Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([C:37]([O:39]C)=[O:38])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Li+].[OH-].Cl>C1COCC1.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([C:37]([OH:39])=[O:38])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(=O)OC)c3ccccc3n2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(=O)O)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.4 %

Procedure:
Alternatively, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-(methoxycarbonyl)quinoline (200 mg, 0.359 mmol) was treated with LiOH (2 eq.) in a solution of THF:H2O (3:1, 8 mL). The reaction mixturre was stirred at ambient temperature for 5 hours. The pH value was adjusted to between pH 3 and pH 4 with 1N HCl solution. Evaporation of the solvents, extraction with ethyl acetate, washing with H2O and brine, followed by evaporation and flash column chromatography with 100% ethyl acetate, 1–5% MeOH in ethyl acetate gave 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-carboxyquinoline (106 mg). To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-carboxyquinoline (500 mg (two batches combined), 0.922 mmol) in THF (10 mL) was added 1-methyl 5-t-butyl ester glutamic acid (300 mg, 1.5 eq), EDCI (216 mg, 1.2eq.), HOBt (140 mg, 1.1 eq.), and the resulting mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%–3% MeOH in CH2Cl2 afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-[(1-(methoxycarbonyl)-3-(1,1-dimethylethoxycarbonyl)propyl)aminocarbonyl]quinoline (387 mg); NMR (CDCl3) 1.28 (t, 3), 1.40 (s, 9), 1.47 (s, 9), 1.83 (m, 1), 2.16 (m, 2), 2.35–2.50 (m, 5), 3.5–3.76 (m, 8), 3.8 (s, 3), 4.18 (q, 2), 4.85 (m, 1), 5.35 (m, 1), 7.15 (d, 1), 7.65 (m, 1), 7.80 (m, 1), 8.20 (d, 1), 8.30 (d, 1), 8.35 (s, 1), 8.70 (d, 1) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22].CO>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:28](=[O:29])[C:27]3[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:32][CH:31]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccc([N+](=O)[O-])cc4)c3C2=O)C(=O)N1
Yield: 74 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (2.2 g, 8.0 mmol) and 4-nitrobenzoyl chloride (3.0 g, 16.0 mmol) in THF (80 mL) was heated to reflux for 15 h. To the mixture was added methanol (20 mL) to give a suspension. The suspension was filtered and washed with methanol (20 mL) to give N-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-nitro-benzamide as a white solid (2.5 g, 73% yield): mp, 298-300° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H, CHH), 2.49-2.65 (m, 2H, CH2), 2.83-2.98 (m, 1H, CHH), 5.18 (dd, J=5.2, 12.6 Hz, 1H, NCH), 7.73 (d, J=7.2 Hz, 1H, Ar), 7.93 (t, J=8.0 Hz, 1H, Ar), 8.19-8.22 (m, 2H, Ar), 8.42-8.47 (m, 3H, Ar), 10.65 (s, 1H, NH), 11.18 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.92, 48.99, 119.30, 119.56, 124.06, 127.49, 129.01, 131,58, 135.77, 136.23, 138.96, 149.69, 163.65, 166.57, 167.48, 169.68, 172.72; Anal Calcd for C21H14N4O7: C, 56.88; H, 3.34; N, 13.27. Found: C, 57.15; H, 3.02; N, 13.22.
