Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:45](Cl)(=[O:47])[CH3:46].[OH-].[Na+]>O1CCCC1>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([NH:37][C:45](=[O:47])[CH3:46])=[CH:35][CH:36]=3)[CH2:28][CH2:29]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccc(N)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(CC2CCN(CCCN(C(=O)C3CCN(C(C)=O)CC3)c3ccc(Cl)c(Cl)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
1-Acetyl-N-(3-[4-(4-aminobenzyl)-1-piperidinyl]propyl}-N-(3,4-dichlorophenyl)-4-piperidinecarboxamide (Example 303) (18 mg, 0.033 mmol) was dissolved in tetrahydrofuran (0.3 mL). To the solution were added triethylamine (5.0 mg, 0.050 mmol) and acetyl chloride (3.4 mg, 0.043 mmol), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added aqueous solution of 1N-sodium hydroxide (5 mL), and the mixture was extracted with ethyl acetate (5 mL×2). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to alumina column chromatography (alumina 2 g, ethyl acetate), and the desired fraction was concentrated under reduced pressure to give the titled compound (18 mg, 0.031 mmol, Yield 93%) as a colorless oily substance.
Reaction SMILES: [ClH:1].[CH2:2]([C:9]1[N:10]=[C:11]([NH2:14])[NH:12][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8].[N:15]([CH2:18][C:19]([CH3:27])=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N+:16]=[N-:17]>>[ClH:1].[CH3:27][C:19](=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:18][N:15]1[CH:8]=[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:9]2[N:10]=[C:11]([NH2:14])[NH:12][CH:13]=2)[N:17]=[N:16]1
Reactant: C#CCCCCCc1c[nH]c(N)n1
Reactant: CC(=Cc1ccccc1)CN=[N+]=[N-]
Agent: Cl
Product: CC(=Cc1ccccc1)Cn1cc(CCCCCc2c[nH]c(N)n2)nn1
Yield: 58.9 %

Procedure:
4-Hept-6-ynyl-1H-imidazol-2-ylamine hydrochloride (0.060 g, 0.281 mmol) was reacted with (3-Azido-2-methyl-propenyl)-benzene (0.058 g, 0.336 mmol) following the general procedure for click reactions outlined above to produce 4-{5-[1-(2-Methyl-3-phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-pentyl}-1H-imidazol-2-ylamine hydrochloride (0.064 g, 65%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.23 (s, δ 6.93-6.83 (m, 5H), δ 6.38 (s, 1H), δ 6.08 (s, 1H), δ 4.93 (s, 2H), δ 2.51 (t, 2H), δ 2.09 (t, 2H), δ 1.43 (s, 3H), δ 1.41 (m, 2H), δ 1.25 (m, 2H), δ 1.05 (m, 2H) ppm; 13C (75 MHz, CD3OD) δ 147.7, 144.8, 136.3, 132.8, 129.8, 128.9, 128.6, 128.5, 128.2, 127.6, 127.5, 127.0, 108.5, 61.3, 28.0, 27.6, 27.5, 24.0, 22.9, 14.7 ppm; HRMS (ESI) calcd for C20H27N6 (M+) 351.2291. found 351.2291.
Reaction SMILES: [C:1](N1CCNCC1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N[CH:20]1[CH2:24][CH2:23][NH:22][CH2:21]1)=O>>[C:1]([C:23]1[NH:22][O:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:21][C:20]=2[CH:24]=1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=CNC1CCNC1
Product: O=C(OCc1ccccc1)C1=Cc2ccccc2ON1

Procedure:
In the described fashion as Example 2(b)-2(e), replacing the N-carbobenzoxypiperazine in Example 2(e) with 3-formamidopyrrolidine, one can obtain compound (F) (R8 =CH3, R9 =C2H5, R10 =C6H5, ##STR20##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]([F:26])([F:25])[F:24])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:18][CH:19]3[CH2:21][CH2:20]3)[C:15](O)=[O:16])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]([F:26])([F:24])[F:25])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:18][CH:19]3[CH2:20][CH2:21]3)[C:15]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=3)=[O:16])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(O)C(CC1CC1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O
Product: COC(=O)c1ccc(NC(=O)C(CC2CC2)n2ccc(-c3cc(Cl)ccc3C(F)(F)F)cc2=O)cc1

