Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH2:16])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1.Cl[C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH:16][C:18]4[CH:26]=[C:25]5[C:21]([CH2:22][C:23](=[O:27])[NH:24]5)=[CH:20][CH:19]=4)[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: Cn1cc(-c2nccn3nc(N)nc23)cn1
Product: Cn1cc(-c2nccn3nc(Nc4ccc5c(c4)NC(=O)C5)nc23)cn1

Procedure:
8-(1-methylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, synthesized as described earlier, is coupled with 6-chloro-oxindol according to general procedure 2.
Reaction SMILES: [CH:1]([N:4](C(C)C)[C:5](=O)[C:6]1C=CN=CC=1)(C)[CH3:2].[C:16]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[N:28]=[C:27]([CH3:29])[O:26][C:25](=[O:30])[C:24]=2[CH:31]=1)(=[O:18])[CH3:17]>>[C:16]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[NH:28][C:27](=[O:26])[C:29]3[CH:2]=[CH:1][N:4]=[CH:5][C:6]=3[C:25](=[O:30])[C:24]=2[CH:31]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Oc1ccc2nc(C)oc(=O)c2c1
Reactant: CC(C)N(C(=O)c1ccncc1)C(C)C
Product: CC(=O)Oc1ccc2[nH]c(=O)c3ccncc3c(=O)c2c1

Procedure:
The entitled compound (II-3) was synthesized from the compound (1a) and 6-acetoxy-2-methyl-4H-3,1-benzoxazin-4-one (2c) in the same manner as in Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].[Br:11]Br>C(O)(=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6]
Reactant: BrBr
Reactant: Nc1ccccc1CCO
Solvent: CC(=O)O
Product: Nc1ccc(Br)cc1CCO
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of 2-aminophenethyl alcohol (10.0 g, 72.9 mmol) in acetic acid (60 mL) at 10° C. was added Br2 (3.8 mL, 72.9 mmol) in acetic acid (5 mL). Additional acetic acid (30 mL) was added and the reaction was stirred for 1 hour. The mixture was filtered and the filter cake washed with diethyl ether. The solid was then partitioned between ethyl acetate and aqueous 3N NaOH. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide the titled compound (15.8 g).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[C:11]([OH:19])=[C:10]([C:20](OCC)=[O:21])[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([NH:39][NH2:40])(=[O:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[C:11]([OH:19])=[C:10]([C:20]([NH:40][NH:39][C:26](=[O:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:21])[C:9]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ccc(Cl)cc2n(Cc2ccccc2)c1=O
Reactant: CCCCCCCCCCCC(=O)NN
Product: CCCCCCCCCCCC(=O)NNC(=O)c1c(O)c2ccc(Cl)cc2n(Cc2ccccc2)c1=O

Procedure:
Reagents: Comp 41 (0.56 mmols, 0.20 g); dodecanoyl hydrazine (0.62 mmols, 0.133 g). Yield: 0.25 g (85%), white solid, m.p.=167° C.-168° C.
Reaction SMILES: C([O:4][CH2:5][CH:6]1[CH2:10][CH2:9][C:8]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[NH:7]1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[Si:22]([O:21][CH2:20][C:8]1([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[NH:7][CH:6]([CH2:5][OH:4])[CH2:10][CH2:9]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(=O)OCC1CCC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC1(CO[Si](C)(C)C(C)(C)C)CCC(CO)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A mixture of [5,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-2-yl]methyl acetate (4.48 g, 10.4 mmol) and K2CO3 (g, mmol) in methanol (50 mL) was stirred at 25° C. for 2 h. Then the insoluble solid was filtered off and the filtrate was concentrated in vacuo. And then the residue was extracted with ethyl acetate (50 mL) two times, washed with water (20 mL) three times, dried over anhydrous sodium sulfate and concentrated in vacuo to afford [5,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-2-yl]methanol 81g (4 g, 98%) which was used for next step without further purification. MS: calc'd (MH+) 390, measured (MH+) 390.
Reaction SMILES: [CH3:1][N:2]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:3][C@@H:4]([NH:12]C(=O)OCC1C=CC=CC=1)[CH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][O:8][CH2:7]1>CO.[OH-].[OH-].[Pd+2]>[NH2:12][C@@H:4]([CH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][O:8][CH2:7]1)[CH2:3][N:2]([CH3:1])[C:23](=[O:24])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29]
Reactant: CN(C[C@H](C[C@H]1CCCOC1)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN(C[C@@H](N)C[C@H]1CCCOC1)C(=O)OC(C)(C)C
Yield: 89.5 %

