Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.F[C:16]1[CH:21]=[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])[C:19]([F:35])=[CH:18][C:17]=1[N+:36]([O-:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:35][C:19]1[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:21][C:16]([O:1][C:2]2[C:3]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:4][C:5]([CH3:8])=[N:6][CH:7]=2)=[C:17]([N+:36]([O-:38])=[O:37])[CH:18]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Reactant: COC(=O)COc1nc(C)ncc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1nc(C)ncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a mixture of 0.15 g of 5-hydroxy-4-(methoxycarbonyl)methoxy-2-methylpyrimidine, 0.16 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and 2 ml of N,N-dimethylformamide was added 74 mg of potassium carbonate, and the mixture was stirred for 1 hour at 70° C. The reaction solution was cooled to room temperature, then, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.20 g of 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-4-(methoxycarbonyl)methoxy-2-methylpyrimidine.
Reaction SMILES: C1(C)C=CC(C2C=CC=CN=2)=CC=1.[Br:14]Br.[Br:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:20][CH:19]=1>ClC1C=CC=CC=1>[Br:16][CH:17]([Br:14])[C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:22][CH:23]=1
Reactant: BrBr
Reactant: BrCc1ccc(-c2ccccn2)cc1
Agent: Cc1ccc(-c2ccccn2)cc1
Solvent: Clc1ccccc1
Product: BrC(Br)c1ccc(-c2ccccn2)cc1
Temperature: 115 °C
Yield: 60.7 %

Procedure:
In a 100 ml four neck flask were placed 2-(4-tolyl)pyridine (5.0 g, 29.6 mmol) and chlorobenzene (18 ml), and bromine (9.4 g, 59.1 mmol) was added dropwise while heating the mixture at 110-120 ° C. over 12 hours. The reaction mixture was stirred with heating at a temperature in the above-mentioned range for 1 hour and analyzed by HPLC. As a result, 2-(4-bromomethylphenyl)pyridine was confirmed to have been produced in a 60.7% yield. The obtained reaction mixture was cooled and the precipitated 2-(4-bromomethylphenyl)pyridine salt was collected by filtration. The filtrate was neutralized with 5% aqueous sodium hydroxide solution. After washing with water, the mixture was dried over anhydrous magnesium sulfate. Chlorobenzene was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate-hexane) to give 2-(4-dibromomethylphenyl)pyridine in a 1.2 g yield. From the 1H-NMR analysis, the product was found to be 2-(4-dibromomethylphenyl)pyridine. 2-(4-dibromomethylphenyl)pyridine 1H-NMR(CDCl3, ppm) δ: 6.70(s,1H), 7.23-7.29(m,1H), 7.66-7.68(d,2H), 7.68-7.78(m,2H), 7.98-8.01(d,2H), 8.69-8.71(m,1H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][CH:21]=C)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CC([OH:26])C>O.O=[Os](=O)(=O)=O>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][CH:21]=[O:26])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CCCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: CCOC(=O)C1(CCC=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 6 h

Procedure:
4-But-3-enyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (13.5 g, 43.48 mmol, 1 eq) was dissolved in i-PrOH (217 mL) and a solution of NaIO4 (20.23 g, 94.6 mmol, 2.18 eq) in 217 mL of water was added followed by OsO4 (37 mg, 0.144 mmol, 0.003 eq). The reaction mixture was vigorously stirred for 6 h. The reaction mixture was then quenched with 1500 mL of water, transferred to a separatory funnel and extracted with ethyl acetate (3×200 mL). The combined organics were dried over Na2SO4 and purified by column chromatography on silica gel (300 g column, 30% EtOAc in heptanes; 50 mL/min). This afforded 8.5 g (63%) of the title compound as a beige oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[C:10](=[O:13])([O-])[O-].[Na+].[Na+].[CH3:16][O:17][C:18]1[N:25]=[CH:24][CH:23]=[CH:22][C:19]=1CCl>O.C(Cl)Cl>[CH3:16][O:17][C:18]1[N:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:10]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[O:13]
Reactant: COc1ncccc1CCl
Reactant: NCCc1ccncc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ncccc1C(=O)NCCc1ccncc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 3 liter, three neck, round bottom flask equipped with a mechanical stirrer, reflux condenser and dropping funnel was charged with 4-(2-aminoethyl)pyridine (61.0 g., 0.5 mole) in 50 ml. of methylene chloride. Sodium carbonate (124.0 g., 1.0 mole) in water was added in one portion, and with stirring the heterogeneous reaction mixture was cooled in an ice-bath. 2-Methoxynicotinyl chloride (86 g., 0.5 mole) in methylenechloride (500 ml.) was added drop-wise and the mixture was allowed to warm to room temperature as vigorous stirring was continued for 2 hours. At this point the organic layer was removed and the aqueous layer extracted twice with 100 ml. portions of methylene chloride. The combined organic layers were then extracted three times with cold, dilute (0.5N) sodium hydroxide. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to a yellow oil, which solidified upon standing, affording 97 g. (0.37 mmole, 75%) of product. Recrystallization from cyclohexane gave the analytical sample, a white crystalline solid, m.p. 84°-97°.