Procedure:
105 mg (purity 94%, 0.26 mmol) of 2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-cyclopropylpropanoic acid (racemate) and 1.1 eq. of methyl 4-aminobenzoate were reacted according to General Method 5A. After aqueous work-up, the crude product was reacted further without further purification. Yield: 200 mg (purity 48%, 72% of theory)
Reaction SMILES: [C:1]([C:9]1[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH:31](C(OCC)=O)[C:32]([O:34]CC)=[O:33]>CN(C=O)C>[CH3:18][C:16]1[CH:17]=[C:9]2[C:10](=[CH:14][C:15]=1[CH3:19])[C:11](=[O:12])[O:13][C:31]([C:32]([OH:34])=[O:33])=[C:1]2[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)O)c(C(=O)c2ccccc2)cc1C
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: Cc1cc2c(-c3ccccc3)c(C(=O)O)oc(=O)c2cc1C
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 2-benzoyl-4,5-dimethylbenzoic acid (11.4 g), acetone (300 ml), DMF (10 ml), potassium carbonate (6.83 g) and diethyl bromomalonate (12.84 g) was stirred at room temperature for 60 hours. After the solvent was distilled off, ethyl acetate was added to the residue. This mixture was washed with water and then dried, after which the solvent was distilled off. To the residue were added acetic acid (180 ml) and hydrochloric acid (180 ml), followed by heating at 110° C. for 5 hours. The reaction mixture was concentrated, and water was added to the concentrate, followed by extraction with ethyl acetate. The extract was washed with water and then dried, after which the solvent was distilled off, to yield colorless crystals. The crystals were recrystallized from ethyl acetate-isopropyl ether to yield 6,7-dimethyl-4-phenylisocoumarin-3-carboxylic acid (≡6,7-dimethyl-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH2:14]([S:26][CH2:27][CH2:28]O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:28][CH2:27][S:26][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:7][CH:6]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: CCCCCCCCCCCCSCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCSCCOc1ccc(CCC(=O)OC)cc1
Reaction time: 3 h
Yield: 84.6 %

