(=O)(=O)CCC
Temperature: 25 °C
Yield: 78.8 %

Procedure:
To a solution of propane-1-sulfonic acid cyclopropyl-(2-hydroxy-ethyl)-amide (150 mg, 0.8 mmol) in CH2Cl2 and DMAP (97 mg, 0.8 mmol) was added dropwise a solution of propane-1-sulfonyl chloride (97 mg, 0.8 mmol) in CH2Cl2. The resulting mixture was stirred at room temperature over night, diluted with 50 ml of CH2Cl2, extracted subsequently with water, 1 M HCl, and brine, tried over Na2SO4, filtered and the solvent evaporated to obtain 197.5 mg of product which was used in the next step without further purification.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)(=O)C(O)=O.[CH2:19]([NH:21][NH2:22])[CH3:20]>C(O)(=O)C>[CH2:19]([N:21]1[C:9]([CH2:10][CH3:11])=[CH:8][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:22]1)[CH3:20]
Reactant: CCNN
Reactant: CCOC(=O)C(=O)CC(=O)CC
Agent: O=C(O)C(=O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC)n(CC)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
Ethyl 2,4-dioxohexanoate (21.5 g) in glacial acetic acid (125 ml) was cooled in an ice-bath and treated with N-ethylhydrazine oxalate (18.75 g) over 15 minutes. After addition was complete the mixture was stirred for 3 hours at room temperature. The acetic acid was then removed by evaporation in vacuo. The orange oily residue was dissolved in EtOAc and the solution washed repeatedly with saturated aqueous NaHCO3 and once with brine. Following drying over MgSO4 the solvent was evaporated in vacuo to give ethyl 1,5-diethylpyrazole-3-carboxylate as an oil (20.7 g); δ(CDCl3) 1.25-1.45 (9H, 3×3H,t, J 7 Hz), 2.62 (2H, q, J 7 Hz), 4.17 (2H, q, J 7 Hz), 4.38 (2H, q, J 7 Hz), 6.57 (1H, s) ppm.
Reaction SMILES: [CH:1](=O)[CH3:2].B(F)(F)F.CCOCC.[CH3:13][C:14]([OH:22])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH3:15]>C(OCC)C>[CH3:13][C:14]1([CH3:15])[CH2:16][CH2:17][CH:18]([C:19]([CH3:21])=[CH2:20])[CH:1]([CH3:2])[O:22]1
Reactant: CC=O
Reactant: CC(C)=CCCC(C)(C)O
Agent: FB(F)F
Solvent: CCOCC
Product: C=C(C)C1CCC(C)(C)OC1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 55.9 %

