Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].N(OC(C)(C)C)=O.[C:19]([C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1)N)([CH3:22])([CH3:21])[CH3:20]>N1C=CC=CC=1>[C:19]([C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1)[O:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC1(C)CCCC(C)(C)N1O
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(ON2C(C)(C)CCCC2(C)C)cc(C(C)(C)C)c1
Yield: 84.4 %

Procedure:
The procedure of Example 1 is repeated using 1.50 g (9.6 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidine, 2.38 g (24 mmol) of tert-butyl nitrite, 5.8 mg (0.0096 mmol) of (S,S)-(+)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II), 90 mL of pyridine and 3.93 g (19.2 mmol) of 3,5-di-tert-butylaniline at 70° C. The crude product obtained is purified by vacuum flash chromatography (heptane) to give 2.8 g of the title compound as an off-white solid in 84.8% yield. The structure is confirmed by 1Hnmr and elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]2[CH:14]=[O:15])=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:16]N1C(=O)CCC1=O.O>O1CCCC1>[Br:13][C:11]1[CH:10]=[C:9]([CH:14]=[O:15])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[C:12]=1[Cl:16]
Reactant: O=Cc1cc(Br)cn1-c1ncccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(Br)c(Cl)n1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.4 %

Procedure:
To a solution of 3.0 g of 3-chloro-2-(4-bromo-2-formyl-1H-pyrrol-1-yl)-pyridine in 30 ml of tetrahydrofuran was added 1.5 g of N-chlorosuccinimide. The resulting mixture was stirred at room temperature for 2 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.5 g of 4-bromo-5-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]#[N:12].[H-].[Na+].Cl[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1.Cl>C1COCC1.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:11]#[N:12]
Reactant: N#CCc1nc2ccccc2s1
Reactant: Clc1ncccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(=C1Nc2ccccc2S1)c1ncccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(Benzothiazol-2-yl)acetonitrile (0.69 g, 4 mmol) was added in portions to a suspension of 95% sodium hydride ((0.21 g, 6 mmol) in THF (12 mL). The resulting yellow suspension was stirred at room temperature for 30 min, and 2-chloropyrimidine (0.45 g, 4 mmol) was added. The mixture was stirred for 3 d, and water was added to the dark solution. The mixture was acidified with 1N hydrochloric acid, and the precipitate that formed was collected by filtration, washed with water and acetonitrile, and dried under vacuum to give 2-[benzothiazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetonitrile as a brown solid.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:20])[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=1)[C:15]([O:17]C)=[O:16])=[O:8])(=O)C.C(SCC(C)C(NC1N=CC=CC=1C(OC)=O)=O)(=O)C.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>>[SH:4][CH2:5][CH:6]([CH3:20])[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=1)[C:15]([OH:17])=[O:16])=[O:8]
Reactant: COC(=O)c1cncc(NC(=O)C(C)CSC(C)=O)c1
Agent: COC(=O)c1cccnc1NC(=O)C(C)CSC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(CS)C(=O)Nc1cncc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Following the procedure of Example 3, but substituting an equivalent amount of methyl 5-(2-acetylthiomethyl-propionamido)-nicotinate, obtained as disclosed in Example 12, for methyl 2-(2-acetylthiomethyl-propionamido)-nicotinate and substituting an equivalent amount of potassium carbonate for sodium hydroxide and maintaining the reaction mixture under stirring for six hours at room temperature, 5-(2-mercaptomethyl-propionamido)-nicotinic acid is obtained after purification on a silica gel column (eluent methylene chloride/methanol 99:1); m.p. 160°-165° C., from acetone.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([S:21][CH3:22])[N:15]=1.CON(C)[C:26](=[O:28])[CH3:27]>C1COCC1>[CH3:20][C:18]1[N:17]=[C:16]([S:21][CH3:22])[N:15]=[C:14]([CH2:13][C:26](=[O:28])[CH3:27])[CH:19]=1
Reactant: CSc1nc(C)cc(C)n1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSc1nc(C)cc(CC(C)=O)n1
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
