Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=O)[CH:14](Br)[F:15])[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[CH3:20][C:21]1[N:26]=[C:25]([NH:27][C:28]([NH2:30])=[S:29])[CH:24]=[CH:23][CH:22]=1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:30]=[C:28]([NH:27][C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([CH3:20])[N:26]=4)[S:29][C:14]=3[F:15])[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cc(C(=O)C(F)Br)cn2)cc1
Reactant: Cc1cccc(NC(N)=S)n1
Solvent: CC(C)=O
Product: COc1ccc(Cn2cc(-c3nc(Nc4cccc(C)n4)sc3F)cn2)cc1
Yield: 92.3 %

Procedure:
According to Scheme 6 Step 3: A solution of 1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-bromo-2-fluoroethanone (0.26 mmol, 110 mg) and of 1-(6-methylpyridin-2-yl)thiourea (0.26 mmol, 44 mg) in acetone (3 mL) was stirred at 50° C. for 5 hours. A precipitate was formed, was filtered and was washed with Et2O to yield N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-fluorothiazol-2-yl)-6-methylpyridin-2-amine (0.24 mmol, 95 mg, 92%) as a beige solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[O:8]=[C:9]1[NH:17][CH:16]=[N:15][C:14]2[N:13]([CH2:18][CH2:19][C:20](OCC)=[O:21])[CH:12]=[N:11][C:10]1=2>C(#N)C>[O:8]=[C:9]1[NH:17][CH:16]=[N:15][C:14]2[N:13]([CH2:18][CH2:19][C:20]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])=[O:21])[CH:12]=[N:11][C:10]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: NCCOCCO
Solvent: CC#N
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCCOCCO
Reaction time: 0.33 h
Yield: 84.7 %

Procedure:
0.500 g (4.76 mmol) of 2-(2-aminoethoxy)ethanol was heated with 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) in a 10 ml round bottom flask at 120° C. for one hour. The solution was treated with 8 ml of acetonitrile and stirred vigorously for 20 minutes. The white precipitate was obtained by filtration and was washed with acetonitrile and then with ether. Upon drying, 265 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[2-(2-hydroxyethoxy)ethyl]propanamide (AIT-047) as a white solid was obtained. Yield: 85%.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=[O:7])[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.C(O)(=O)C.[N+:16]([O-])([OH:18])=[O:17]>C(OC(=O)C)(=O)C>[N+:16]([C:10]1[CH:9]=[CH:8][C:3]2[C:4]([CH:6]=[O:7])=[CH:5][S:1][C:2]=2[CH:11]=1)([O-:18])=[O:17]
Reactant: O=Cc1csc2ccccc12
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=Cc1csc2cc([N+](=O)[O-])ccc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 9 g of benzo[b]thiophene-3-carboxaldehyde in 50 ml of acetic anhydride was cooled to 0° C. by means of an external ethanol/ice bath. A solution of 40 ml of acetic acid and 20 ml of fuming nitric acid was added at such a rate to maintain the temperature of the reaction at 0°-5° C. Following the addition of the reagents, the reaction mixture was stirred for 1.5 hours. The reaction mixture was poured into 500 ml of ice and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The resulting oil was treated with ethanol. A solid formed, which was recovered by filtration providing 1.3 g of 6-nitrobenzo[b]thiophene-3-carboxaldehyde, m.p. 187°-192° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([NH:15][NH:16]C(OC(C)(C)C)=O)([CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([OH:13])[CH:7]=1.Br[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28](=[O:29])[O:27]1.[C:36]([O-:39])([O-])=[O:37].[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:24])[C:4]([NH:15][NH2:16])([CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:28](=[O:29])[O:27]2)=[C:8]([O:13][CH:5]2[C:6]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:36](=[O:37])[O:39]2)[CH:7]=1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: COC(=O)C(C)(Cc1ccc(O)c(O)c1)NNC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)C(C)(Cc1ccc(OC2OC(=O)c3ccccc32)c(OC2OC(=O)c3ccccc32)c1)NN
Temperature: 40 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
A mixture of compound 108 (170 mg, 0.5 mmol), bromophthalide (213 mg, 1 mmol) and Cs2CO3 (325 mg, 1 mmol) in acetone was stirred at 40° C. for 16 h. After removing the solvent under reduced pressure, the residue was partitioned between 10% citric acid and ethyl acetate. The organic phase was separated and dried over MgSO4, and concentrated to dryness. The resulting residue was treated with 50% trifluoroacetic acid in dichloromethane at room temperature for 30 min. Removal of the solvent and purification of the resulting residue by reverse phase HPLC afford 81 mg of 119 as a mixture of diastereomers. 1H NMR (CD3OD, 400 MHz): 1.50 (3H), 3.10 (2H), 3.84 (3H), 6.86–7.18 (m, 3H), 7.22–7.44 (m, 2H), 7.61–7.95 (m, 8H). MS (ESI) m/z 505.26.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18](F)(F)[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br[CH2:44][C:45]1C(C)=[N:48][O:47][N:46]=1.C[OH:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C@H:18]([OH:52])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:45]([CH3:44])=[N:46][O:47][N:48]=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: CO
