Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[CH:15]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH:15]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3c[nH]c4cc(F)ccc34)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1ccc2c(-c3cnn(C4CCNCC4)c3)c[nH]c2c1
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To a solution of tert-butyl 4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Intermediate 16B; 230 mg; 0.60 mmol) in dioxane (3 mL) was added conc. aqueous HCl (3 mL; 36%). The reaction mixture was stirred for 0.5 hour and concentrated to dryness, neutralized with saturated aqueous NaHCO3 (50 mL), extracted with EtOAc (50 ml×2). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated. The residue was purified by preparative TLC (DCM/MeOH=10/1) to afford 70 mg (41%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]2([S:20]([C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:4][CH:3]=1.[N+:30]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)([O-:32])=[O:31].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]2([S:20]([C:23]3[CH:24]=[CH:25][C:26]([I:29])=[CH:27][CH:28]=3)(=[O:21])=[O:22])[S:17][C:16](=[O:18])[N:15]([CH2:37][C:36]3[CH:39]=[CH:40][C:33]([N+:30]([O-:32])=[O:31])=[CH:34][CH:35]=3)[C:14]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C(CCCC#Cc2ccc(Cl)cc2)(S(=O)(=O)c2ccc(I)cc2)S1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1SC(CCCC#Cc2ccc(Cl)cc2)(S(=O)(=O)c2ccc(I)cc2)C(=O)N1Cc1ccc([N+](=O)[O-])cc1

Procedure:
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-thiazolidine-2,4-dione is reacted with 4-nitrobenzyl bromide and potassium carbonate in DMF to give the title compound as a light tan solid, mp 172-175° C.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][C:7]([C:10]1[CH:15]=[C:14]([CH:16]([NH:23][OH:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[C:12]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:11]=1[OH:29])([CH3:9])[CH3:8].[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>O.O1CCOCC1>[CH3:26][C:25]([C:12]1[CH:13]=[C:14]([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:23]([OH:24])[C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:15]=[C:10]([C:7]([CH3:6])([CH3:8])[CH3:9])[C:11]=1[OH:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)c1cc(C(NO)c2ccccc2)cc(C(C)(C)C)c1O
Reactant: CC(C)C(=O)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C(=O)N(O)C(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 0.82 g (0.01 mole) of sodium acetate in 7 mL H2O is added to a solution of 1.08 g (0. 0033 mole) of 2,6-bis (1,1-dimethylethyl)-4-[(hydroxyamino)phenylmethyl]phenol in 30 mL dioxane. Isobutyryl chloride (0.51 g, 0. 00477 mole) is added dropwise and the mixture is stirred at room temperature for 17 hours. Water (25 mL) is added to the mixture and the solid material is filtered off and washed with water. After drying it is recrystallized from Et2O-n-hexane to give off-white crystals, 0.477 g (36%), m.p. 179°-180° C.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4](O)([C:7]#[N:8])[CH2:3][CH2:2]1.CC(C)(O)C#[N:13]>>[NH2:13][C:4]1([C:7]#[N:8])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: CC(C)(O)C#N
Reactant: N#CC1(O)CCCCC1
Product: N#CC1(N)CCCCC1