n-Butyllithium (1.6 M in hexanes, 67 ml, 107 mmol) is added dropwise to a stirred solution of diisopropylamine (15 ml, 107 mmol) in dry THF (90 ml) under argon at −78° C. After 15 minutes at −78° C. to 50° C. the mixture is cooled to −78° C. and a solution of 4,6-dimethyl-2-methylsulfanyl-pyrimidine (15 g, 97.4 mmol) in dry THF (45 ml) is added dropwise. The reaction is stirred for 2.5 hours at −78° C. then N-methoxy-N-methylacetamide (10.4 ml, 97.4 mmol) is added dropwise. The reaction is allowed to warm to room temperature over 1 hour followed by quenching with saturated aqueous ammonium chloride solution (10 ml). The mixture is concentrated to remove most of the THF then partitioned between water (200 ml) and DCM (200 ml). The organic extract is separated, dried (MgSO4), and the solvent is removed to afford the titled compound. The material is a mixture of keto and enol forms as observed by 1H nmr (CDCl3)
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1>O>[NH2:3][C:4]1[C:12]([Br:1])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1
Reactant: BrBr
Reactant: Nc1ccc(C(=O)O)cn1
Solvent: O
Product: Nc1ncc(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Bromine (2.3 mL, 44.6 mmol) was added dropwise to a suspension of the 6-aminonicotinic acid Compound 112a (5.08 g, 36.8 mmol) in water (20 mL) at 4° C. After the completion of the addition, the cooling bath was removed and the reaction mixture was stirred at room temperature for 4.5 h. Saturated Na2S2O5 was added slowly to the stirred mixture. The solid was collected through filtration, washed with water, and dried under vacuum overnight to give 9.30 g of 6-amino-5-bromonicotinic acid along with 3,5-dibromo-2-aminopyridine in ˜1:1 ration as a greenish solid; MS (ES) m/z: 217 (M+H+). A mixture of the solid (4.00 g) containing 6-amino-5-bromonicotinic acid, DPPA (6.08 g, 22.1 mmol), triethylamine (2.80 g, 27.7 mmol), benzyl alcohol (3.8 mL, 36.8 mmol), and toluene (50 mL) was heated at 70° C. for 1 h, then 100° C. for 1 h. After concentration, the reaction mixture was purified by flash chromatography (EtOAc/hexane as solvent) to give 1.31 g (26% in 2 steps) of Compound 112b as a yellow solid; 1H NMR (300 MHz, CDCl3) δ7.99 (brs, 1H), 7.91(d, J=2.3 Hz, 1H), 7.39-7.34 (m, 5H), 6.50 (brs, 1H), 5.19 (s, 2H), 4.79 (brs, 2H); MS (ES) m/z: 324 (M+H+). Anal. Calcd. For C13H12BrN3O2.0.1H2O : C, 48.20; H, 3.80; N, 12.97. Found: C, 48.40; H, 3.90; N, 12.64.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:20])([CH3:19])[CH2:11]2)[CH:7]=[N:8][CH:9]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[F-].[Na+]>C1COCC1.O>[CH3:19][C:12]1([CH3:20])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([N:6]2[C:5]([CH2:3][OH:2])=[CH:9][N:8]=[CH:7]2)[CH2:11]1
Reactant: COC(=O)c1cncn1C1CC(C)(C)c2ccccc21
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC(n2cncc2CO)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(3,3-dimethyl-indan-1-yl)-3H-imidazole-4-carboxylic acid methyl ester (1.31 g, 4.85 mmol), which can be prepared as described in Example 2, in THF (405 mL) at 0° C. is added LiAlH4 (220 mg, 5.6 mmol). The reaction is permitted to stir at room temperature for 2 hours at which time the reaction is cooled to 0° C., charged with sodium fluoride (205 mg, 4.88 mmol), and diluted with water. The reaction is brought to room temperature and stirred overnight. The reaction is then filtered and the eluent is extracted three times with ethyl acetate. The combined organic extracts are dried with Na2SO4, filtered and concentrated. The resulting residue is purified by silica gel flash chromatography (methanol-dichloromethane, 0:1 to 1:10) to provide 3-(3,3-dimethyl-indan-1-yl)-3H-imidazol-4-yl]-methanol; MS: (ESI) m/z 243.1 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][O:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][S:38]([C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1)(=[O:40])=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:44]2[CH:45]=[CH:46][C:41]([S:38]([CH3:37])(=[O:40])=[O:39])=[CH:42][CH:43]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][O:22]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCO2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(C(=CC2CCCO2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 41.4 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-furan-2-yl)-vinyl ester (0.6 g, 1.14 mmol), 4-(methanesulfonyl)phenylboronic acid (0.57 g, 2.86 mmol) and dichlorobis(triphenylphosphine)palladium (II) (81 mg, 0.11 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 1.4 mL). The resulting mixture was subjected to microwave irradiation for 8 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 30% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-furan-2-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (0.24 g, 41%) as a white solid: LC/MS m/e calcd for C26H24N2O5S2 [M+H]+ 509.62, observed 509.3.