Procedure:
To a solution of benzyl (5)-1-(N-methyl-tert-butoxycarbonylamino)-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate (20 g, 49.2 mmol) in MeOH (400 mL) was added Pd(OH)2 (2 g). The reaction bottle was degassed and filled into H2. Upon completion of the reaction, the mixture was filtered through Celite, dried over Na2SO4, and concentrated to give the product (12 g). 1H NMR (CD3OD) δ 1.0-1.2 (m, 3H), 1.4-1.5 (m, 9H), 1.6-1.7 (m, 2H), 1.7-1.9 (m, 2H), 2.8-2.9 (s, 3H), 2.9-3.1 (m, 4H), 3.3-3.4 (m, 1H), 3.8-3.9 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Cl[C:18]1[N:23]=[N:22][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:20]2[S:29][C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:31][C:19]=12.CCOC(C)=O>CN1C(=O)CCC1>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([O:1][C:18]2[N:23]=[N:22][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:20]3[S:29][C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=4)=[CH:31][C:19]=23)[CH2:3]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: CCOC(=O)c1nnc(Cl)c2cc(-c3cccc(F)c3)sc12
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nnc(OC2CCCN(C(=O)OC(C)(C)C)C2)c2cc(-c3cccc(F)c3)sc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
tert-Butyl 3-hydroxypiperidine-1-carboxylate (100 mg, 0.5 mmol) was dissolved in dry NMP (5 mL) and NaH (20 mg, 60% in oil, 0.5 mmol) was added carefully. The mixture was stirred at room temperature for 10 min. Then, ethyl 4-chloro-2-(3-fluorophenyl)thieno[2,3-d]pyridazine-7-carboxylate (130 mg, 0.5 mmol) was added. The mixture was heated up to 80° C. and stirred for 30 min. After cooling to room temperature, EtOAc was added to dilute the reaction and washed with water and brine. The organics was dried over Na2SO4 and filtered, concentrated. The crude product was purified with column (silica gel) to give the product ethyl 4-(1-(tert-butoxycarbonyl)piperidin-3-yloxy)-2-(3-fluorophenyl)thieno[2,3-d]pyridazine-7-carboxylate (151 mg). HPLC-MS tR=2.17 min (UV254 nm); mass calculated for formula C25H28FN3O5S 501.2, observed LCMS m/z 502.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.O>N1C=CC=CC=1.C(#N)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)cc1
Reaction time: 3 h
Yield: 102 %

Procedure:
To a solution of 4-chloroaniline (98%, 500 g (3.84 mol) in pyridine (338 ml) and acetonitrile (800 ml), p-toluenesulfonyl chloride (807.8 g (4.11 mol)) was added with stirring at temperature below 15° C. After stirring for 16 hours at room temperature, water (4000 ml) was added to the reaction mixture and stirring was continued for 3 hours to have crystals separated. The crystals were then filtered and washed with water to give 1100 g (102%) of 4′-chloro-p-toluenesulfonanilide as pale red crude crystals.
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1cccc2c1SCCC2
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc2c1SCCC2
Temperature: 60 °C
Yield: 98.1 %