Procedure:
A solution of methyl 3-[4-hydroxyphenyl)propionate (2.46 g, 13.6 mmol), 2-(dodecylthio)ethanol (3.40 g, 13.7 mmol) and triphenylphosphine (3.60 g, 13.8 mmol) in dry benzene (50 ml) was treated at 22° C. with diethyl azodicarboxylate (2.43 g, 13.9 mmol) added dropwise over 10 min. After 3 h at 22° C., the reaction mixture was diluted with ethyl acetate, washed with water, brine and dried (magnesium sulfate). Evaporation under reduced pressure gave an oil which was triturated with hexane to precipitate the triphenylphosphine oxide and the hydrazine side products. The filtrate was chromatographed on silica gel using a gradient of ethyl acetate (0-5%) in hexane as eluent to give 4.70 g(84%) of 3-[4-[2-(dodecylthio)ethoxy]phenyl]propanoic acid methyl ester as a white solid. Recrystallization from methanol gives white leaflets: m.p. 48° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[OH:13])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1.O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]2[C:7]3([CH2:12][CH2:11][CH2:10][CH2:9][C:8]3([CH2:14][N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)[OH:13])[O:30]2)=[CH:20][CH:21]=1
Reactant: OC1(Cn2cncn2)CCCCC1=Cc1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: OC1(Cn2cncn2)CCCCC12OC2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
A mixture of 9 g of 2-(4-chlorobenzylidene)-1-(1,2,4-triazol-1-ylmethyl)cyclohexan-1-ol and 14.8 g of m-chloroperbenzoic acid in 50 ml of dichloromethane is stirred for 3 h at room temperature. 200 ml of water are then added and extracted with 3×100 ml of dichloromethane. The organic phase is washed with a potassium carbonate solution. The organic phase is dried over sodium sulphate and evaporated. The residue is crystallised from diisopropyl ether to produce 6 g of white solid (M.p.=150.5° C.)
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[N:27]=[C:26]([C:28](OC)=[O:29])[O:25][N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:32]=1.[CH3:33][NH:34][CH3:35].C1COCC1>C1COCC1>[CH3:33][N:34]([CH3:35])[C:28]([C:26]1[O:25][N:24]=[C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([N:14]3[CH2:13][C@H:12]4[N:8]([CH2:9][CH2:10][CH2:11]4)[C:7]4[N:32]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[C:15]3=[O:16])[CH:18]=2)[N:27]=1)=[O:29]
Reactant: COC(=O)c1nc(-c2cccc(N3C[C@@H]4CCCN4c4nc(SC)ncc4C3=O)c2)no1
Reactant: CNC
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(C(=O)N(C)C)n3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
Methyl (S)-3-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,2,4-oxadiazole-5-carboxylate (162 mg, 0.36 mmol) obtained in Step 1 of Example 80 was dissolved in THF (3.0 mL), and the mixture was stirred at room temperature for 2 hours after adding a 2.0 mol/L dimethylamine/THF solution (1.80 mL, 3.58 mmol). The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)—N,N-dimethyl 3-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,2,4-oxadiazole-5-carboxamide (151 mg, 90%).
Reaction SMILES: [Br:1]Br.[CH2:3]([C@@:7]1([CH2:26][CH3:27])[NH:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:10]=2[S:9][CH2:8]1)[CH2:4][CH2:5][CH3:6].Cl>C(O)(=O)C>[Br:1][C:21]1[C:22]([O:24][CH3:25])=[CH:23][C:10]2[S:9][CH2:8][C@:7]([CH2:3][CH2:4][CH2:5][CH3:6])([CH2:26][CH3:27])[NH:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]=2[CH:20]=1
Reactant: BrBr
Reactant: CCCC[C@]1(CC)CSc2cc(OC)ccc2[C@@H](c2ccccc2)N1
Agent: Cl
Solvent: CC(=O)O
Product: CCCC[C@]1(CC)CSc2cc(OC)c(Br)cc2[C@@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Bromine (18.6 g) was added to a solution of the product (10.4 g) from step (f) dissolved in glacial acetic acid (150 ml). The reaction mixture was stirred at room temperature for 2 hours. Acetic acid was removed in vacuo, added another 100 ml and concentrated in vacuo. The resulting residue was dissolved in EtOAc and washed with sodium metabisulfite and 1N NaOH. The organic layer was separated, dried and concentrated in vacuo to give a brown oil which was then converted to the hydrochloride salt with ethereal HCl. This solid was filtered, washed with ether and then treated with 1N NaOH and EtOAc to get the title product (8.9 g) as an orange oil. 1H NMR consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]2[CH2:15][CH2:16][NH:17][CH2:18][C:7]1=2.C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32].C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:29][CH2:30][C:31]([N:17]1[CH2:16][CH2:15][C:8]2[C:9]3[C:10]([N:6]([CH2:5][C:4]4[CH:19]=[CH:20][CH:21]=[C:2]([F:1])[CH:3]=4)[C:7]=2[CH2:18]1)=[N:11][CH:12]=[CH:13][CH:14]=3)=[O:32]
Reactant: Fc1cccc(Cn2c3c(c4cccnc42)CCNC3)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCc2c(n(Cc3cccc(F)c3)c3ncccc23)C1
Reaction time: 0.5 h

Procedure:
To a suspension of 9-(3-fluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine (500 mg) produced by operation in accordance with Reference manufacturing example 1 in THF (10 mL) were sequentially added triethylamine (0.59 mL) and chloroacetyl chloride (0.135 mL), and the mixture was stirred for 30 minutes. The reaction mixture was poured into an aqueous saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (459 mg) having the following physical property values.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9](Cl)[CH:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[N:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:23][O-:24].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([O:24][CH3:23])[CH:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[N:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Fc1cccc(F)c1C1N=CC=C(c2ccc(Br)cc2)N1Cl
Agent: [Na+]
Solvent: CO
Product: CON1C(c2ccc(Br)cc2)=CC=NC1c1c(F)cccc1F

Procedure:
6 g of 4-(4-bromophenyl)-2-(2,6-difluorophenyl)-3-chloropyrimidine, 60 ml of methanol and 3.3 g of methanolic sodium methanolate solution (30%) are boiled under reflux for 24 hours, concentrated by evaporation, and the residue taken up in ethyl acetate and the organic phase washed with water. After drying with magnesium sulfate, filtering and concentrating, the title compound is obtained with a melting point of 104-106° C. (compound 3.350).
Reaction SMILES: [OH:1][C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7](O)[C@H:5]([OH:6])[C@H:3]1O.[C:13]([O:16][C:17](=[O:19])[CH3:18])(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:16][C@H:17]1[O:19][C@H:7]([CH2:5][O:6][C:11](=[O:12])[CH3:9])[C@@H:9]([O:10][C:2](=[O:1])[CH3:3])[C@H:11]([O:12][C:5](=[O:6])[CH3:7])[C@H:18]1[O:10][C:2](=[O:1])[CH3:3])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 88 %