Procedure:
In a similar manner, 1-aminoisobutyronitrile was prepared by substituting for cyclohexanone cyanohydrin an equivalent amount of acetone cyanohydrin.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]2[N:22]=[C:21]([CH:23]=O)[CH:20]=[C:19]([CH2:25][O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:18]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[N:11][CH:10]=1.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CN(C=O)C.C1COCC1>[CH2:32]([NH:39][CH2:23][C:21]1[CH:20]=[C:19]([CH2:25][O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:18]=[C:17]([NH:16][C:5]2[CH:6]=[CH:7][C:8]([C:9]3[CH:14]=[C:13]([CH3:15])[N:12]=[N:11][CH:10]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:22]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1cc(Nc2nc(C=O)cc(COCC(F)(F)F)n2)ccc1-c1cnnc(C)c1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(Nc2nc(CNCc3ccccc3)cc(COCC(F)(F)F)n2)ccc1-c1cnnc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-Methoxy-4-(6-methylpyridazin-4-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)-pyrimidine-4-carbaldehyde (100 mg, 0.23 mmol) was dissolved in DCE (4 mL), THF (1 mL) and DMF (0.1 mL). Benzylamine (0.030 mL, 0.28 mmol) and acetic acid (0.013 mL, 0.23 mmol) were added followed by sodium triacetoxyborohydride (69 mg, 0.32 mmol). The mixture was stirred at rt under nitrogen atmosphere for 1 hour. The reaction was quenched with water. The water phase was extracted by DCM (×2). The combined organic layer was dried over anhydrous sodium sulfate and evaporated onto silica. The silica was loaded on a pre-packed silica column. The column was eluted with a gradient of methanol in DCM to give the title compound as a solid, 58 mg (48%).
Reaction SMILES: [C:1](ON=O)(C)([CH3:3])[CH3:2].C(Br)C=C.[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)N)([O-:14])=[O:13].NC1C=CC=CC=1>CC#N>[CH2:3]([C:17]1[CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:21]=[CH:20][CH:19]=1)[CH:1]=[CH2:2]
Reactant: CC(C)(C)ON=O
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: C=CCBr
Solvent: CC#N
Solvent: Nc1ccccc1
Product: C=CCc1cccc([N+](=O)[O-])c1
Temperature: 35 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (30 ml), 3-nitroaniline (414 mg, 3.0 mmol) was added during 20 minutes, while maintaining the temperature of the reaction mixture at 34-36° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 35° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 47:3) gave 420 mg of 3-allylnitrobenzene as a light yellow oil containing 36% of 3-bromonitrobenzene. This corresponds to 50% yield of 3-allylnitrobenzene. 1H NMR (CDCl3, 400 MHz) δ 8.10-8.08, (m, 1H), 8.08-8.05, (m, 1H), 7.56-7.51, (m, 1H), 7.50-7.44, (m, 1H), 6.02-5.91, (m, 1H), 5.20-5.10, (m, 2H), 3.50, (d, 2H, J=6.7 Hz); 13C NMR (CDCl3, 100 MHz) δ 148.8, 142.5, 136.1, 135.3, 129.7, 123.9, 121.8, 117.8, 40.1.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:25][CH2:26][OH:27])[CH:20]=[CH:19]3)=[N:12][CH:13]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](OB(O)O)=[CH:31][CH:30]=1>O1CCOCC1.CO>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([CH2:25][CH2:26][OH:27])[CH:20]=[CH:19]4)=[N:12][CH:13]=2)=[CH:31][CH:30]=1
Reactant: OCCn1ccc2cc(C#Cc3ccc(Br)cn3)ccc21
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: OCCn1ccc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc21
Temperature: 110 °C

Procedure:
Under an N2 atmosphere 56 mL 2 M Na2CO3 solution and 1.29 g (1.1 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 19.0 g (55.7 mmol) 2-[5-(5-bromo-pyridin-2-ylethynyl)-indol-1-yl]-ethanol and 11.55 g (72.4 mmol) 4-chlorophenyl-boric acid in 320 mL 1,4-dioxane and 80 mL MeOH and the reaction mixture is heated to 110° C. for 16 h. The mixture is evaporated down i. vac., the residue is combined with 300 mL water and the suspension is stirred vigorously. The precipitate is filtered off and washed with 200 mL water. The precipitate is suspended three times, each time with 600 mL PE/DCM (5:1), suction filtered and finally dried in the air until a constant weight is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][OH:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:14][C:4]1[CH:3]=[C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:13])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(Cl)c2ccc(CO)cc2n1
Reactant: C1CCNC1
Product: Cc1cc(N2CCCC2)c2ccc(C(=O)N3CCCC3)cc2n1
Yield: 54 %