Procedure:
Under argon and with stirring, 1.5 g (9.02 mmol) of 8-thiochromanol are dissolved in 5 cm3 of dimethylformamide (DMF). 3.74 g (27.06 mmol) of K2CO3 are added and then 1.94 g (9.92 mmol) of ethyl 4-bromobutyrate dissolved in 6 cm3 of DMF are added dropwise. The mixture is heated at 60° C. for 5 hours. The DMF is evaporated off. The residue is taken up in H2O. The product is extracted with CH2Cl2 and then dried over MgSO4. Purification over a silica column (eluant:ether/petroleum ether 3:7) yields 2.48 g of the title compound (white solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=3)[N:15]=[C:14]([CH3:27])[N:13]=2)[N:10]=[CH:9][N:8]=1>ClCCl.C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=3)[N:15]=[C:14]([CH3:27])[N:13]=2)[N:10]=[CH:9][N:8]=1
Reactant: COc1ccc(Cc2ncnn2-c2cc(C#Cc3ccc(C)cn3)nc(C)n2)cc1OC
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(Cc2ncnn2-c2cc(CCc3ccc(C)cn3)nc(C)n2)cc1OC

Procedure:
A slurry of 4-(5-(3,4-dimethoxybenzyl)-1H-1,2,4-triazol-1-yl)-2-methyl-6-((5-methylpyridin-2-yl)ethynyl)pyrimidine (1-4, 80 mg, 0.188 mmol, 1.0 eq.) in a mixture of dichloromethane (3 ml) and ethanol (3 ml) was treated with palladium on carbon (60 mg, 0.564 mmol, 3.0 eq.) under a hydrogen balloon for 4 hours. The reaction mixture was filtered through C-lite, and the C-lite was washed with dichloromethane (3×100 mL). The filtrate was concentrated and purified by reverse phase liquid chromatography (H2OCH3CN gradient w/ 0.1% TFA present) to afford 4-(5-(3,4-dimethoxybenzyl)-1H-1,2,4-triazol-1-yl)-2-methyl-6-(2-(5-methylpyridin-2-yl)ethyl)pyrimidine (1-5). 1H NMR (500 MHz, CDCl3) δ 8.36 (s, 1H), 7.95 (s, 1H), 7.57 (s, 1H), 7.38 (dd, 1H, J=7.9 Hz, 2.3 Hz), 7.04 (d, 1H, J=7.9 Hz), 6.86 (m, 2H), 6.79 (d, 1H, J=8.1 Hz), 4.75 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.22 (s, 4H), 2.75 (s, 3H), 2.69 (s, 3H), 2.30 (s, 3H) HRMS m/z (M+H) 431.2185 found, 431.2190 required.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](I)=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)CC)C>C(O)C.[OH-].[Pd+2].[OH-].[C]>[Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1nc(Cl)[nH]c1I
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1c[nH]c(Cl)n1
Reaction time: 5 h
Yield: 83.5 %

Procedure:
2-Chloro-5-iodo-4-nitroimidazole (273 mg) was dissolved in ethanol (5 ml), then triethylamine (420 μl) and 20% palladium hydroxide-carbon (27 mg) were added, the reaction mixture was subjected to hydrogenation at a room temperature under normal pressure for 5 hours, there was obtained 2-chloro-4-nitroimidazole (123 mg, yield: 83.4%) as colorless solid product.
Reaction SMILES: CO[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]([O:9]C)=O.[NH2:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1>CN(C=O)C>[O:9]=[C:7]1[N:15]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6]1
Reactant: COC=C(C=CC(=O)OC)C(=O)OC
Reactant: Nc1nccs1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(=O)n(-c2nccs2)c1
Temperature: 150 °C
Yield: 43 %