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[N:11]([CH2:14][CH2:15][C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)=[N+:12]=[N-:13]>>[ClH:1].[S:18]1[CH:19]=[CH:20][C:16]([CH2:15][CH2:14][N:11]2[CH:4]=[C:3]([CH2:2][C:5]3[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=3)[N:13]=[N:12]2)=[CH:17]1
Reactant: C#CCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCCc1ccsc1
Agent: Cl
Product: Nc1nc(Cc2cn(CCc3ccsc3)nn2)c[nH]1
Yield: 60 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.101 g, 0.641 mmol was reacted with 3-(2-Azido-ethyl)-thiophene (0.118 g, 0.769 mmol) following the general procedure for click reactions outlined above to produce 4-[1-(2-Thiophen-3-yl-ethyl)-1H [1,2,3]triazol-4-ylmethyl]-1H-imidazol-2-ylamine hydrochloride (0.119 g, 60%) of a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.42 (s, 1H), δ 7.19 (t, 1H), δ 6.90 (s, 1H), □ 6.78 (d, 1H), S 6.09 (s, 1H), δ 4.47 (t, 2H), δ 3.67 (s, 2H), δ 3.09 (t, 2H) ppm; 13C; (75 MHz, CD3OD) δ 151.2, 145.7, 137.7, 130.5, 127.8, 125.8, 122.9, 121.9, 110.3, 50.798, 30.7, 23.3 ppm; HRMS (ESI) calcd for C12H14N6S (M+) 274.1001. found 274.1007.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:15]([CH3:14])(=[O:17])=[O:16])=[CH:4][N:3]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CS(=O)(=O)Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 59 %

Procedure:
To a solution of 2,5-dibromopyridine (50 g, 211 mmol) in tetrahydrofuran (175 mL) at 0° C. was added 2.0 M isopropylmagnesium chloride (274 mmol) at a rate to maintain the temperature below B° C. The reaction mixture was stirred at 0° C. for 45 minutes, then cooled to −15° C. A solution of methanesulfonyl chloride (32.2 g, 281 mmol) in tetrahydrofuran (40 mL) was added to the reaction mixture at such a rate to maintain the temperature below 5° C. The reaction mixture was allowed to warm to room temperature and then quenched with waler (500 mL) and tert-butylmethylether (300 mL). The layers were separated the aqueous layer was extracted twice with tert-butylmethylether (2×200 mL). The combined organic extracts were washed with water (200 mL) and concentrated. The crude product was crystallized from toluene (110 mL), the solids were filtered to afford 29.4 g (59% yield) of 2-bromo-5-(methanesulfonyl)-pyridine. 1H NMR (300 MHz, CDCI3) δ3.13 (s, 3H), 7.73 (d, J=8.3 Hz, 1H), 8.07 (dd, J1=8.3 Hz, J2=2.7 Hz, 1H), 8.91 (d, J=2.5 Hz, 1H).