Procedure:
Analogously, as described in the synthesis of title compound Aa), the reaction of 100 g (555.0 mmol) of α-D-glucopyranose with a mixture of 1000 ml of absolute pyridine and 1000 ml of acetic acid anhydride after working-up and recrystallization from 95% aqueous ethanol yields 190.6 g (88.0%) of the above-mentioned title compound as a colorless and crystalline compound. By 1H-NMR-spectroscopic study of the title compound that is thus obtained, it was possible to determine the α to β-ratio of two possible anomers with ≧98:2. Accordingly, the title compound is the exclusively α-configured anomer.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:27](Cl)=[O:28]>>[CH:1]1([CH2:7][C:8]2[S:12][C:11]([NH:13][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:24]([O:23][CH3:22])[CH:25]=3)=[N:10][C:9]=2[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: COc1ccc(-c2nc(N)sc2CC2CCCCC2)cc1
Product: COc1ccc(-c2nc(NC(=O)c3ccc(OC)c(OC)c3)sc2CC2CCCCC2)cc1
Yield: 67.5 %

Procedure:
A procedure similar to that in Example 4 was used. 5-cyclohexylmethyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 47 and 3,4-dimethoxy-benzoyl chloride prepared in the step 1 of Example 12 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to give a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (20:1) to obtain a product as a white solid in a yield of 67.5%, mp: 171-172 └. 1H-NMR (CDCl3, 400 MHz) δ: 0.82˜0.98 (2H, m), 1.08˜1.28 (3H, m), 1.58˜1.88 (6H, m), 2.74 (2H, d, J=7.28 Hz, CHCH2Ar), 3.82 (3H, s, OCH3), 3.89 (3H, s, OCH3), 3.94 (3H, s, OCH3), 6.82˜6.89 (3H, m, ArH), 7.35˜7.47 (4H, m, ArH), 11.00 (1H, br, CONH); EI-MS m/e (%): 466.2 (M+, 46), 383.2 (29), 165.1 (100); HREI-MS Calcd. for C26H30N2O4S: 466.1926. found: 466.1920. Anal. Calcd. for C26H30N2O4S: C, 66.93; H, 6.48; N, 6.00. found: C, 66.88; H, 6.68; N, 6.02.
Reaction SMILES: N1C2C(=CC=CC=2)C(CCCC(O)=O)=[CH:2]1.[CH2:16]([N:23]([CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[O:46][CH3:47])[C:24](=[O:36])[CH2:25][CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]([CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[O:46][CH3:47])[C:24](=[O:36])[CH2:25][CH:26]([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[CH3:2])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccccc1OCCN(Cc1ccccc1)C(=O)CCc1c[nH]c2ccccc12
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Product: COc1ccccc1OCCN(Cc1ccccc1)C(=O)CC(C)c1c[nH]c2ccccc12

Procedure:
Replacing 3-indole propionic acid with 3-indole butyric acid (1.8 g, 8.9 mmol) in (4a) above afforded N-benzyl-3-(1H-indol-3-yl)-N-[2-(2-methoxy-phenoxy)-ethyl]buty-anide (1.3 g; 78%) as a white foam. MS FAB m/e 443 (M+H)+ MS FAB m/e 465 (M+Na)+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:13][CH2:12][C:11](=[O:19])[CH2:10]1.[CH3:20]OC(OC)OC>S(=O)(=O)(O)O.CO>[CH3:20][O:19][C:11]12[CH2:12][CH2:13][CH:14]([CH2:15][CH2:16][CH2:17][OH:18])[CH:9]([CH2:10]1)[C:3]1[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=1[O:1]2
Reactant: O=C1CC[C@@H](CCCO)[C@H](c2ccc(O)cc2O)C1
Reactant: COC(OC)OC
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC12CCC(CCCO)C(C1)c1ccc(O)cc1O2
Yield: 82 %