Procedure:
After 2 g (9.9 mmol) of dimethyl 4-(methoxymethylene)2-pentenedioate obtained in Example 1-1 was dissolved in 10 mL of DMF, 1 g (9.9 mmol) of 2-aminothiazole was added to the solution. Afterward, the resulting reaction solution was stirred under reflux at about 150° C. for 6 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo and was then washed using brine, followed by drying using magnesium sulfate, and filtration. After distillation under reduced pressure, the resulting product was purified using column chromatography (hexane:ethylacetate=1:3) to obtain a target compound (Actual yield: 1 g, Percent yield: 43%).
Reaction SMILES: C(C1[O:6][C:7]2[C:13]([S:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)(=[O:16])=[O:15])=[C:12]([Cl:24])[CH:11]=[CH:10][C:8]=2[N:9]=1)(C)(C)C.O.OS(O)(=O)=O.[OH-].[Na+]>O1CCOCC1>[NH2:9][C:8]1[C:7]([OH:6])=[C:13]([S:14]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)(=[O:16])=[O:15])[C:12]([Cl:24])=[CH:11][CH:10]=1
Reactant: CN1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN(S(=O)(=O)c2c(Cl)ccc(N)c2O)CC1
Temperature: 85 °C
Yield: 67.3 %

Procedure:
To a solution of 2-tert-Butyl-6-chloro-7-(4-methyl-piperazine-1-sulfonyl)-benzooxazole (2.44 g, 6.56 mmol) in 1,4-dioxane (20 mL) was treated with water (4 mL) and conc. H2SO4 (4 mL). The mixture was heated to 85° C. for 14 h. The reaction was cooled to room temperature, and then basified to pH=14 with 25% aq NaOH. washed. The mixture was extracted with ethyl acetate (3 times), dried with MgSO4, filtered, and concentrated to afford the title compound (1.35 g, 68%). EI-MS m/z 306(M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([Cl:22])[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24].O1CCOCC1>>[ClH:22].[ClH:24].[Cl:22][C:21]1[C:16]2[CH:15]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[NH:23][C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ncnc2[nH]c(C3=CCNCC3)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (601.6 mg, 1.797 mmol, 1 eq), a 4.0 M solution of HCl in 1,4-dioxane (15 mL, 33 eq) was added and the reaction was stirred at rt for 18 h. The solid was then filtered off, washed several times with ether, and dried under vacuum pressure, yielding the title compound as a yellow solid. 1H NMR (400 MHz, DMSOd6): δ=2.77 (s, 2H), 3.33 (d, J=4.8 Hz, 2H), 3.83 (s, br, 2H), 5.27-5.65 (s, br, —NH+H2O), 6.60 (s, 1H), 6.71 (d, J=1.6 Hz, 1H), 8.59 (s, 1H), 9.30 (s, br, —NH), 12.85 (s, H+). MS (ES+): m/z 235.09/237.11 (3) [MH+]; 206.12/208.14 (100) [MH+—CH3N). HPLC: tR=1.52 min (ZQ2000, polar—5 min).
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH2:20][N:19]([CH3:21])[CH2:18][CH2:17][CH:16]=3)[CH:10]=2)=[C:6]([N+:24]([O-])=O)[CH:5]=1)(=[O:3])[CH3:2].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[Cl-].[NH4+].[CH3:41]O>C(O)=O>[C:1]([C:4]1[CH:23]=[CH:22][C:7]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]4[CH2:20][N:19]([CH3:21])[CH2:18][CH2:17][CH:16]=4)[CH:10]=3)[CH:41]=[N:24][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Nc2cccc(C3=CCCN(C)C3)c2)c([N+](=O)[O-])c1
Reactant: CO
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: CC(=O)c1ccc2c(c1)ncn2-c1cccc(C2=CCCN(C)C2)c1