Procedure:
(4-Chloro-2-methyl-quinolin-7-yl)-methanol (example 2, 200 mg, 0.80 mmol) was heated in pyrrolidine (2 mL) at 70° C. for 48 h. After cooling the reaction mixture was partitioned between sat. aq. ammonium chloride solution and dichloromethane. The organic layer was separated, dried (MgSO4), and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 19:1) afforded the title compound (134 mg, 54%). Light yellow solid, ISP-MS: m/e=310.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:7](=[O:8])[C:6]4[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:11]([F:14])([F:13])[F:12])[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1cc(Cl)ccc1C(F)(F)F
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3cc(Cl)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 5-chloro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (58% yield). m.p. 164-166° C. 1H NMR (300 MHz, CDCl3) δ 8.07, 7.96, 7.69, 7.54, 7.02, 4.07-3.35, 1.52, 0.79-0.68, 0.48-0.43, 0.14-0.08. MS (ES+) m/z 482.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:20]#[N:21])([CH3:19])[CH3:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[CH2:30]([O:32][C:33]1[N:34]=[C:35]2[CH:41]=[C:40]([C:42](Cl)=[O:43])[S:39][C:36]2=[N:37][CH:38]=1)[CH3:31].O>C(Cl)Cl>[C:20]([C:17]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:10]([NH:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH:1][C:42]([C:40]2[S:39][C:36]3=[N:37][CH:38]=[C:33]([O:32][CH2:30][CH3:31])[N:34]=[C:35]3[CH:41]=2)=[O:43])[CH:3]=1)=[O:22])([CH3:19])[CH3:18])#[N:21]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Reactant: CCOc1cnc2sc(C(=O)Cl)cc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOc1cnc2sc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.6 %

Procedure:
To a solution of N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 5 (38 mg, 0.132 mmol) and triethylamine (0.092 mL, 0.66 mmol) in CH2Cl2 (1 mL) was added 2-ethoxythieno[2,3-b]pyrazine-6-carbonyl chloride (32 mg, 0.132 mmol) in CH2Cl2 (1 mL) and stirred overnight at rt. Water was added and extracted with CH2Cl2. Organic layer was washed with water, dried and evaporated. Purification by HPLC gave N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-2-ethoxythieno[2,3-b]pyrazine-6-carboxamide (5 mg, 7%). 1H-NMR (400 MHz, DMSO-d6). 1.42 (t, J=7.0 Hz, 3H), 1.76 (s, 6H), 2.26 (s, 3H), 4.46 (q, J=7.0 Hz and 14.0 Hz, 2H), 7.31 (d, 8.2 Hz, 1H), 7.58-7.66 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 7.87 (d, J=1.9 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 8.05 (s, 1H), 8.35 (s, 1H), 8.41 (s, 1H), 10.35 (s, 1H), 10.37 (s, 1H). (m/z)=500 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([S:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)=[O:17])=[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:13][C:12]=2[CH:31]=1.C(N(C(C)C)C(C)C)C>ClCCl>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([S:16]([C:15]2[C:11]3[CH:10]=[CH:9][C:8]([CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:31][C:12]=3[S:13][C:14]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:17])[CH:23]=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1sc2cc(CO)ccc2c1S(=O)c1cccc(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1sc2cc(COS(C)(=O)=O)ccc2c1S(=O)c1cccc(OC)c1
Yield: 66.2 %