Procedure:
A solution of 1.5 g. (5.68 mmole) of trans-3-(2,4-dihydroxyphenyl)-4-(3-hydroxypropyl)cyclohexanone in 40 ml. methanol, 6 ml. trimethylorthoformate and 7 drops of concentrated sulfuric acid was stirred at 0° C. for 45 minutes. The reaction was quenched by the addition of excess solid sodium bicarbonate and then evaporated on a rotovapor. The residue was diluted with 300 ml. saturated sodium bicarbonate-300 ml. ether. The ether extract was dried over magnesium sulfate and evaporated. The crude product was purified via column chromatography on 150 g. of silica gel eluted in 15 ml. fractions with ether to yield 1.29 g. (82%) of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([NH2:20])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[CH:5]=[C:4]([CH3:21])[N:3]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([NH:20][C:29]([NH:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:30])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[CH:5]=[C:4]([CH3:21])[N:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cccc(-c2sc(N)nc2-c2cc(C)nc(C)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cccc(-c2sc(NC(=O)Nc3ccccc3)nc2-c2cc(C)nc(C)c2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 48.2 %

Procedure:
To a solution of [4-(2,6-dimethyl-4-pyridyl)-5-(3-methylphenyl)-1,3-thiazol-2-yl]amine (0.50 g, 1.7 mmol) in N,N-dimethylacetamide (20 mL) was added phenyl isocyanate (0.28 mL, 2.6 mmol), and the mixture was stirred for 14 hours at 80° C. Aqueous sodium hydrogen carbonate was poured into the reaction mixture, and extracted with ethyl acetate. The extracts were washed with brine, then, dried to be concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=1:1). The resulted crude crystal was recrystallized from ethyl acetate-hexane to obtain a title compound (0.34 g, yield 48%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[N:4]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH:2]([C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:17][CH:16]=2)[N:4]=1)=[O:1]
Reactant: Cc1ccc(-c2cc(CO)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C=O)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Reaction time: 6 h
Yield: 45.9 %

Procedure:
To a solution of alcohol 8c (0.46 g, 1.34 mmol) and 0.43 g of powdered 4 Å molecular sieves in 20 mL of DCM, was added PCC (0.43 g, 2.0 mmol) at room temperature. After 6 hours, the reaction mixture was filtered through a 0.75-in. pad of Celite. The filtrate was concentrated in vacuo then the residue was purified by column chromatography to afford the titled compound (0.21 g, 46%) as a white solid. mp 195.9-197.9° C. 1H NMR (300 MHz, DMSO-d6): δ 10.01 (s, 1H), 7.88 (d, J=9 Hz, 2H), 7.56 (d, J=9 Hz, 2H), 7.55-7.52 (m, 2H), 7.25-7.17 (m, 4H), 7.15 (s, 1H), 2.32 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)=[O:3].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[O:20][CH3:21]>>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:8][C:7]2[CH:9]=[CH:10][C:4]([S:2]([CH3:1])=[O:3])=[CH:5][CH:6]=2)=[CH:14][C:13]=1[O:20][CH3:21]
Reactant: CS(=O)c1ccc(N)cc1
Reactant: COc1cc(C=O)ccc1F
Product: COc1cc(C=Nc2ccc(S(C)=O)cc2)ccc1F

Procedure:
Following a similar procedure to that described in section a of example 1, but starting from 4-methylsulfinylaniline (obtained in reference example 2) instead of 4-methylsulfonylaniline and from 4-fluoro-3-methoxybenzaldehyde instead of 4-isopropoxybenzaldehyde, the desired compound was obtained, which was directly used in the next step.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10].Cl[C:17]1[N:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:20]([N+:33]([O-:35])=[O:34])=[CH:19][CH:18]=1>C(#N)C>[CH2:7]([N:11]([CH2:12][CH2:13][CH2:14][CH3:15])[C:17]1[N:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:20]([N+:33]([O-:35])=[O:34])=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH3:10]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NCCCN1CCCCC1
Reactant: CCCCNCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN(CCCC)c1ccc([N+](=O)[O-])c(NCCCN2CCCCC2)n1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
Potassium carbonate (54 mg, 2 eq) and a solution of dibutylamine (30 mg, 1.2 eq) in acetonitrile (2 ml) are added successively to a solution of 6-chloro-3-nitro-N-(3-piperidin-1-ylpropyl)pyridin-2-amine (59 mg, 1 eq) in acetonitrile (3 ml). The mixture is heated to reflux for 15 hours then cooled down to ambient temperature and concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (200 ml) and water (90 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue obtained, by flash chromatography on silica gel (eluent: heptane/ethyl acetate 1:1 to 100% ethyl acetate), produces the expected compound (73 mg; 95% yield).