Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:5][CH:6]=1.ClS([N:16]=[C:17]=O)(=O)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:5][C:6]=1[C:17]#[N:16]
Reactant: CCOC(=O)c1cc(Br)c[nH]1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)c(C#N)[nH]1
Temperature: 25 °C
Reaction time: 17 h
Yield: 74.4 %

Procedure:
To a cooled (0° C.) solution of ethyl 4-bromo-1H-pyrrole-2-carboxylate (Belanger, P. Tetrahedron Lett. 1979, 20, 2505) (9.50 g, 43.6 mmol) in acetonitrile (200 mL) was added chlorosulfonyl isocyanate (3.87 mL, 43.6 mmol), drop wise. The reaction was allowed to warm to rt and stir for 17 h. The reaction was quenched with the addition of DMF (17 mL) and the reaction was heated (50° C.) for 2 h then cooled to rt and stirred an additional 2 h. The mixture was poured over ice water (500 mL) and was extracted with ethyl acetate (3×250 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The crude material was purified via flash chromatography on silica gel eluting with 10% to 25% ethyl acetate in hexanes to afford 7.88 g (74%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 13.77 (br s, 1 H), 7.01 (s, 1 H), 4.28 (q, 2 H), 1.29 (t, 3 H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:11][NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]#[CH:23])=[O:14])[CH2:7][CH2:6]1)=[O:4].O.[OH-].[Li+].O.Cl>CO>[C:3]([CH:5]1[CH2:10][CH2:9][C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:11][NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]#[CH:23])=[O:14])[CH2:7][CH2:6]1)([OH:4])=[O:2]
Reactant: C#COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(C(=O)OC)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(C(=O)O)CC1
Temperature: 60 °C

Procedure:
To a solution of 1-methoxycarbonylmethylidenyl-4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)-cyclohexane (32.2 mg, 0.082 mmol) in 3.0 mL of methanol was added lithium hydroxide monohydrate (6.9 mg, 0.164 mmol) and water (1 mL) and the reaction mixture was heated at 60° C. for 8 h. To the solution was then added 2N HCl to bring the pH=3.0 and volatiles were removed by vacuum. The white solid was dissolved in CH2Cl2 and filtered through celite (to remove LiCl) and evaporated to give the title compound.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:37])=[C:34]([OH:36])[CH:35]=1>C1COCC1>[OH:36][C:34]1[CH:35]=[C:30]([NH:29][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]5[S:24][CH:25]=[CH:26][CH:27]=5)=[O:22])=[CH:16][CH:15]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:28])[CH:31]=[CH:32][C:33]=1[CH3:37]
Reactant: O=C1Nc2cc(C(=O)c3ccc(NC(=O)c4cccs4)cc3)ccc2C1=CO
Reactant: Cc1ccc(N)cc1O
Solvent: C1CCOC1
Product: Cc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4ccc(NC(=O)c5cccs5)cc4)ccc32)cc1O
Temperature: 65 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 20, 100 mg, 0.257 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methylphenol (34.7 mg, 0.282 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 70% (89 mg, 0.180 mmol) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7]([CH2:18][CH2:19][CH2:20][N:21](C)C)([OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](Cl)=[O:28])[CH3:25].[CH:30]1C=CC=CC=1>>[CH3:1][C:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7]([CH2:18][CH2:19][CH:20]([NH:21][C:27]([O:26][CH2:24][CH3:25])=[O:28])[CH3:30])([OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1CCc1ccccc1C2(O)CCCN(C)C
Reactant: CCOC(=O)Cl
Reactant: c1ccccc1
Product: CCOC(=O)NC(C)CCC1(O)c2ccccc2CCc2c(C)cccc21