Procedure:
Methanesulfonyl chloride (0.043 ml, 0.55 mmol) was added to a stirred solution of ethyl 6-(hydroxymethyl)-3-[(3-methoxyphenyl)sulfinyl]benzo[b]thiophene-2-carboxylate (Preparation 17, 195 mg, 0.5 mmol) and N-ethyl-N,N-diisopropylamine (0.1 ml, 0.55 mmol) in dichloromethane (3 ml) at 0° C. After 3 hours the solution was washed twice with water, dried (magnesium sulfate), and the solvent removed under reduced pressure. The residue was crystallised from diethyl ether to give the title compound as a colourless solid (155 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[I:22]Cl.II>C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][C:14]([I:22])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: ClI
Reactant: CCOC(=O)c1ncc2[nH]c3ccccc3c2c1COC
Agent: II
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ncc2[nH]c3ccc(I)cc3c2c1COC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.0 g of 4-methoxymethyl-beta-carboline-3-carboxylic-acid-ethylester in 20 ml of methylene chloride and 1.5 ml of pyridine is mixed dropwise with 1.5 ml of iodine chloride at room temperature. After 60 minutes, another 1.5 ml of iodine chloride is added and then 200 mg of iodine. The mixture is stirred for another 2 h at room temperature and then poured into an ice-cold saturated sodium thiosulfate solution, followed by extraction with methylene chloride. Crystallization in ethyl acetate yields 520 mg of 6-iodo-4-methoxymethyl-beta-carboline-3-carboxylic-acid-ethylester with a m.p. of 204°-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[S:19](=[O:22])(=[O:21])[NH2:20].C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C.[N:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[CH2:57][CH2:58][NH2:59].FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:59][CH2:58][CH2:57][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][N:51]=3)=[O:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[S:19](=[O:21])(=[O:22])[NH2:20]
Reactant: NCCc1ccccn1
Reactant: NS(=O)(=O)c1cc(C(=O)c2ccc(C(=O)O)cc2)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cc(C(=O)c2ccc(C(=O)NCCc3ccccn3)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
4-(4-Chloro-3-sulfamoyl-benzoyl)-benzoic acid (50 mg, 0.15 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (57 mg, 0.30 mmol), 1-hydroxy-7-azabenzotriazole (41 mg, 0.30 mmol) were dissolved in dichloromethane (5 mL), then triethylamine (61 mg, 0.60 mmol) is added followed by 2-pyridin-2-yl-ethylamine (23 mg, 0.19 mL) and the reaction is allowed to stir at ambient temperature overnight. The reaction is then quenched with trifluoroacetic acid (1 mmol) and loaded directly onto a silica gel column, chromatography (gradient of ethyl acetate in hexanes 10-100%) followed by crystallization from ether afforded 20 mg of the title compound. 1H NMR (DMSO) δ 3.02 (t, 2H, J=7.57 Hz), 3.63-3.68 (m, 2H), 7.22-7.25 (m, 1H), 7.30 (d, 1H, J=7.83 Hz), 7.70-7.74 (m, 1H), 7.83-7.87 (m, 5H), 7.92-7.99 (m, 3H), 8.31 (d, 1H, J=2.02), 8.51-8.53 (m, 1H), 8.85-8.82 (m, 1H). MS (m/z): 442 (M−1). CHN Calc C, 56.82; H, 4.09; N, 9.47. Found C, 55.65; H, 3.90; N, 9.22 (+0.5 water).
Reaction SMILES: C1([Li])C=CC=CC=1.[Cl-].[C:9]1([CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:13][CH:12]=[CH:11][CH:10]=1.[CH2:34]([N:38]([CH2:47][CH2:48][CH2:49][CH3:50])[C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=1)[CH2:35][CH2:36][CH3:37].II>C1(C)C=CC=CC=1.O.O1CCCC1>[CH2:34]([N:38]([CH2:47][CH2:48][CH2:49][CH3:50])[C:39]1[CH:46]=[CH:45][C:42]([CH:43]=[CH:14][C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[CH:41][CH:40]=1)[CH2:35][CH2:36][CH3:37]
Reactant: c1ccc([P+](Cc2cccs2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCN(CCCC)c1ccc(C=O)cc1
Agent: II
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCN(CCCC)c1ccc(C=Cc2cccs2)cc1
Reaction time: 1 h
Yield: 94.8 %