Procedure:
A mixture of 4-acetyl-N-[3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl]-2-nitroaniline (5) (1 g, 3 mmol), sodium sulfide nonahydrate (4.32 g, 18 mmol) and ammonium chloride (0.96 g, 18 mmol) in methanol (50 ml) was heated to reflux over night. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate and concentrated to leave an oil (m/e: 321) which was stirred in formic acid (10 ml) at 80° C. for 4 hours. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water and filtered. The filtrate was rendered alkaline by addition of solid sodium carbonate and extracted with ethyl acetate. This extract was dried over sodium sulfate. Evaporation of the solvent left 5-acetyl-1-[3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl]benzimidazole (7) as an oil. Yield: 0.5 g (50%), m/e: 331. A minor sample of this oil was dissolved in ethanol and precipitated as the hydrochloride by addition of hydrogen chloride in diethyl ether. Mp 227-233° C.
Reaction SMILES: N[CH2:2]CCNC(=O)C.[OH-].[Na+].[C:11]([NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[S:21])[S-:20])(=[O:13])[CH3:12].[Na+].CI>O1CCOCC1.O.C(=S)=S>[C:11]([NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[S:20])[S:21][CH3:2])(=[O:13])[CH3:12]
Reactant: CC(=O)NCCCNC(=S)[S-]
Reactant: CC(=O)NCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CI
Product: CSC(=S)NCCCNC(C)=O
Reaction time: 0.58 h

Procedure:
A solution of N-(3-aminopropyl)acetamide (146 g) in dioxane (710 ml) was added to a solution of 97% sodium hydroxide (52 g) in water (620 ml) and then carbon disulfide (96 g) was added dropwise thereto over 35 minutes at -1° to 3° C. The mixture was stirred for 1 hour at 0° to 2° C. To the mixture containing sodium N-(3-acetamidopropyl)dithiocarbamate was added dropwise methyl iodide (179 g) over 35 minutes at 0° to 5° C. and then the resulting mixture was stirred for 3 hours at the same temperature. Dioxane was distilled off in vacuo from the reaction mixture and the residue was extracted with ethyl acetate (300 ml, 200 ml×4). The extracts were dried over magnesium sulfate and concentrated in vacuo to give oil of methyl N-(3-acetamidopropyl)dithiocarbamate (193.18 g).
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.[NH2:23][NH:24][C:25](=O)[CH2:26][NH:27][CH3:28].C[O-].[Na+]>CO>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[N:6]=[C:25]([CH2:26][NH:27][CH3:28])[NH:24][N:23]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:17][CH:18]=1
Reactant: CNCC(=O)NN
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNCc1nc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)n[nH]1
Reaction time: 24 h
Yield: 11 %

Procedure:
A suspension of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (0.300 g, 0.94 mmol) and N-amino-2-(methylamino)acetamide (0.290 g, 2.81 mmol) in 4 mL of anhydrous methanol was prepared. An excess of a commercial solution of sodium methoxide in methanol (0.643 mL, 4.37 M) was added. After an hour, the temperature was raised to reflux and was maintained for 48 hours although no further conversion was observed after 24 hours. The reaction was then quenched with water, the pH adjusted to neutral and the crude product extracted with ethyl acetate. The title compound was purified by preparative HPLC (0.034 g, 11% yield): 1H NMR (CD3OD) δ 8.71 (s, 1H), 8.11–8.03 (m, 3H), 7.69 (d, 1H), 7.3 (t, 2H), 3.95 (s, 2H), 2.49 (s, 3H); ES-MS (m/z) 323 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:3]=1[CH:4]=[C:5]1[S:9]C(=S)N[C:6]1=[O:11].[OH-:18].[Na+]>>[F:1][C:2]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:3]=1/[CH:4]=[C:5](\[SH:9])/[C:6]([OH:18])=[O:11]
Reactant: COc1ccc(F)c(C=C2SC(=S)NC2=O)c1
Reactant: [OH-]
Agent: [Na+]
Product: COc1ccc(F)c(/C=C(\S)C(=O)O)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
5-(2-Fluoro-5-methoxybenzylidene)-2-thioxo-1,3-thiazolidin-4-one (8.00 g, 9.7 mmol) was added in one portion to 25% w/v sodium hydroxide solution (40 mL). This was allowed stir at reflux for 1 h. After this time the reaction was allowed to cool to room temperature and poured onto water (50 mL). This was washed with dichloromethane (50 mL), and the aqueous layer acidified to pH 2 with aqueous hydrochloric acid (2 N, 50 mL) to give a white suspension. Product was extracted with ether (2×60 mL), dried (MgSO4) and solvent removed in vacuo to give a white solid (6.71 g, 100%); δH (300 MHz, CD3OD) 7.85 (1H, s, Ar), 7.46–7.35 (1H, m, Ar), 7.11 (1H, t, Ar), 7.01–6.75 (2H, m, CH═, and SH), 3.80 (3H, s, OCH3).
Reaction SMILES: [CH2:1]([OH:11])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C=CC=CC=1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1>CCOCC>[CH:18]1([C:21]([O:11][CH2:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:22])[CH2:20][CH2:19]1
Reactant: O=C(Cl)C1CC1
Reactant: CCCCCCCC#CCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCC#CCOC(=O)C1CC1
Reaction time: 8 h