Reactant: Cc1nonc1CBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1nonc1Cn1nnc2c(N3CC[C@H](O)C3)nc(C(C)(C)C)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-4-methyl-1,2,5-oxadiazole. After completion of the substitution reaction methanol was added and the mixture was stirred for 1 h at room temperature and subsequently subjected to purification with preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. After evaporation of the product containing fractions the title compound was isolated as light-yellow gum. MS(m/e): 359.3 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6](Cl)(=[O:8])[CH3:7].C(OC(=O)C)(=[O:12])C>CC(C)=O>[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH3:7].[S:1]1(=[O:12])[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccsc1
Reactant: CC(=O)Cl
Solvent: CC(C)=O
Product: CC(=O)c1cccs1
Product: O=S1C=CC=C1

Procedure:
Acetylation of thiophene by acetyl chloride or acetic anhydride in the presence of various catalysts (U.S. Pat. No. 2,458,514) to obtain acetylthiophene or aceto-2 thienone or thienyl-2 methylketone and conversion of this methylketone into thienyl-2 acetamide or thienyl-2 thioacetamide by a WILLGERODT reaction, then hydrolysis of the amide (German Pat. No. 832 755).
Reaction SMILES: [CH:1](=[N:6][OH:7])[C:2]([CH3:5])([CH3:4])[CH3:3].ClN1C(=O)CCC1=O.[Cl-].[CH:17]([P:19]([CH3:23])(=[O:22])[O:20][CH3:21])=[CH2:18].C(N(CC)CC)C>ClCCl.N1C=CC=CC=1>[C:2]([C:1]1[CH2:18][CH:17]([P:19]([CH3:23])(=[O:22])[O:20][CH3:21])[O:7][N:6]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: C=CP(C)(=O)OC
Reactant: CC(C)(C)C=NO
Agent: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COP(C)(=O)C1CC(C(C)(C)C)=NO1
Yield: 50 %

Procedure:
40.4 g (0.4 mol) of pivalaldoxime are converted in analogy to Example 1(a) with 58.7 g (0.44 mol) of N-chlorosuccinimide and 2 ml of pyridine in dichloromethane into the hydroxamoyl chloride which is subsequently reacted with 52.8 g (0.44 mol) of methyl vinyl(P-methyl)phosphinate and 61.2 ml (0.44 mol) of triethylamine, and worked up, as described in Example 1(b), the oily product being obtained with a yield of about 50%.
Reaction SMILES: Br[CH2:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][CH3:15])[CH:8]=1)([CH3:6])[CH3:5].[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.O>[N:17]([CH2:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][CH3:15])[CH:8]=1)([CH3:6])[CH3:5])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(C(C)(C)C(=O)CBr)ccc1F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)(C)C(=O)CN=[N+]=[N-])ccc1F
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 1-bromo-3-(4-fluoro-3-methoxyphenyl)-3-methylbutan-2-one (125.4 g, 0.44 mol) in DMF (500 mL) was added NaN3 (37.2 g, 0.572 mol) at 0° C., and the mixture was warmed to room temperature over 3 h with stirring. The reaction mixture was diluted with water (2 L) and extracted with EtOAc (1 L×2). Combined extracts were washed with brine, dried over MgSO4, and concentrated to give 1-azido-3-(4-fluoro-3-methoxyphenyl)-3-methylbutan-2-one (99.5 g), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 7.07 (m, 1H), 6.79 (m, 2H), 3.92 (s, 3H), 3.78 (s, 2H), 1.53 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20](=[S:22])[NH2:21])[NH:8]2)=[CH:4][CH:3]=1.Br[CH:24]([CH:27]=O)[CH:25]=[O:26].CN(C)C(=O)C>O>[Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]3[S:22][C:24]([CH2:25][OH:26])=[CH:27][N:21]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: NC(=S)c1cc2ccc(Cl)c(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: O=CC(Br)C=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=S(=O)(Nc1c(Cl)ccc2cc(-c3ncc(CO)s3)[nH]c12)c1cccs1
Temperature: 90 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
A mixture of 6-chloro-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.75 g), bromomalonaldehyde (0.45 g) and N,N-dimethylacetamide (10 mL) was stirred at 90° C. for 3 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. To a mixture of the obtained crystals, tetrahydrofuran (10 mL) and methanol (5 mL) was added sodium borohydride (84 mg) at 0° C., and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.46 g, yield 55%) was obtained as pale-yellow crystals from a fraction eluted with tetrahydrofuran-hexane (3:1, volume ratio). melting point 197-199° C.