Procedure:
A solution containing 15.5 g. of 1-methyl-10,11-dihydro-5-(3-dimethylaminopropyl)-5-hydroxy-5-H-dibenzo[a,d]cycloheptene in 180 ml. of dry benzene is added dropwise to a mixture of 16.4 g. of chloroformic acid ethyl ester and 50 ml. of dry benzene and thereafter boiled at reflux for 20 hours. After cooling, the reaction mixture is washed with three 100 ml. portions of hydrochloric acid, then with water, dried over sodium sulfate and evaporated. The 1-methyl-10,11-dihydro-5-(3-methyl-carbethoxyaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene obtained is recrystallized from high-boiling petroleum ether and has a melting point of 132°-134° C.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)=[O:8].[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:30]C)[C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19]>C1COCC1.C(OCC)(=O)C.C(OC(C)C)(C)C>[F:17][C:12]1[CH:11]=[C:10]([NH:9][C:7]([C:3]2[N:2]([NH:1][C:27](=[O:28])[C@@H:26]([NH:25][C:23](=[O:24])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21])[CH3:30])[CH:6]=[CH:5][N:4]=2)=[O:8])[CH:15]=[C:14]([F:16])[CH:13]=1
Reactant: Nn1ccnc1C(=O)Nc1cc(F)cc(F)c1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1ccnc1C(=O)Nc1cc(F)cc(F)c1
Temperature: 55 °C
Reaction time: 48 h
Yield: 59.7 %

Procedure:
1.60 g (6.18 mmol) of 1-amino-N-(3,5-difluorophenyl)-1H-imidazole-2-carboxamide, 1.64 g (8.65 mmol) of (S)-2-(tert-butoxycarbonylamino)butanoic acid and 1.34 g (8.65 mmol) of EDCHCl were dissolved in 45 mL of THF and stirred at 55° C. overnight and at room temperature for 2 days. Then the solvent was evaporated and the crude residue was taken up in ethyl acetate and washed with brine. The organic layer was dried over magnesium sulphate, filtered and the solvent was evaporated. The solid obtained was redissolved in the minimum amount of ethyl acetate and diisopropylether was added until a solid precipitated, which was filtered to furnish 1.51 g (57% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N+]#N)[C:9]([O:11][CH3:12])=[O:10])=[C:4]([O:15][CH3:16])[CH:3]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[CH:8]([C:9]([O:11][CH3:12])=[O:10])[CH2:16][O:15][C:4]=2[CH:3]=1
Reactant: COC(=O)C([N+]#N)c1ccc(Cl)cc1OC
Solvent: Cc1ccccc1
Product: COC(=O)C1COc2cc(Cl)ccc21
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
A nitrogen gas was blown into a solution of 1-(4-chloro-2-methoxyphenyl)-2-methoxy-2-oxoethanediazonium (200 mg, 0.83 mmol) obtained in Example (74-1) in toluene (5 ml) at room temperature for 5 minutes. The reaction mixture was heated to 80° C. while blowing a nitrogen gas into the mixture and tetrakis(triphenylacetate)dirhodium (II) (1 mg) was added thereto, and the mixture was stirred for 15 minutes. The reaction mixture was cooled to room temperature and the residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=5/1) to give the title compound as a pale yellow oil (127 mg, yield: 72%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH:13]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:14][CH2:15][C:16]([N:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29](OC)=[O:30])=[CH:25][CH:24]=2)[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC>[C:33]1([CH:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:14][CH2:15][C:16]([N:19]([CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:29][OH:30])=[CH:27][CH:28]=2)[CH3:20])([CH3:17])[CH3:18])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)c1ccc(CCN(C)C(C)(C)COC(c2ccccc2)c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CN(CCc1ccc(CO)cc1)C(C)(C)COC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 86.9 %

Procedure:
Lithium aluminium hydride (38 mg) was added to a stirred, ice-cooled solution of 1-diphenylmethoxy-2-[N-(4-methoxycarbonylphenethyl)-N-methylamino]-2-methylpropane (160 mg) (see Example 13) in ether (15 ml) and the mixture was stirred at room temperature for 17 hours, heated under reflux for 4 hours, quenched by the sequential dropwise addition with stirring of a solution of water (38 mg) in tetrahydrofuran (2 ml), 15% aqueous sodium hydroxide solution (38 mg) and water (114 mg), stirred at room temperature for 30 minutes and filtered. The filtrate was washed with 5% aqueous sodium carbonate solution and water, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica (17 g) using hexane:n-propanol: saturated methanolic ammonia (95:5:1) as the eluant. Appropriate fractions were combined and evaporated to give the title compound as a colourless oil (130 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Cl-].[Cl-].[Al+3].[C:16]1([O:22][CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([C:19]1[CH:20]=[CH:21][C:16]([O:22][CH3:23])=[CH:17][CH:18]=1)=[O:5]
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1cc(I)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc(I)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
2-chloro-5-iodobenzoyl chloride (10.7 g, 35.5 mmol) was dissolved in methylene chloride (200 mL). The resulting mixture was cooled in an ice-water bath. To the mixture was added aluminum trichloride (10.4 g, 78.2 mmol), and then added dropwise a solution of anisole (4.2 g, 38.9 mmol) in methylene chloride (50 mL). After the completion of dropwise addition, the resulting mixture was warmed up to room temperature and stirred for 3 hr. The reaction mixture was poured into ice-water and quenched. To the reaction mixture was added 3 mol/L hydrochloric acid. The resulting mixture was separated into an aqueous phase and an organic phase. The aqueous phase was extracted with methylene chloride (150 mL×2). The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under a reduced pressure. The resulting crude product was purified with a silica-gel column chromatography (ethyl acetate:petroleum ether=0-1:100) to produce 12.0 g of a product in a yield of 91%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:18])[C:11]3[N:12]([C:14](I)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=1)#[CH:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:18])[C:11]3[N:12]([C:14]([C:20]#[C:19][C:21]4[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cn2c(I)cnc12
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(C#Cc3ccc(N)nc3)cnc12