Procedure:
To a solution of 3.85 g. of 2-decyn-1-ol and 3.95 g. of pyridine in 100 ml. ether is added 3.0 g. of cyclopropanecarboxylic acid chloride. The mixture is stirred overnight under nitrogen. The reaction mixture is poured into distilled water, washed with dilute hydrochloric acid and then with sodium bicarbonate and solvent removed to yield 2-decynyl cyclopropanecarboxylate, b.p. 96°-97° (bath) at 0.1 mm.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:10][C:4]1[N:3]=[CH:2][CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: Cc1nc(Cl)ccc1C#N
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ncccc1C#N
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.8 %

Procedure:
6-Chloro-2-methylnicotinonitrile (132, 10 g, 66 mmol) and ammonium formate (41 g, 0.65 mol) were dissolved in methanol (250 mL), and palladium (5% on activated carbon, 3.5 g, 2.5 mol %) was added. The mixture was stirred at room temperature for 12 h, filtered through Celite, and washed with methanol (3×50 mL). The combined filtrates were evaporated, and the yellow oily residue was subjected to flash column chromatography on silica gel, eluting with chloroform to provide 133 as an off-white solid (6.3 g, 81%): mp 55° C. (lit. (J. Med. Chem. 2000, 43, 3168-3185) mp 56-58° C.). 1H NMR (300 MHz, CDCl3) δ 7.80 (dd, J=4.9, 1.6 Hz, 1H), 7.02 (dd, J=7.8, 1.7 Hz, 1H), 6.37 (dd, J=7.8, 5.0 Hz, 1H), 1.88 (s, 3H); positive ion ESIMS m/z (rel intensity): 119 (MH+, 100).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[O:9][CH:10]=[C:11]([CH3:13])[N:12]=1)=[O:6]>C1C=CC=CC=1>[CH3:13][C:11]1[N:12]=[C:8]([N:7]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])[O:9][CH:10]=1
Reactant: Cc1coc(NC(=O)CCCCl)n1
Solvent: c1ccccc1
Product: Cc1coc(N2CCCC2=O)n1
Reaction time: 0.17 h
Yield: 41.57 %

Procedure:
2(4-Chlorobutyramido)-4-methyloxazole (2.20 g., 0.018 mol) prepared as described in Example 36 was dissolved with stirring under nitrogen in dry benzene (350 mls.) and 1:5-diazobicyclo[4,3,0]non-5-ene (1.47 g., 0.0118 mol) in dry benzene (50 mls.) was added with stirring over 10 minutes. The mixture was stirred at room temperature, wrapped in foil overnight. The organic layer was washed with water (3 × 100 mls.) dried over magnesium sulphate and evaporated under vacuum. The product was recrystallised from ethyl acetate/hexane. WT.= 0.75 g. m.p. 116° C. (Yield = 41.57%).