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:6]=1[CH2:16][CH2:17][C:18]#[C:19][C:20]([O:22][CH3:23])=[O:21].CO.[Cl-].[NH4+]>CCOCC.C1COCC1.[Cu]I>[CH3:3][O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:6]=1[CH2:16][CH2:17]/[C:18](/[CH3:1])=[CH:19]\[C:20]([O:22][CH3:23])=[O:21]
Reactant: [Li]C
Reactant: COC(=O)C#CCCc1c(C)c(OC)c(C)c(C)c1OC
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)/C=C(/C)CCc1c(C)c(OC)c(C)c(C)c1OC
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of lithium dimethylcuprate (prepared from 0.97 g (5.1 mmol) of copper-(I) iodide and 6.4 ml of a 1.6M ethereal methyllithium solution) in ether (30 ml) was cooled to -78° C. and treated dropwise with a solution of methyl 5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2-pentynoate (1 g; 3.4 mmol) in THF (10 ml). The mixture was stirred at -78° C. for 90 minutes, treated with 0.5 ml of methanol, warmed to room temperature and treated with saturated ammonium chloride solution. The mixture was extracted twice with ether and the combined extracts were washed with water and dried. The remaining residue was purified on silica gel with hexane/ethyl acetate (95:5), yielding 0.81 g of crystalline methyl (Z)-5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenoate. M.P. 87.5°-89° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[CH3:16][O:17][C:18]1[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=1.C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH3:16])=[O:6]
Reactant: COc1ccccc1N
Reactant: Nc1cccc(Cl)c1C(=O)O
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COc1ccccc1NC(=O)c1c(N)cccc1Cl
Yield: 80.6 %

Procedure:
Prepared according to Procedure A using 2-amino-6-chlorobenzoic acid (2.0 g, 11.7 mmol) and SOCl2 (2.1 mL, 29.1 mmol) in benzene (60 mL), followed by o-anisidine (2.6 mL, 23.4 mmol) and CHCl3 (60 mL). The product was chromatographed in CH2Cl2 to provide 2.61 g of a dark yellow oil (81%). 1H NMR (CDCl3) δ: 8.53 (dd, J=1.7, 7.9 Hz, 1H); 8.39 (br s, 1H); 7.11 (dt, J=1.6, 7.8 Hz, 1H); 7.09 (t, J=8.1 Hz, 1H); 7.02 (dt, J=1.4, 7.8 Hz, 1H); 6.92 (dd, J=1.4, 8.0 Hz, 1H); 6.62 (dd, J=0.9, 8.2 Hz, 1H); 4.66 (br s, 2H); 3.87 (s, 3H). MS (ES): m/z 277.0 (M+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH2:17][CH2:16][O:15][CH:14]1[C:18]1[CH:19]=[CH:20][C:21]([F:24])=[N:22][CH:23]=1.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>C1COCC1>[O:13]1[CH2:17][CH2:16][O:15][CH:14]1[C:18]1[CH:19]=[C:20]([B:25]([OH:30])[OH:26])[C:21]([F:24])=[N:22][CH:23]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(C2OCCO2)cn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OB(O)c1cc(C2OCCO2)cnc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
Diisopropylamine (4.60 mL, 32.5 mmol) was dissolved in THF (80 mL) and cooled in an ice water bath. Then, n-butyllithium solution (1.6 M in hexanes, 21.0 mL, 33.6 mmol) was added via syringe. After 30 minutes, the reaction was cooled to −78° C. and 5-(1,3-dioxolan-2-yl)-2-fluoropyridine (3.73 g, 22.1 mmol) was added as a solution in THF (12 mL) dropwise over 5 minutes via syringe, followed by a THF (4 mL) rinse. The reaction was stirred at −78° C. under nitrogen for 1 hour, and then triisopropyl borate (Fluka 98+%, 8.0 mL, 34.9 mmol) was added via syringe, and the reaction was allowed to warm up to room temperature. After 4.5 hours, the reaction was quenched with 1 N NaOH (75 mL). The layers were separated, and the aqueous phase was treated with 5N HCl to lower the pH to between 6 and 7. The aqueous phase was extracted with 10:1 DCM/MeOH. 5N HCl was added to the aqueous phase to lower the pH to about 5, and extraction was continued with 10:1 DCM/MeOH. The organic extracts were combined, concentrated and dried under high vacuum to give 5-(1,3-dioxolan-2-yl)-2-fluoropyridin-3-ylboronic acid (3.165 g, 91% purity, 61% yield over 2 steps). MS (ESI pos. ion) m/z 214 (M+H)+.