Procedure:
In a stream of argon, to 70 ml of tetrahydrofuran was added 10.45 g of phenyllithium (19% solution in dibutylether) (23.6 mmol), and 8.09 g (20.5 mmol) of 2-thenyl triphenylphosphonium chloride was added thereto under cooling. To this mixture was added dropwise 4.92 g (21.0 mmol) of 4-(dibutylamino)benzaldehyde. The mixture was stirred at the same temperature for 1 hour. After the reaction mixture was poured into water, extraction with toluene, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give an orange liquid. This liquid was dissolved in 200 ml of toluene and 200 mg of iodine was added thereto. After stirred at room temperature for 15 minutes, the mixture was added to water and the phases were separated. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 6.09 g of an orange oily matter (yield: 94.8%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[C:24]1[C:28](O)=[O:29].CCN=C=NCCCN(C)C>CC(N(C)C)=O.CN(C1C=CN=CC=1)C.ClCCl>[CH2:16]([O:15][C@H:3]1[C@@H:2]([NH:1][C:28]([C:24]2[NH:23][CH:27]=[CH:26][N:25]=2)=[O:29])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1ncc[nH]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)c2ncc[nH]2)[C@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
tert-Butyl cis(±)-4-amino-3-(benzyloxy)piperidine-1-carboxylate obtained in Example (90d) (0.92 g, 3.0 mmol) was dissolved in DMA (10 mL). 1H-Imidazol-2-ylcarboxylic acid (0.19 g, 1.70 mmol), WSC (0.82 g, 0.43 mmol) and DMAP (60 mg, 0.49 mmol) were added, and the mixture was stirred at room temperature for one hour. The reaction solution was diluted with dichloromethane, washed with water and brine, and dried over anhydrous magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=2/1, 1/1, 1/3) to obtain 0.31 g of the title compound as a colorless solid (46%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:23]([CH3:33])[C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:9])[N:23]([CH3:33])[C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2nc(Sc3ccccc3)n(C)c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccccc3)n(C)c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.03 g of 4,5-bis(4-methoxyphenyl)-2-phenylthio-1-methylimidazole in 100 ml of dichloromethane. The solution is agitated for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 200 g of silica gel with ethyl acetate/cyclohexane 2:3, thus obtaining 3.05 g of 4,5-bis(4-methoxyphenyl)-2-phenylsulfinyl-1-methylimidazole, which has a melting point of 114°-115° after recrystallization from dichloromethane/ether.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:20]Br>C(O)(=O)C>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]([Br:20])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: COc1cccc2cc(C(C)=O)oc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Br)c2cc(C(C)=O)oc12
Reaction time: 1 h
Yield: 70.7 %

Procedure:
2-Acetyl-7-methoxybenzofuran (1.0 g, 5.3 mmol) was dissolved in glacial acetic acid (29 mL) followed by addition of sodium acetate (1.3 g, 15.8 mmol). The reaction was treated dropwise with a solution of bromine (0.26 mL, 5.26 mmol) in glacial acetic acid (10 mL) at room temperature followed by stirring for one hour. The solvent was removed under vacuum. The residue was dissolved in water and extracted three times with dichloromethane. The combined organic extracts were washed with 2% aqueous sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel using a 50-100% dichloromethane/hexane gradient affording 1.00 g (75%) of the product as a white solid. 1H NMR (CDCl3, 300 MHz) δ 7.44 (s, 1H), 7.32 (d, 1H), 6.80 (d, 1H), 4.0 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:16])([CH3:15])[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:20]1[S:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][N:24]=1>C1COCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:16])([CH3:15])[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:23][N:24]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncc(-c2ccccc2)s1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccnc(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccnc(Nc2ncc(-c3ccccc3)s2)c1

Procedure:
4-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine (8-5), 1.00 g (4.19 mmol) was dissolved in 20 mL anhydrous THF at room temp, and NaH (60% dispersion, 0.670 g, 16.8 mmol) was added. When the bubbling stopped, 2-chloro-5-phenyl-thiazole (Hafez, E. A. A.; Abed, N. M.; Elsakka, I. A.; J. Heterocycl. Chem. 1983; 20, 285-288), 0.739 g (3.78 mmol) was added, and the reaction was heated to reflux. After 2 hours the THF was removed in vacuo and the resulting solution was taken to neutral pH with 1M HCl (aq) and filtered. The residue was purified by flash column chromatography using 20% EtOAc in hexane. 1H NMR (CDCl3): δ 9.09 (bs, 1H), 8.32 (d, 1H, J=5.2 Hz), 7.62 (s, 1H), 7.56 (d, 2H, J=7.4 Hz), 7.38 (t, 2H, J=7.6 Hz), 7.26 (overlapping with CHCl3, 1H), 6.90 (s, 1H), 6.82 (d, 1H, J=5.2 Hz), 4.75 (s, 2H), 0.96 (s, 9H), 0.14 (s, 6H). mp 207° C.