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[F:10][C:11]1[C:12]([CH2:22]Br)=[C:13]([CH:19]=[CH:20][CH:21]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15].O>C(O)C>[F:10][C:11]1[C:12]([CH2:22][O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)=[C:13]([CH:19]=[CH:20][CH:21]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Oc1cccc(F)c1
Reactant: CCOC(=O)c1cccc(F)c1CBr
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cccc(F)c1COc1cccc(F)c1
Yield: 89.3 %

Procedure:
To a solution of 1.3 g of sodium metal in 100 ml of ethanol are added 6.3 g of 3-fluorophenol and 13 g of ethyl 3-fluoro-2-bromomethylbenzoate and the mixture is refluxed with heating for 8 hours. After cooling, 300 ml of water is added and the mixture is extracted with toluene. After the extract is washed with water and a saturated saline solution and dried over magnesium sulfate, the solvent is distilled off under reduced pressure. The residue is subjected to silica-gel chromatography and eluted with toluene to give 13 g of ethyl 3-fluoro-2-[(3-fluorophenyl oxy)methyl]benzoate (oil). Mass spectrum m/z: 292(M+).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][N:17]=2)[CH2:12][CH2:11]1.[H-].[Na+].[CH3:34]I>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[CH:10]1[CH2:11][CH2:12][N:13]([C:16]2[N:21]=[CH:20][C:19]([CH2:22][O:23][CH3:34])=[CH:18][N:17]=2)[CH2:14][CH2:15]1
Reactant: CI
Reactant: CS(=O)(=O)c1ccc(COC[C@@H]2C[C@@H]2C2CCN(c3ncc(CO)cn3)CC2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(S(C)(=O)=O)cc3F)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-(4-((1R,2R)-2-(((2-fluoro-4-(methylsulfonyl)benzyl)oxy)methyl)cyclopropyl)piperidin-1-yl)pyrimidin-5-yl)methanol (Step F product, 198 mg, 0.44 mmol) was dissolved in Acetonitrile (6 mL) at room temperature under N2 and sodium hydride (26 mg of a 60% dispersion in oil, 0.66 mmol) was added followed by CH3I (313 mg, 2.2 mmol). The mixture was stirred at RT overnight. The mixture was diluted with EtOAc, washed with sat. NH4Cl, dried over MgSO4, filtered and evaporated in vacuo. The crude material was purified by column chromatography (SNAP, 10 g, 70% EtOAc in hexane) to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 8.30 (s, 2H), 7.78 (dd, 1H), 7.73 (m, 1H), 7.67 (dd, 1H), 4.80-4.64 (m, 4H), 4.28 (s, 2H), 3.71 (dd, 1H), 3.61-3.54 (m, 1H), 3.37 (s, 3H), 3.08 (s, 3H), 2.93-2.80 (m, 2H), 1.96 (d, 1H), 1.85 (d, 1H), 1.43-1.22 (m, 3H), 1.15-1.04 (m, 1H), 0.94-0.71 (m, 2H), 0.12-0.08 (m, 1H). MS (ESI) m/z 464 [M+H]+. GPR119 Human EC50: 1.6 nM.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[NH:10]N.[N:12]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C:15](=O)[CH2:14][CH2:13]2>Cl.C(O)(=O)C>[Br:2][C:3]1[C:4]2[NH:10][C:15]3[CH:16]4[CH2:19][CH2:20][N:12]([CH2:13][C:14]=3[C:5]=2[CH:6]=[C:7]([F:9])[CH:8]=1)[CH2:18][CH2:17]4
Reactant: NNc1ccc(F)cc1Br
Reactant: O=C1CCN2CCC1CC2
Agent: Cl
Solvent: CC(=O)O
Product: Fc1cc(Br)c2[nH]c3c(c2c1)CN1CCC3CC1
Temperature: 80 °C

Procedure:
(2-Bromo-4-fluorophenyl)hydrazine hydrochloride (1.14 g, 4.72 mmol; Enamine) was suspended in HCl-acetic acid (1.0 M, 25 mL; Aldrich). The product of Example 1A (684 mg, 4.91 mmol) was added and the reaction was heated to 80° C. for 5 hours. The reaction was then allowed to cool and then concentrated. The product was triturated with acetonitrile and isolated by filtration, washing with additional acetonitrile (2×10 mL). The solid was partitioned between 1.0 M NaOH (50 mL) and CHCl3 (3×50 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.05-2.11 (m, 4H), 3.01-3.14 (m, 3H), 3.19-3.26 (m, 2H), 4.17 (s, 2H), 6.96-7.04 (m, 2H); MS (DCI/NH3) m/z 309/311 (M+H)+. Anal. Calcd. for C14H14BrFN2: C, 54.39; H, 4.56; N, 9.06. Found: C, 54.04; H, 4.28; N, 8.90.