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-3-iodo-8-methyl-imidazo[1,2-a]pyridine (example C.21 step 2) (737 mg, 2 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (307 mg, 2.6 mmol) according to general procedure II. Obtained as an off-white solid (240 mg, 33%). MS (ISP) 359.0 [(M+H)+], 361.0 [(M+2+H)+]; mp 231-234° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:41]([O:43][C:44](=[O:50])[CH2:45][CH2:46][N:47]=[C:48]=[O:49])[CH3:42]>>[CH2:41]([O:43][C:44](=[O:50])[CH2:45][CH2:46][NH:47][C:48]([N:27]1[C:17]2[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:20]=[C:15]([C:12]3[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=4)[CH2:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[N:14][CH:13]=3)[C:16]=2[CH2:29][CH2:28]1)=[O:49])[CH3:42]
Reactant: CCOC(=O)CCN=C=O
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: CCOC(=O)CCNC(=O)N1CCc2c(-c3cnc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)nc3)nc(N3CCOCC3)nc21

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 3-isocyanato-propionic acid ethyl ester (244 μl) instead of isocyanato-acetic acid ethyl ester, in the same manner as Example 1-D-29 in Step A, a crude product of the desired compound was obtained (114 mg, quant.).
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:39])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][CH2:29][C:30]3[C:38]4[C:33](=[N:34][CH:35]=[CH:36][CH:37]=4)[NH:32][CH:31]=3)=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:39])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][CH2:29][C:30]3[C:38]4[C:33](=[N:34][CH:35]=[CH:36][CH:37]=4)[NH:32][CH:31]=3)=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3NCc3c[nH]c4ncccc34)ccc2C(C)(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CNCc2cc(NC(=O)c3ccccc3NCc3c[nH]c4ncccc34)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4,4-Dimethyl-7-{2-[(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amino]-benzoylamino}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (Step B, 0.45 g, 0.86 mmol) was treated with 10 mL of 1/1 TFA/CH2Cl2 solution and stirred at RT for 1 h. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to obtain the titled compound as a white solid. MS (ES+): 426.1 (M+H)+. Calc'd for C26H27N5O-425.22.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[S:11]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12]1>>[S:11]1[CH:15]=[CH:14][C:13]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[CH:12]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: OB(O)c1ccsc1
Product: c1cc2cc(-c3ccsc3)ccc2[nH]1

Procedure:
The title compound was prepared as in (D29) from 5-bromoindole and thiophene-3-boronic acid to give (D40) (1.1 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=O)[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1.C(Cl)(=O)C([Cl:30])=O>ClCCl>[Cl:30][C:13]1[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Temperature: 50 °C