Reaction SMILES: CN(C=O)C1C=CC=CC=1.C([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=C.ClC(OC(=O)OC(Cl)(Cl)Cl)(Cl)Cl.P(Cl)(Cl)(Cl)=O.[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:44]([CH:51]([CH3:53])[CH3:52])C=2)=[CH:38][CH:37]=1>C(#N)C>[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:44]([CH:51]([CH3:53])[CH3:52])[C:17]=2[CH:16]=[CH:15][CH:14]=[O:13])=[CH:38][CH:37]=1
Reactant: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Reactant: C=COCCCC
Agent: CN(C=O)c1ccccc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)n1c(C=CC=O)c(-c2ccc(F)cc2)c2ccccc21
Temperature: 5 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of N-methylformanilide (30 g), butyl vinyl ether (22.2 g) in 15 ml of acetonitrile under stirring at 5° C., a solution of bis-trichloromethylcarbonate (26.1 g) in 70 ml of acetonitrile is added dropwise in 80 min. The reaction mixture is kept under stirring at 5° C. overnight, then phosphorus oxychloride (31.4 g) is added dropwise in 30 minutes, then the reaction mixture is stirred at 5° C. for 15 minutes. 3-[3-(4-Fluorophenyl)-1-(1-Methylethyl)-1H-Indole (35.8 g) and acetonitrile (25 ml) are added. The mixture is warmed to 80° C. and kept under stirring for about 24 hours. The reaction mixture is worked up as described in Example 3b to give the product (69% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:13][CH:14]([NH:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:39])[CH2:25][CH2:24]2)=[O:22])[C:15]2[NH:19][N:18]=[N:17][N:16]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[C:8]2[CH3:12])[CH3:2].[C:40](=O)([O-])[O-].[Na+].[Na+].IC>CS(C)=O.O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:13][CH:14]([NH:20][C:21]([N:23]2[CH2:24][CH2:25][CH:26]([N:29]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:39])[CH2:27][CH2:28]2)=[O:22])[C:15]2[N:16]([CH3:40])[N:17]=[N:18][N:19]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[C:8]2[CH3:12])[CH3:2]
Reactant: CCc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nnn[nH]2)cc2c(C)n[nH]c12
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Solvent: O
Product: CCc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nnnn2C)cc2c(C)n[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(7-ethyl-3-methyl-1H-indazol-5-yl)-1-(1H-tetrazol-5-yl)-ethyl]-amide (50 mg, 0.1 mmol, 1.0 equiv), sodium carbonate (40.0 mg, 3.0 equiv), and iodomethane (24 μL, 3.0 equiv) were combined in dimethylsulfoxide and the mixture stirred at room temperature overnight. The mixture was then diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine (3×), dried over sodium sulfate, and concentrated. Purification by preparative HPLC afforded the title compound. 1H-NMR (CD3OD) δ 1.30 (m, 4H), 1.57 (m, 3H), 2.50 (s, 3H), 2.75-2.95 (m, 5H), 3.40 (m, 2H), 3.68 (m, 3H), 4.05-4.40 (m, 6H), 5.35 (m, 1H), 6.75 (m, 1H), 6.95 (dd, J=7.3, 7.6, 1H), 6.98 (s, 1H), 7.12 (m, 2H), 7.35 (s, 1H). Mass spec.: 543.42 (MH)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([C:13]3[N:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=4)[C:23]#[N:24])[O:15][N:14]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[CH3:30][S:31]([CH:34]=[CH2:35])(=[O:33])=[O:32]>CC(N(C)C)=O>[CH:27]([O:26][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[O:15][N:14]=[C:13]([C:8]3[C:9]4[CH2:10][CH2:11][CH2:12][C@@H:3]([NH:2][CH2:35][CH2:34][S:31]([CH3:30])(=[O:33])=[O:32])[C:4]=4[CH:5]=[CH:6][CH:7]=3)[N:17]=2)=[CH:25][C:22]=1[C:23]#[N:24])([CH3:29])[CH3:28]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4N)no2)cc1C#N