Reaction SMILES: Br[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[S:9]2(=[O:25])=[O:24])=[CH:5][CH:4]=1.[CH3:28][NH:29][CH3:30]>>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]([CH2:7][C:6]2[CH:26]=[CH:27][C:3]([CH2:2][N:29]([CH3:30])[CH3:28])=[CH:4][CH:5]=2)[S:9]1(=[O:24])=[O:25]
Reactant: O=S1(=O)N(Cc2ccc(CBr)cc2)c2ccccc2N1c1ccccc1F
Reactant: CNC
Product: CN(C)Cc1ccc(CN2c3ccccc3N(c3ccccc3F)S2(=O)=O)cc1
Yield: 92 %

Procedure:
In an analogous manner to general procedure V, 1-[4-(bromomethyl)benzyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.11 g, 0.24 mmol) was treated with dimethylamine (10 mL) to provide 0.09 g, (92%) of 1-(4-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]methyl}phenyl)-N,N-dimethylmethanamine. MS (ES) m/z 411.0. HPLC purity 97.3% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:3]1[C:13]([O:15][CH3:16])=[O:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[S:41]([C:45]1[CH:46]=[N:47][CH:48]=[C:49]([CH:53]=1)[C:50](O)=[O:51])(=[O:44])(=[O:43])[NH2:42]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:7]1([C:4]2[CH:5]=[CH:6][N:2]([NH:1][C:50](=[O:51])[C:49]3[CH:53]=[C:45]([S:41](=[O:43])(=[O:44])[NH2:42])[CH:46]=[N:47][CH:48]=3)[C:3]=2[C:13]([O:15][CH3:16])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NS(=O)(=O)c1cncc(C(=O)O)c1
Reactant: COC(=O)c1c(-c2ccccc2)ccn1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccccc2)ccn1NC(=O)c1cncc(S(N)(=O)=O)c1
Reaction time: 0.25 h
Yield: 32.4 %

Procedure:
To a stirred solution of methyl 1-amino-3-phenyl-1H-pyrrole-2-carboxylate (2.00 g, 9.25 mmol) in DMF (20 mL) was added DMAP (3.39 g, 27.7 mmol) and HATU (10.6 g, 27.7 mmol). The reaction mixture was stirred for 15 minutes and a solution of 5-sulfamoylnicotinic acid (3.74 g, 18.5 mmol) dissolved in DMF was added. The reaction mixture was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure to remove DMF and saturated solution of citric acid was added to the residue until the pH was 3. The solution was extracted with CH2Cl2 and the organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, neutral alumina, 40 g, 13% methanol in CH2Cl2) to afford methyl 3-phenyl-1-(5-sulfamoylnicotinamido)-1H-pyrrole-2-carboxylate (1.20 g, 32.4%). LCMS Condition B-39: retention time 1.79 min, [M−1]=399.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.54 (s, 3H), 6.34 (d, J=3.2 Hz, 1H), 7.32-7.44 (m, 7H), 7.80 (br s, 2H), 8.68 (t, J=2.0 Hz, 1H), 9.20 (d, J=2.0 Hz, 1H), 9.30 (d, J=2.0 Hz, 1H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][Cl:13].C(N(CC)CC)C>C(O)C>[Cl:13][CH2:12][CH2:11][CH2:10][CH2:9][S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Sc1ccncc1
Reactant: ClCCCCBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: ClCCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
To a suspension of 33.35 g (0.30 mol) of 4mercaptopyridine and 51.44 g (0.30 mol) of 1-bromo-4-chlorobutane in 500 ml of ethanol, 41.9 ml (0.30 mol) of triethylamine was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off and chloroform was added to the residue. The mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate/n-hexane=1:1) to give 54.27 g of the desired compound (89.7% yield, colorless oil).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:12][CH:9]2[CH2:8][CH2:7][N:6]([CH2:5][C:4]3[CH:13]=[CH:14][CH:15]=[C:2]([Cl:1])[CH:3]=3)[CH2:11][CH2:10]2)=[O:30])=[CH:25][CH:24]=1
Reactant: OC1CCN(Cc2cccc(Cl)c2)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC2CCN(Cc3cccc(Cl)c3)CC2)cc1
Yield: 41 %

Procedure:
0.25 g (0.0011 mol) of 1-(3-chloro-benzyl)-piperidin-4-ol and 0.39 ml (0.0028 mol) of triethylamine were dissolved in 11 ml of toluene, treated with 0.184 ml (0.0014 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:3). 0.155 g (41%) of 1-(3-chloro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]([CH2:13][SH:14])[CH2:11][CH:10]([CH2:15][SH:16])[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1>CCOCC.C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]([CH2:13][S:14][CH:23]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH2:11][CH:10]([CH2:15][S:16][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][O:18]2)[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(CS)CC(CS)N1Cc1ccccc1
Reactant: C1=COCCC1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C1C(CSC2CCCCO2)CC(CSC2CCCCO2)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-benzyl-2,4-bis(mercaptomethyl)-4-butanelactam (compound No.15-2, 134 mg) in dry ether (2 ml), dihydropyran (110 mg) dissolved in dry ether (2 ml) is added under nitrogen atmosphere and then boron trifluoride diethyl ether complex (15 mg) dissolved in dry ether (1 ml) is added to the mixture. The mixture is stirred overnight at room temperature. The mixture is diluted with a mixture of benzene and ethyl acetate and washed with 10% aqueous sodium bicarbonate solution, water and saturated sodium chloride solution. The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue is purified by silica gel column chromatography to give the titled compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Br[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][CH2:16][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: NC(=O)c1ccnc(-c2c[nH]cn2)c1
Reactant: Clc1ccccc1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccnc(-c2cn(CCc3ccccc3Cl)cn2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
A mixture of 2-(1H-imidazol-4-yl)pyridine-4-carboxamide (400 mg, 2.13 mmol, PREPARATION 7), 1-(2-bromo-ethyl)-2-chloro-benzene (557 mg, 2.55 mmol) and K2CO3 (587 mg, 4.26 mmol) in DMF (10 mL) was stirred overnight at 80° C. LC/MS showed the reaction was completed. It was then purified by flash column chromatography to give the title compound (228 mg, 33%) as a yellow solid. [M+H] Calc'd for C17H15ClN4O, 327. Found, 327.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].CS(C)=O.[F:12][C:13]1[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[C:38]4[C:33](=[CH:34][C:35]([S:39](OC5C(F)=C(F)C(F)=C(F)C=5F)(=[O:41])=[O:40])=[CH:36][CH:37]=4)[CH:32]=[CH:31][C:30]3=[O:54])=[C:25]([O:55][CH3:56])[CH:24]=2)[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(OCC)(=O)C.C1COCC1>[F:12][C:13]1[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[C:38]4[C:33](=[CH:34][C:35]([S:39]([NH:7][C:2]5[CH:3]=[N:4][CH:5]=[CH:6][N:1]=5)(=[O:40])=[O:41])=[CH:36][CH:37]=4)[CH:32]=[CH:31][C:30]3=[O:54])=[C:25]([O:55][CH3:56])[CH:24]=2)[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=1
Reactant: COc1cc(-c2cc(F)cc(C(F)(F)F)c2)ccc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1cnccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(-c2cc(F)cc(C(F)(F)F)c2)ccc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3cnccn3)ccc21
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