Reaction SMILES: Br[CH2:2][CH:3]([N:10]1[C:14]2[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=2[N:12]=[C:11]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[OH:28][C:29]1[CH:34]=[C:33]([C:35]([O:37][CH3:38])=[O:36])[CH:32]=[CH:31][N:30]=1.CCCCCCC>C(OCC)(=O)C>[CH3:38][O:37][C:35](=[O:36])[C:33]1[CH:32]=[CH:31][N:30]=[C:29]([O:28][CH2:2][CH:3]([N:10]2[C:14]3[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=3[N:12]=[C:11]2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:34]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(CBr)C3CCCCC3)c2cc1F
Reactant: COC(=O)c1ccnc(O)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)c1ccnc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c1

Procedure:
The title compound was prepared in analogy to Example 35 from 1-(2-bromo-1-cyclohexyl-ethyl)-2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole (Ex. 34, int.) and methyl 2-hydroxypyridine-4-carboxylate after a reaction time of 4 days at room temperature and using a gradient of n-heptane:ethyl acetate of 100:0 to 70:30. Light yellow solid (19%). MS: (Turbo Spray): m/z=526.2 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:31]([CH2:30][Cl:29])(=[O:33])=[O:32])[CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCNCC2=O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)CCl)CC2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a solution of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (2.5 g) and triethylamine (1.7 g) in dichloromethane (35 ml) was added at 0° C. a solution of chloromethanesulfonyl chloride (1.26 g) in dichloromethane (2 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was washed with water, 10% citric acid solution and brine, dried and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate) to give colorless syrup of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-(chloromethanesulfonyl)-2-piperazinone (2.47 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38](Cl)=[N:37][C:36]=1[CH3:41])(=[O:34])=[O:33])([CH3:30])[CH3:29]>>[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[N:37][C:36]=1[CH3:41])(=[O:34])=[O:33])([CH3:30])[CH3:29]
Reactant: Cc1nc(Cl)sc1S(=O)(=O)NC(C)(C)CO
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1nc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 2-Chloro-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.22) (256 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (190 mg, 32%). MS (ISP) 604.0 [(M+H)+]; mp 216-218° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:26]N1C(=O)CCC1=O>ClCCCl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:26][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:19]=[C:20]([Cl:25])[CH:21]=[C:22]([Cl:24])[CH:23]=3)([C:14]([F:16])([F:15])[F:17])[O:11][N:10]=2)=[CH:3][C:2]=1[Cl:1]
Reactant: Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(CBr)c(Cl)c2)=NO1
Temperature: 70 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
In a solution of 13.7 g of 3-(3-chloro-4-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole in 100 mL of 1,2-dichloroethane, 6.6 g of N-bromosuccinimide and 0.1 g of α,α′-azobisisobutyronitrile were added, and stirred at 70° C. for 3 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, washed with water (70 mL×2), and dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and then the solvent was distilled off under reduced pressure. The residual solid was washed with diisopropyl ether to obtain 12.1 g of the aimed product as pale yellow crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH2:20][CH2:21][C:22]#[N:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:24](=[O:29])[C@@H:25]([O:27][CH3:28])[CH3:26])[N:10]=1.[ClH:30].[CH2:31]([OH:33])[CH3:32]>>[ClH:30].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH2:20][CH2:21][C:22](=[NH:23])[O:33][CH2:31][CH3:32])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:24](=[O:29])[C@@H:25]([O:27][CH3:28])[CH3:26])[N:10]=1
Reactant: CCO
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCC#N)c1ccccc1
Agent: Cl