Reactant: C=CS(C)(=O)=O
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4NCCS(C)(=O)=O)no2)cc1C#N
Temperature: 80 °C

Procedure:
To a solution of (R)-5-(3-(5-amino-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride 3 (20 mg, 0.05 mmol) in DMA (0.5 mL) was added TEA (136 μL, 0.97 mmol) and methylvinylsulfone (52 mg, 0.5 mmol). The reaction was heated to 80° C. for 24 h. The crude reaction mixture was purified by preparative HPLC to give (R)-2-isopropoxy-5-(3-(5-((2-(methylsulfonyl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)benzonitrile 48. LCMS-ESI (m/z) calculated for C25H28N4O4S: 480.6; found 481.2 [M+H]+, tR=2.58 min. 1H NMR (400 MHz, CDCl3) δ 8.37 (t, J=9.1 Hz, 1H), 8.31 (dd, J=8.9, 2.2 Hz, 1H), 8.08 (d, J=7.1 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.42 (t, J=7.7 Hz, 1H), 7.12 (d, J=9.1 Hz, 1H), 4.85-4.73 (m, 1H), 4.53 (t, J=5.0 Hz, 1H), 3.63 (dd, J=15.3, 4.0 Hz, 2H), 3.61-3.50 (m, 2H), 3.33-3.17 (m, 1H), 3.18-3.04 (m, 1H), 3.04 (d, J=8.6 Hz, 3H), 2.16 (ddd, J=29.6, 18.8, 12.2 Hz, 2H), 2.00 (dd, J=36.4, 18.4 Hz, 2H), 1.47 (d, J=6.1 Hz, 6H).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:1]([N:22]1[CH2:23][CH2:24][CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][CH2:21]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: c1ccc(C2CCNCC2)cc1
Product: CCCCCCC/C=C/C(=O)N1CCC(c2ccccc2)CC1

Procedure:
The same procedures as in Example 1 were carried out using (E)-2-decenoic acid and 4-phenylpiperidine as starting raw materials, to produce an intended compound.
Reaction SMILES: [C:1]([CH2:3][C:4]([N:6]([CH:17]([CH3:19])[CH3:18])[C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12]([SH:14])[S:13][C:9]=2[CH:8]=1)=[O:5])#[N:2].[CH:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)=O.N1CCCCC1>C(O)C>[C:1]([C:3]([C:4](=[O:5])[N:6]([CH:17]([CH3:19])[CH3:18])[C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12]([SH:14])[S:13][C:9]=2[CH:8]=1)=[CH:20][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)#[N:2]
Reactant: CC(C)N(C(=O)CC#N)c1ccc2nc(S)sc2c1
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)N(C(=O)C(C#N)=Cc1ccc(C(=O)O)cc1)c1ccc2nc(S)sc2c1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
α-cyano-N-isopropyl-N-(2-mercaptobenzothiazol-6-yl)acetamide (99 mg, 0.339 mmol) and 4-formylbenzoic acid (56 mg, 0.374 mmol) were combined in absolute ethanol (1.4 ml). The mixture was stirred 15 minutes with activated 4 A molecular sieves in a sealed vessel. Piperidine (67 μL, 0.678 mmol) was added and the mixture was heated to 80° C. After 1 hour, the solution was concentrated in vacuo and purified by preparative TLC (10% methanol, 90% dichloromethane) to yield 49 mg (34%). 1H NMR (CDCl3) δ1.17 (d, 6H), 4.93 (m, 1H), 7.16 (dd, 1H), 7.28 (dd, 1H), 7.32 (d, 1H), 7.69 (d, 2H), 7.93 (s, 1H), 7.98 (d, 2H); ESIMS: m/z 422 (M-H).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:8]2[CH:9]=[C:10]([C:13]([O:15]C)=[O:14])[CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:17]>CO>[CH3:3][N:4]1[C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:17]
Reactant: COC(=O)c1ccc2[nH]c(=O)n(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(=O)[nH]c2ccc(C(=O)O)cc21
Temperature: 65 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