Procedure:
42 g of acetaldehyde in 600 ml diethylether were placed in a 2 liter three-necked flask and cooled to 0° C. 140 g of a 48% solution of boron trifluoride diethyl etherate were then added and stirred for 10 minutes at 0° C. 124 g of 2,6-dimethyl-hept-5-en-2-ol dissolved in 100 ml diethyl ether were droppered into the reaction solution at 0° C. Once addition was complete stirring continued for a further hour at 0° C. followed by heating to room temperature. Once the reaction solution had been stirred for 12 hours at room temperature, quenching was carried out with saturated ammonium chloride solution (500 ml) and following conditioning of the raw product obtained distillation was performed via a 30 cm packed column. 82 g of 2,2,6-trimethyl-5-isopropenyltetrahydropyran with a purity of 98% were obtained (55% of theoretical yield).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C@@H:26]([C@H:28]2[CH2:32][O:31]C(C)(C)[O:29]2)[CH3:27])[N:12]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C@H:26]([CH3:27])[C@H:28]([OH:29])[CH2:32][OH:31])[N:12]=1
Reactant: C[C@@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@H]1COC(C)(C)O1
Agent: Cl[Fe](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@H](O)CO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy]-4-pyrimidinyl]-1-azetidinesulfonamide (the product of step yl) (0.13 g) in DCM (5 mL) was added iron (III) chloride hexahydrate (0.26 g). The reaction mixture was stirred at ambient temperature for 1.5 h, then saturated aqueous sodium bicarbonate (1 mL) was added. The layers were separated and the aqueous material extracted with DCM (×3) and ethyl acetate (×3). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and evaporated. The residual pale yellow solid was slowly precipitated from DCM, filtered and the resulting material washed with minimal cold DCM (2×1 mL) to afford the title compound as a white powder. Yield: 64 mg,
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[CH:35]=[CH:34][C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[S:20][C:16]=3[CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].FC(F)(F)C(O)=O>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[CH:35]=[CH:34][C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[S:20][C:16]=3[CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(NC(=O)c2ccc3nc(N4CCN(C(=O)OC(C)(C)C)CC4)sc3c2)cc1OC
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(NC(=O)c2ccc3nc(N4CCNCC4)sc3c2)cc1OC
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-(6-(3,4-dimethoxyphenylcarbamoyl)benzo[d]thiazol-2-yl)piperazine-1-carboxylate (507.1 mg, 1.15 mmol) was treated with trifluoroacetic acid (24 mL). The resulting homogenous mixture was stirred for 30 min, then diluted with diethyl ether and cooled in ice bath. The resulting solid was collected by filtration and dried in vacuum oven at room temperature to yield N-(3,4-dimethoxyphenyl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide as a khaki colored amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=1)(=[O:18])=[O:17]>CS(C)=O>[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccccc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
A solution of 4-chlorophenol (5.54 g, 43 mmol) in DMSO (75 mL) was treated sequentially with potassium t-butoxide (5.15 g, 46 mmol) then with a solution of 4-fluorophenyl methyl sulfone (5.00 g, 29 mmol) in DMSO (25 mL), heated at 120° C. for 2 hours, cooled to rt, then partitioned between dichloromethane and 1 N sodium hydroxide, dried (Mg2SO4), filtered, and concentrated to give crude product as a white solid. Recrystallization from ethyl acetate and hexane afforded 5.44 g (66%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][C:7]1[C:8]2[CH2:29][NH:28][CH2:27][CH2:26][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])=[CH:16][CH:15]=2)[N:12]=1.[CH2:33]=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][C:7]1[C:8]2[CH2:29][N:28]([CH3:33])[CH2:27][CH2:26][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])=[CH:18][CH:19]=2)[N:12]=1
Reactant: COc1cccc(Cc2nc(Nc3ccc(-n4ccnc4C)cc3)nc3c2CNCC3)c1
Reactant: C=O
Product: COc1cccc(Cc2nc(Nc3ccc(-n4ccnc4C)cc3)nc3c2CN(C)CC3)c1
Yield: 10.4 %

Procedure:
4-(3-Methoxybenzyl)-6-methyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (14.3 mg, 10.4%) was synthesised from 4-(3-methoxybenzyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and formaldehyde according to the general procedure for reductive amination. MS (ES+) m/z 441.3 (M+H)+
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[N:18]1C=CC=C[CH:19]=1>>[CH:5]1[C:6]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:2]([C:19]#[N:18])=[CH:3][CH:4]=1
Reactant: Clc1cccc2c1CCCCc1ccccc1-2
Reactant: c1ccncc1
Product: N#Cc1cccc2c1CCCCc1ccccc1-2

Procedure:
The reaction of 4-chloro-5,6,7,8-tetrahydrodibenzo[a,c]cyclooctene (3.3 g, 0.014 mole), cuprous cyanide (2.44 g, 0.027 mole) and pyridine (2.5 g, 0.027 mole) produced 5,6,7,8-tetrahydrodibenzo[a,c]cycloocten-4-carbonitrile as an oil (60% product, 40% starting material by gas chromatography). The IR spectrum possessed an adsorption at 4.45μ indicating a CN group.
Reaction SMILES: O.[O:2]=[CH:3][C:4]([Cl:7])([Cl:6])[Cl:5].[CH2:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12]>C1C=CC=CC=1>[CH2:8]([O:2][CH:3]([O:13][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:4]([Cl:7])([Cl:6])[Cl:5])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCO
Reactant: O=CC(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: O
Product: CCCCCOC(OCCCCC)C(Cl)(Cl)Cl