A RBF was charged with pyrazin-2-amine (0.047 g, 0.493 mmol) and DMSO (0.948 ml) to give a solution. Perfluorophenyl 1-(3′-fluoro-3-methoxy-5′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (0.250 g, 0.379 mmol) and THF (2.84 ml) were added, and the mixture remained a solution. The flask was cooled in an ice-bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (0.872 ml, 0.872 mmol) was added dropwise. The reaction was stirred for 15 minutes. The reaction was diluted with ethyl acetate and washed twice with 1N HCl solution. The organic layers was washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 40 g, gradient elution 0-50% [3:1 EtOAc/EtOH]:Heptane) to afford 1-(3′-fluoro-3-methoxy-5′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-2-oxo-N-(pyrazin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (0.153 g, 0.268 mmol, 70.7% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=11.62 (br. s., 1H), 8.47 (d, J=2.2 Hz, 1H), 8.36 (d, J=1.1 Hz, 1H), 8.29-8.19 (m, 3H), 8.09 (d, J=9.9 Hz, 1H), 8.03 (s, 1H), 7.94 (dd, J=2.2, 9.0 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.58 (dd, J=1.9, 8.1 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 6.79 (dd, J=9.3, 13.7 Hz, 2H), 3.80 (s, 3H). m/z (ESI) 571.1 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.CN1C=CN=C1.S(Cl)(Cl)=O.[CH2:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>C(#N)C.COC(C)(C)C>[CH2:20]([O:5][C:4]([C:1]1([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:6])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)C1(C(=O)O)CC1
Reactant: OCc1ccccc1
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: O=C(O)C1(C(=O)OCc2ccccc2)CC1
Yield: 69.7 %

Procedure:
1,1-Cyclopropanedicarboxylic acid (50 g) was dissolved in acetonitrile (500 ml) under a nitrogen atmosphere, and N-methylimidazole (31 ml) was added dropwise with stirring and cooling in an ice water bath. After stirring at the same temperature for 30 minutes, thionyl chloride (29 ml) was added dropwise. After stirring at the same temperature for 30 minutes, a mixed solution of benzyl alcohol (45.7 g) and N-methylimidazole (31 ml) was added with cooling in an ice water bath, and the reaction mixture was stirred at the same temperature for 6 hours. A 2N aqueous solution of sodium hydroxide (900 ml) was added to adjust pH 8. tert-Butyl methyl ether (500 ml) was added to the resultant solution, and the mixture was stirred. The organic layer and the aqueous layer were separated, and the organic layer was extracted with a 5% aqueous solution of sodium hydrogencarbonate (200 ml). The aqueous layers were combined, cooled in an ice water bath, and 5N hydrochloric acid (300 ml) was added to adjust pH 4. Ethyl acetate (1000 ml) was added, and the mixture was stirred for a while. The organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was dissolved in methanol (120 ml), and water (120 ml) was added dropwise with stirring at room temperature. After stirring at room temperature for 30 minutes, and with cooling in an ice water bath for 2 hours, the precipitated solid was suction filtered, and washed with water (60 ml, twice). The resultant solid was dried under reduced pressure at 40° C. to give the title compound (59 g, 69%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][C:7](=O)[C:6]=2[CH:14]=1.C([SiH](CC)CC)C.[OH-].[Na+]>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH3:12])[CH2:8][CH2:7][C:6]=2[CH:14]=1
Reactant: CC1(C)CC(=O)c2cc(Br)ccc2O1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCc2cc(Br)ccc2O1
Reaction time: 96 h
Yield: 150.5 %

Procedure:
TO a solution of 6-bromo-2,2-dimethyl-2,3-dihydro-4H-1-benzopyran-4-one (7.57 g) in trifluoroacetic acid (21.4 ml) was added at room temperature triethylsilane (10.4 ml), and the mixture was stirred for 4 days. To the mixture was added triethylsilane (7.1 ml), and the mixture was stirred at 50° C. for 24 hours. To the mixture was added at 0° C. 12N sodium hydroxide solution to make the solution alkaline, and the mixture was extracted with diethylether. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane) to give colorless oil of 6-bromo-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran (10.77 g).