Add 1N sodium hydroxide (6.1 mL, 6.1 mmol) to a suspension of methyl 3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (420 mg, 2.04 mmol) in methanol (10 mL). The suspension turned to a solution upon addition of 1N sodium hydroxide. Stir at 65° C. for 16 hours. Cool to room temperature then concentrate to remove the methanol. Extract the aqueous with ethyl acetate (5 mL). Acidify the aqueous with 2N hydrogen chloride (3 mL) to pH˜2. Concentrate the aqueous layer to a solid. Triturate the solid with water (3 mL). Filter the precipitate and dry under high vacuum to yield the title compound (234 mg, 59%) as a pale brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28 (s, 3H). 7.01 (d, J=8.21 Hz, 1H), 7.57 (s, 1H), 7.63 (dd, J=8.11, 127 Hz, 1H), 11.19 (s, 1H), 12.60 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6](C(OC(C)(C)C)=O)[N:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.N1C=CC=CC=1.[C:24]1([CH3:41])[CH:29]=[CH:28][CH:27]=[C:26]([S:30][CH2:31][C:32]2[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=2[C:34](Cl)=[O:35])[CH:25]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:17][O:16][C:14]([C:4]1[CH:3]=[C:2]([NH:1][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=2[CH2:31][S:30][C:26]2[CH:25]=[C:24]([CH3:41])[CH:29]=[CH:28][CH:27]=2)[NH:6][N:5]=1)=[O:15]
Reactant: COC(=O)c1cc(N)n(C(=O)OC(C)(C)C)n1
Reactant: Cc1cccc(SCc2ccccc2C(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)c2ccccc2CSc2cccc(C)c2)[nH]n1
Temperature: 25 °C

Procedure:
A solution of 1.1 eq. of 20, 1.1 eq. of pyridine, and 0.07 eq. of DMAP in CH2Cl2 was cooled to 0° C. While stirring, a solution of 1.0 eq. of 59 in CH2Cl2 was added. The reaction solution was allowed to warm to rt. After a time sufficient for reaction completion, the reaction solution was concentrated by rotary evaporation and 1.0 M HCl was added. The acidified solution was extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaHCO3, followed by drying over MgSO4 and filtering. The filtrate was rotary evaporated and the crude material was purified by flash chromatography on silica gel using a mixture of EtOAc-hexanes as eluant to give 60.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][NH2:5].C(N1C=CN=C1)([N:14]1C=CN=C1)=O.C(N(CC)CC)C.FC1C=C(OC)C=C(F)C=1CN1[C:40]2[N:41]=[CH:42][CH:43]=[CH:44][C:39]=2[S:38](=[O:46])(=[O:45])[N:37]([C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([O:55][CH3:56])C=2)[C:36]1=[O:57]>CN(C=O)C>[CH3:54][O:53][C:50]1[CH:51]=[CH:52][C:47]([N:37]2[C:36](=[O:57])[N:5]([CH2:4][C:3]3[C:2]([F:1])=[CH:9][C:8]([F:10])=[CH:7][C:6]=3[F:11])[C:40]3[N:41]=[CH:42][CH:43]=[CH:44][C:39]=3[S:38]2(=[O:46])=[O:45])=[N:14][C:49]=1[O:55][CH3:56]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1
Reactant: NCc1c(F)cc(F)cc1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ncccc3S2(=O)=O)nc1OC

Procedure:
The title compound (118 mg, 0.25 mmol) was prepared in two steps from (IntC3) (165 mg, 0.5 mmol), 2,4,6-trifluorobenzylamine (0.18 mL, 1.5 mmol); followed by 1,1′-carbonyldiimidazole (246 mg, 1.52 mmol), triethylamine (0.11 mL, 0.76 mmol) in DMF (1.5 mL) using the methods of (95).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([SH:10])[C:7]([OH:9])=[O:8].[Cl:11]N1C(=O)CCC1=O>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:11][C:5]1[S:1][C:2]([CH:6]([SH:10])[C:7]([OH:9])=[O:8])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)C(S)c1cccs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C(S)c1ccc(Cl)s1
Reaction time: 0.17 h
Yield: 45 %

Procedure:
To a solution of thiophen-2-yl-sulfanyl acetic acid ethy (0.52 g, 2.6 mmol) in 25 mL of CH2Cl2 is added N-chlorosuccinimide (0.35 g, 2.6 mmol). The solution is stirred for 10 minutes. After this time, 1 drop of TFA is added. The solution is stirred for 16 hours. The reaction mixture is then diluted with 25 mL of CH2Cl2. The resulting solution is washed with 1N NaOH and a saturated NaCl solution. The organic layer is dried over MgSO4, filtered and concentrated. The resulting product is obtained as an oil which is determined to contain 45% of the desired product. The oil is then dissolved in 60 mL of 1:1:1 THF:MeOH:H2O. To the solution is added lithium hydroxide monohydrate (1.26 g, 30 mmol). The solution is stirred for 16 hours. After this time, the solution is acidified to pH=3 with 1N HCl. The aqueous solution is washed with H2O and saturated NaCl solution. The solution is extracted with EtOAc/CH2Cl2 (2:1). The organic layer is dried over MgSO4, filtered and concentrated. The resulting crude product is purified by column chromatography eluting with 20% MeOH:Et2O to give the product as a white solid (0.4 g, 1.9 mmol). MS (EI): m/z 208, 210 (M+), Cl pattern.
Reaction SMILES: C(O[CH:5]1[CH:9]([N+:10]([O-:12])=[O:11])[CH:8]([CH:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH3:14])[S:7][CH2:6]1)(=O)C.S(Cl)(Cl)(=O)=O.O>C1(C)C=CC=CC=1>[CH3:17][CH:16]([CH3:18])[CH2:15][CH:13]([C:8]1[S:7][CH:6]=[CH:5][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:14]
Reactant: CC(=O)OC1CSC(C(C)CC(C)C)C1[N+](=O)[O-]
Solvent: O=S(=O)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)CC(C)c1sccc1[N+](=O)[O-]
Temperature: 4 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
After dissolving 1.1 g of 5-(4-methylpentan-2-yl)-4-nitrotetrahydrothiophen-3-yl acetate in 7 ml of toluene, the solution was cooled to 4° C. A solution prepared by dissolving 0.8 g of sulfuryl chloride in 2 ml of toluene was added thereto. The temperature of the solution was allowed to rise room temperature, and the solution was stirred for 2 hours. Water was added to stop reaction, and the organic layer was washed with 1 mol/l aqueous sodium hydroxide and saturated saline. The organic layer was dried with magnesium sulfate and concentrated, and then purified by silica gel chromatography (hexane/ethyl acetate=10/1), thereby obtaining 0.8 g of 2-(4-methylpentan-2-yl)-3-nitrothiophene (yield: 85.0%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[O:18][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]5[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=5)=[CH:35][CH:34]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]4[N:50]=[CH:51][N:52]=[C:26]34)[CH2:21][CH2:20]2)=[N:16][N:15]=1>C(OCC)(=O)C>[CH3:13][C:14]1[O:18][C:17]([C@H:19]2[CH2:20][CH2:21][C@H:22]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[C:45]5[NH:3][C:4](=[O:7])[O:5][N:46]=5)=[CH:35][CH:34]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]4[N:50]=[CH:51][N:52]=[C:26]34)[CH2:23][CH2:24]2)=[N:16][N:15]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](c3nnc(C)o3)CC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](c3nnc(C)o3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.35 g), sodium hydrogen carbonate (0.57 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({4-[trans-4-(5-methyl-1,3,4-oxadiazol-2-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.18 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.066 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.056 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.083 g, 42%).