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][C:25]=1[Cl:37]>>[CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=3)=[CH:26][C:25]=2[Cl:37])=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OCCOCc1ccc(OCC2CO2)cc1
Reactant: NCCOc1ccc(C2=NNC(=O)CC2)cc1Cl
Product: CC(C)OCCOCc1ccc(OCC(O)CNCCOc2ccc(C3=NNC(=O)CC3)cc2Cl)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isopropoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.ClCCl.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>O>[CH3:28][S:29]([O:17][CH:14]1[CH2:15][CH2:16][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:12][CH2:13]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)N2CCC(O)CC2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2CCC(OS(C)(=O)=O)CC2)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of 90 parts of 1-[(4-methylphenyl)sulfonyl]-4-piperidinol, 37.5 parts of N,N-diethylethanamine and 1300 parts of dichloromethane was added dropwise a solution of 42.3 parts of methanesulfonyl chloride in 130 parts of dichloromethane (exothermic reaction: temperature rose to 35° C.). Upon completion, stirring was continued for 2 hours at room temperature. Water was added and the layers were separated. The organic phase was washed with water, dried, filtered and evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 116 parts (100%) of 1-[(4-methylphenyl)sulfonyl]-4-piperidinol methanesulfonate (ester); mp. 168.5°-175.3° C. (5).
Reaction SMILES: [Mg].[CH3:2]I.[N:4]1([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:11][N:10]=2)[CH:8]=[CH:7][N:6]=[CH:5]1.[Cl-].[NH4+]>CCOCC>[N:4]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([OH:23])[CH3:2])=[CH:11][N:10]=2)[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: CI
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(-n2ccnc2)nc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)(c1ccc(Cl)cc1)c1ccc(-n2ccnc2)nc1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
A Grignard reagent which is prepared by reacting 0.46 g of magnesium with 3 g of methyl iodide in 30 ml of ether is added to a suspension of 4.5 g of 2-(1-imidazolyl)-5-(4-chlorobenzoyl)pyridine in 50 ml of ether at -5° C. After the mixture is stirred at room temperature for an hour, the reaction mixture is poured into an aqueous ammonium chloride solution with caution. The precipitate is extracted with chloroform and the chloroform is distilled off. The residue is recrystallized from toluene to give 4.1 g of 1-[2-(1-imidazolyl)-5-pyridyl]-1-(4-chlorophenyl)ethanol in 90.3% yields as white crystals, melting at 140°-142° C.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCCCCC>C(OCC)(=O)C>[C:2]12([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: BrC12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1ccc(NC23CC4CC(CC(C4)C2)C3)cc1
Temperature: 200 °C
Reaction time: 20 h

Procedure:
Under a nitrogen (N2) atmosphere was combined 10.0 g (46.5 mmol) of 1-bromoadamantane and 20 ml of aniline. The reaction was stirred for 20 hours at 200° C., and then cooled and fractionated on silica gel using 6:1 hexane:ethyl acetate (EtOAc) to afford, after concentration in vacuo and refractionation using toluene, 5.65 g (54%) of N-1-adamantylaniline.