Product: CCOC(=N)CCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)[C@H](C)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 3-(5-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propanenitrile (0.041 g, 0.090 mmol, Example 14, Step C) in ethanol (0.5 mL) was added 9.8 M ethanolic HCl (0.5 mL, 4.9 mmol). After stirring at 0° C. for 1 hour and then at ambient temp for 8 hours, the mixture was concentrated under reduced pressure to provide the product.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]2[C:6]=1[CH2:7][C:8](=[O:15])[NH:9]2.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O>[N:16]([CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]2[C:6]=1[CH2:7][C:8](=[O:15])[NH:9]2)=[N+:17]=[N-:18]
Reactant: O=C1Cc2c(OCCCl)ccc(F)c2N1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOc1ccc(F)c2c1CC(=O)N2

Procedure:
A solution of 4-(2-chloroethoxy)-7-fluoro-1,3-dihydro-indol-2-one (2.04 g, 8.88 mmol) and sodium azide in dimethylformamide (125 mL) was heated to 70° C. for 18 hours. The reaction mixture was partitioned between methylene chloride (100 mL) and water (100 mL). The organic layer separated and washed with water (50 mL) then dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum. The crude product was filtered through a pad of silica to afford a yellow solid, mp 147°-148° C. MS EI m/e 261 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([CH2:11]Br)[C:4]=1[CH2:13]Br.[SH:15][CH2:16][C:17]([O:19][CH2:20]C)=[O:18].C[O-].[Na+].CC[O-].[Na+]>C(Cl)Cl.CO>[C:17]([CH:16]1[CH2:13][C:4]2[C:5](=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:11][S:15]1)([O:19][CH3:20])=[O:18]
Reactant: CCOC(=O)CS
Reactant: COc1ccc(OC)c(CBr)c1CBr
Agent: CC[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1Cc2c(OC)ccc(OC)c2CS1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
1,4-dimethoxy-2,3-dibromomethylbenzene (10.0 g, 30.88 mmol) was dissolved in CH2Cl2 and MeOH (750 ml, 6:4) followed by addition of ethyl 2-mercaptoacetate (4.02 ml, 37.06 mmol) with stirring under argon. The mixture was then cooled to 0° C. followed by dropwise addition of sodium methoxide (4.37M, 8.5 ml, 37.06 mmol) over a period of 2 h using an automatic syringe pump. After 5 minutes the solvent was evaporated and the crude was redissolved in THF (400 ml) and cooled to 0° C. again. NaOEt (2.10 g, 30.88 mmol) was then added. The ice bath was removed and the reaction was stirred for 2 more hours. The reaction mixture was then quenched with NH4Cl (sat.) and extracted with ether. The organic phases were combined, dried over MgSO4, filtered and concentrated. The crude residue was then treated with NaOME in MeOH and THF at 0° C. for 2 hours. The reaction mixture was extracted with ether (100 ml×2). The combined organic phases were washed with H2O, dried over MgSO4, filtered and concentrated to a residue that was purified by flash chromatography to give title compound in 45% yield. 1H NMR (300 MHz, CDCl3, ppm) d:2.97 (dd, 1H, J=16.51, 8.79 Hz, HCHaCHC=O), 3.36 (dd, 1H, J=16.7, 5.1 Hz, HCHeCHC=O), 3.73 (m, 2H, HCHa,e--O), 3.75 (s, 3H, OCH3), 3.78 (s, 6H, 2×OCH3), 3.85 (m, 1H, HC--S), 6.69 (m, 2H, ArH).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH:10]2[CH2:12][O:11]2)=[CH:8][CH:7]=[C:6]([F:13])[C:3]=1[C:4]#[N:5].[OH:14][CH2:15][C@@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>C(O)C>[Cl:1][C:2]1[C:3]([C:4]#[N:5])=[C:6]([F:13])[CH:7]=[CH:8][C:9]=1[CH:10]([OH:11])[CH2:12][N:21]1[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17][C@@H:16]1[CH2:15][OH:14]
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Reactant: N#Cc1c(F)ccc(C2CO2)c1Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc(F)c(C#N)c2Cl)[C@@H](CO)C1

Procedure:
2-Chloro-6-fluoro-3-(oxiran-2-yl)benzonitrile (9.1 g, 46 mmol) and (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (14.9 g, 69.1 mmol) were dissolved in ethanol (105 mL) and dispensed into 9 sealed tubes then microwaved at 140° C. for 1 h. The combined reaction mixture was concentrated and purified through a 330 g ISCO Redi-sep column with 50%-100 ethyl acetate/hexane solvent system to yield the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[Cl:15][C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=1.O>CN(C=O)C>[Cl:15][C:16]1[N:17]=[N:18][C:19]([N:4]([CH3:3])[S:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)(=[O:7])=[O:6])=[CH:20][CH:21]=1
Reactant: CNS(=O)(=O)c1ccc(C)cc1
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)nn2)cc1
Yield: 47.4 %

Procedure:
To a suspension of sodium hydride (60%, 0.42 g (10.5 mmol)) in 10.0 ml of DMF, N-methyl-p-toluenesulfonamide (1.85 g (9.99 mmol)) was added under ice-cooling and with stirring. To the resulting mixture, after 15 minutes' stirring under cooling with ice, 3,6-dichloropyridazine (1.49 g (10.0 mmol)) was added. The reaction mixture was stirred at room temperature for one hour, poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, to give 1.41 g (47%) of the title compound as white crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH2:7]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O>N1C=CC=CC=1>[CH2:7]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:1][C:2]2[S:3][CH:4]=[N:5][N:6]=2)(=[O:21])=[O:20])=[CH:17][CH:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Nc1nncs1
Reactant: CCCCCCc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
To a stirred solution of 2-amino-1,3,4-thiadiazole (2.0 g, 19.7 mmol) in pyridine (30 mL) under argon at −20° C. was added p-hexylbenzenesulfonyl chloride (5.48 g, 21 mmol) over 10 min. The reaction mixture was stirred at room temperature for 16 hours. Water (300 mL) was added to quench the reaction. The mixture was extracted with CH2Cl2 and the organic extracts washed with 2N HCl (2×150 mL), brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluted with methanol:DCM 1:33 to give the product (3.72 g, 11.4 mmol, 58% yield) as a solid, mp 125-126° C.; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, 3H, J=7 Hz), 1.28 (m, 6H), 1.58 (m, 2H), 2.63 (t, 2H, J=7 Hz), 7.27 (d, 2H, J=8 Hz), 7.83 (d, 2H, J=8 Hz), 8.24 (s, 1H); 13C NMR (75 MHz, CDCl3) 14.1, 22.6, 28.9, 31.1, 31.6, 35.9, 126.5, 129.0, 138.1, 142.6, 148.6, 167.4; MS (Q-TOF) Calcd for C14H20N3O2S2 326.0997, found 326.0931 (M+H)+; Calcd for C14H19N3NaO2S2 348.0816, found 348.0816 (M+Na)+.
Reaction SMILES: OO.C(O)=[O:4].[O:6]1[C:17]2[C:9](=[CH:10][C:11](=[CH:15][CH:16]=2)[CH:12]=[CH:13][CH3:14])[O:8][CH2:7]1.S(=O)(=O)(O)O>O.CC(C)=O>[CH2:7]1[O:6][C:17]2[CH:16]=[CH:15][C:11]([CH2:12][C:13](=[O:4])[CH3:14])=[CH:10][C:9]=2[O:8]1
Reactant: CC=Cc1ccc2c(c1)OCO2
Reactant: O=CO
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Cc1ccc2c(c1)OCO2
Reaction time: 8 h

Procedure:
Hydrogen peroxide (70 ml, 30%) was added with caution to a solution of formic acid (350 ml, 88%) in a three-necked flask (1 L) cooled with running water. Isosafrole (72 ml) was added drop-wise, by a dropping funnel, to the reaction mixture at a rate to keep the temperature of the reaction mixture below 35° C. After the complete addition of isosafrole, a non-homogeneous solution was obtained. At this point, acetone (200 ml) was added to the reaction mixture at a rate to keep the temperature below 35° C. The reaction was allowed to stand at room temperature overnight. The solvent was removed by a rotary evaporator equipped with a dry-ice acetone cold trap, a high vacuum pump and a water bath with temperature not exceeding 30° C. Ethyl ether (500 ml) was added to the residue. The solution was transferred into a separatory funnel. The organic phase was washed with sodium bicarbonate (0.1 N, 2×500 ml) and water (3×300 ml). The organic phase was transferred into a round bottom flask. The solvent was removed by rotary evaporation. Concentrated sulfuric acid (75 ml) was diluted drop-wise in water (425 ml). Methanol (160 ml) was added to the oily residue, and mixed to obtain a homogeneous solution. The sulfuric acid solution was added to the methanolic reaction mixture. The flask was equipped with a water-cooled reflux condenser and a heating mantel. The reaction mixture was heated to reflux for 4 hours. The heat was removed and crushed ice (150 g) was added to the reaction mixture. The reaction mixture was transferred into a separatory funnel and extracted with ethyl ether (1×350 ml, 1×150 ml and 1×100 ml). The combined organic layers were washed with water (3×150 ml). Sodium hydroxide (40 ml, 0.1 N) was diluted in water (360 ml). The organic phase was washed with diluted sodium hydroxide (2×200 ml, 10 mM) and saturated sodium chloride solution (100 ml). The organic layer was dried with anhydrous sodium sulfate (20 g) overnight. The drying agent was filtered and the cake was washed with ethyl ether (2×10 ml). The solvent was removed by rotary evaporation. The product was distilled at reduced pressure (2-0.5 mmHg). The second fraction distilling at 90-100° C. (˜1 mmHg) contained product. The product was identified by El/MS with the m/z of 182. Infrared spectrum (cm−1) indicated 1714 (C═O) and 2898 (C—H) stretches corresponding to the product.