Procedure:
A mixture of 5 g of chloral-hydrate, 10 ml of amyl-alcohol, 0.1 g of 4-methyl-sulphonic acid and 50 ml of benzene is kept at reflux temperature and the formed water is separated by means of a Dean-Stark apparatus. After a reaction time of 9 hours the benzene is washed with a sodium hydrogen carbonate solution and water, dried on magnesium sulfate, then it is vacuum-distilled.
Reaction SMILES: [CH:1]1([CH:6]([NH:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)[C:7]2[S:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:6]([NH:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[C:7]2[S:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2sc3ccccc3c2C)C2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCC2)sc2ccccc12
Yield: 94.5 %

Procedure:
To a mixture of methyl 4-{[cyclopentyl(3-methyl-1-benzothiophen-2-yl)methyl]amino}benzoate (1.56 g) synthesized above, tetrahydrofuran (20 mL) and ethanol (20 mL) was added 1N aqueous sodium hydroxide solution (20.0 mL), and the mixture was stirred with heating under reflux for 4 hr, and concentrated under reduced pressure. The residue was dissolved in water (40 mL), and 1N hydrochloric acid (20.0 mL) was added at 0° C. The resulting precipitate was collected by filtration, and the obtained pale-brown solid was dissolved in ethyl acetate. The solution was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (1.42 g, 95%) as a pale-brown solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([NH2:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[OH:11].[OH-].[K+].S(OC)(O[CH3:18])(=O)=O.O>CC(C)=O>[Cl:2][C:3]1[C:4]([O:11][CH3:18])=[CH:5][CH:6]=[C:7]([Cl:10])[C:8]=1[NH2:9]
Reactant: COS(=O)(=O)OC
Reactant: Nc1c(Cl)ccc(O)c1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(Cl)c(N)c1Cl

Procedure:
To a solution of 2,4-dichloro-3-aminophenol hydrochloride (GLSynthesis, 7.70 g, 35.9 mmol, 1.0 eq.) in acetone is added powdered potassium hydroxide 85% (9.48 g, 143.6 mmol, 4.0 eq.) in small portions. Then, dimethyl sulfate (5.13 ml, 53.9 mmol, 1.5 eq.) is added at such a rate that the internal temperature does not rise above 30° C. After 1 h stirring at room temperature water (50 ml) is added and stirring is continued for another hour. The solvent is evaporated and the residue is distributed between ethyl acetate (150 ml) and water (100 ml). The organic layer is isolated, dried over Na2SO4 and evaporated to give a yellow oil. Kugelrohr distillation affords the desired product as a colorless oil: b.p. 150° C./0.3 mbar, HPLC: tR=5.61 min (purity: 90%, gradient A), 400 MHz 1H-NMR (CDCl3) δ: 3.87 (s, 3H, OMe), 4.49 (br s, 2H, NH2), 6.30 (d, 1H, Ar—H4), 7.11 (d, 1H, Ar—H5).
Reaction SMILES: [C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:23](O)(=O)[CH2:24]CCCCCCCCCCCCCCCC.[OH-].[Na+:44].[N+]([O-])(O)=O>O>[C:1]([O-:22])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:23][CH3:24].[Na+:44]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=[N+]([O-])O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 55 °C

Procedure:
In an amount of 32.4 g of behenic acids, 9.9 g of arachidic acid and 5.6 g of stearic acid were dissolved in 945 mL of pure water at 90° C. Then, the solution was added with 98 mL of 1.5 mol/L sodium hydroxide aqueous solution with stirring at high speed. Subsequently, the solution was added with 0.93 mL of concentrated nitric acid, cooled at 55° C. and stirred for 30 minutes to obtain sodium behenate solution.