Reaction SMILES: [O:1]=[C:2]([C:18]1[CH:27]=[C:26]2[C:21]([CH2:22][CH2:23][CH2:24][NH:25]2)=[CH:20][CH:19]=1)[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2C=CC=CC=2)[CH2:7][CH2:6]1.C(O)(=O)/C=[CH:30]/[C:31](O)=[O:32].C([O:38]CC)C>>[C:31]([N:25]1[C:26]2[C:21](=[CH:20][CH:19]=[C:18]([C:2](=[O:1])[CH2:3][CH2:4][CH:5]3[CH2:10][CH2:9][N:8]([C:11](=[O:38])[CH3:12])[CH2:7][CH2:6]3)[CH:27]=2)[CH2:22][CH2:23][CH2:24]1)(=[O:32])[CH3:30]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: O=C(CCC1CCN(Cc2ccccc2)CC1)c1ccc2c(c1)NCCC2
Reactant: CCOCC
Product: CC(=O)N1CCC(CCC(=O)c2ccc3c(c2)N(C(C)=O)CCC3)CC1

Procedure:
Using 1.8 g of the compound obtained in Example 5, the procedure of Example 2 was followed to give 1.82 g of the free base of the title compound mixture A and B. The first crop of crystals (0.65 g) from a solution of this mixture in diethyl ether, i.e. 7-[1-oxo-3-[1-(phenylmethyl)piperidin-4-yl]-propyl]-1,2,3,4-tetrahydroquinoline (m.p. 132°-135° C.), was treated with an equivalent of fumaric acid to give 0.69 g of the title fumarate (B) as colorless crystals melting at 175° to 177° C. (decomp.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[CH3:12][C:13]1[O:17][N:16]=[C:15]([C:18](Cl)=[O:19])[CH:14]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:12][C:13]1[O:17][N:16]=[C:15]([C:18]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:19])[CH:14]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)NCc2cccc([N+](=O)[O-])c2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
A solution containing 500 mg (2.65 mmol) of 3-nitrobenzylamine in 20 mL of dichloromethane was stirred at room temperature as 463 mg (3.18 mmol) of 5-methyl-3-isoxazoyl chloride was added. To this solution was added 0.92 mL (6.62 mmol) of triethylamine. The reaction was stirred an additional 1 hour at room temperature, diluted with 75 mL of ethyl acetate and the organic phase washed with 1N aqueous hydrochloric acid (twice), water (twice) and saturated aqueous sodium bicarbonate (thrice). The resulting organic solution was dried over sodium sulfate, filtered, and concentrated to give 550 mg (79%) of the title compound as a yellow solid. MS(FD) m/z 261 (M+).
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([O:10][CH:4]([O:5]3)[C:3](=[O:12])[O:2]1)[CH2:9]2.[Na].O.C(O)(=O)C>C(O)C>[CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([O:10][CH:4]([O:5]3)[CH:3]([OH:12])[O:2]1)[CH2:9]2
Reactant: O=C1OC2CC3CC(C2)OC1O3
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: OC1OC2CC3CC(C2)OC1O3

Procedure:
A solution of 340 mg of 2,5,11-trioxatricyclo[4,3,1,14,8 ]undecan-3-one in 10 ml of absolute ethanol is treated with 300 mg of sodium. After the metal has dissolved the reaction mixture is treated with 10 ml of water and 0.7 ml of acetic acid, concentrated under reduced pressure to about 3 ml and the concentrate is extracted with methylene chloride. The solvent is evaporated to leave as residue pure 2,5,11-trioxatricyclo-[4,3,1,14,8 ]undecan-3-ol.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[C:14]([C:16]([NH2:18])=O)[N:15]=2)[C:8]([CH3:26])=[CH:7][N:6]=1)(=[O:3])[CH3:2].C[N:28]([CH:30](OC)OC)C.[NH2:35]N.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:13]1[O:12][C:11]([C:9]2[C:8]([CH3:26])=[CH:7][N:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=2)=[N:15][C:14]=1[C:16]1[NH:18][CH:30]=[N:28][N:35]=1
Reactant: COC(OC)N(C)C
Reactant: NN
Reactant: CC(=O)Nc1cc(-c2nc(C(N)=O)c(-c3ccccc3Cl)o2)c(C)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(-c2nc(-c3nnc[nH]3)c(-c3ccccc3Cl)o2)c(C)cn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
A suspension of 2-[2-(acetylamino)-5-methylpyridin-4-yl]-5-(2-chlorophenyl)-1,3-oxazole-4-carboxamide (0.48 g, 1.3 mmol) in dry toluene (7 mL) was sonicated for 15 min. DMF-DMA (0.51 mL, 3.8 mmol) was added and the mixture was allowed to stir at 50° C. for 2 h. The suspension was cooled to rt and was concentrated. The resulting solid was suspended in AcOH (5 mL) at rt. Hydrazine (0.20 mL, 6.4 mmol) was added dropwise. The reaction mixture was allowed to stir at 40° C. for 3 h. Saturated NaHCO3 was added until the mixture became neutral. The solid was filtered, washed with water, and purified by column chromatography to give N-{4-[5-(2-chlorophenyl)-4-(4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide (0.23 g, 45%). LCMS (FA): m/z=395.3 (M+H).