Procedure:
To a solution of methyl 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (0.90 g, 2.2 mmol) from Example 51, Step A in dichloromethane (5 mL) was added oxalyl chloride (1.0 mL, 11.4 mmol) and the reaction was heated at 50° C. for 24 h. The reaction was concentrated in vacuo and the residue was dissolved in methylene chloride and washed with aq. sodium bicarbonate. The organic layer was washed with a portion of brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted with 5 to 10% ethyl acetate in hexanes to yield methyl 2-chloro-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxylate.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[C@H:6]([CH2:8][SH:9])[NH2:7])[CH3:3].C([O-])(=O)C.[K+].CC(C)=O.O.[CH3:21][N:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][C:25](=[O:32])[N:24]([C:33]2[CH:34]=[CH:35][C:36]3[S:40][N:39]=[C:38]([CH:41]=O)[C:37]=3[CH:43]=2)[C:23]1=[O:44]>CC(C)=O>[CH3:21][N:22]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][C:25](=[O:32])[N:24]([C:33]2[CH:34]=[CH:35][C:36]3[S:40][N:39]=[C:38]([C@@H:41]4[NH:7][CH:6]([C:5]([O:4][CH2:2][CH3:3])=[O:10])[CH2:8][S:9]4)[C:37]=3[CH:43]=2)[C:23]1=[O:44]
Reactant: CCOC(=O)[C@@H](N)CS
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C1CS[C@H](c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)N1
Reaction time: 8 h
Yield: 43.9 %

Procedure:
To a mixture of L-cysteine ethyl ester hydrochloride (0.580 g, 3.12 mmol), potassium acetate (0.300 g, 3.06 mmol) and 50% acetone-water is added dropwise a solution 5-[3,6-Dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxaldehyde (1.00 g, 2.81 mmol) in acetone. The resultant mixture is stirred four days at room temperature and treated with additional L-cysteine ethyl ester hydrochloride (0.580 g, 3.12 mmol) and, potassium acetate (0.300 g, 3.06 mmol). The resultant mixture is warmed to 35° C. and stirred overnight. The mixture is concentrated in vacuo and the residue is extracted with methylene chloride. The organic layer is washed with water, treated with charcoal, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with methylene chloride-ethyl acetate to afford the title compound as an off-white solid (0.600 g, 43.9%, mp 97-98° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:22](=O)[C:23]([O:25]C)=O)=[CH:12]1)(C(C)(C)C)(C)C.[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[CH2:38][C:39]([NH2:41])=[O:40])[CH:31]=[CH:30]1.CC(C)([O-])C.[K+].Cl>CN(C=O)C>[OH:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:22]2[C:23](=[O:25])[NH:41][C:39](=[O:40])[C:38]=2[C:36]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:37]=2[N:29]([CH3:28])[CH:30]=[CH:31]3)=[CH:12]1
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1cn(CCO[Si](C)(C)C(C)(C)C)c2cc(OC)ccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)cn(CCO)c2c1
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of methyl {1-[2-(tert-butyldimethylsilyloxy)ethyl]-6-methoxy-1H-indol-3-yl}oxoacetate (10.4 g, 26.5 mmol) and 2-(1-methyl-1H-indol-7-yl)acetamide (5.0 g, 26.5 mmol) in DMF (250 mL) was added a 1.0 M solution of potassium tert-butoxide (79.5 mL, 79.5 mmol) at room temperature and under nitrogen. The reaction was stirred overnight. A solution of concentrated HCl (10 mL) was added and the mixture was stirred at room temperature for 1 h, then quenched with water (200 mL) and diluted with EtOAc (300 mL). The two layers were separated and the aqueous phase was extracted with EtOAc (3×200 mL). The organic phases were combined and washed with water (3×300 mL), brine (500 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 30% hexanes/EtOAc) gave the title compound (9.5 g, 86%) as a red solid. 1H NMR (300 MHz, DMSO-d6) 11.10 (s, 1H), 8.08 (s, 1H), 7.65 (d, J=6.1 Hz, 1H), 7.22 (d, J=2.8 Hz, 1H), 7.00–6.83 (m, 3H), 6.49 (d, J=2.8 Hz, 1H), 6.03 (d, J=5.8 Hz, 1H), 5.94 (d, J=6.3 Hz, 1H), 4.88 (t, J=5.3 Hz, 1H), 4.22 (t, J=5.5 Hz, 2H), 3.70–3.55 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccc(F)cc2)cc1
Yield: 63.6 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 4-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.044 g (63%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:8]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCBr
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCN1CCCCC1
Temperature: 55 °C
Yield: 50.4 %

Procedure:
N-decylpiperidine was synthesized by reacting 45.7 g piperidine with 118.7 g 1-bromodecane in 237 mL acetone in the presence of 74 g potassium carbonate. After refluxing this reaction mixture at 55° C. for 24 hr, it was filtered and acetone was removed from the filtrate to yield 61 g N-decylpiperidine. 5 g N-decylpiperidine and 42 g 1-bromo-3-chloropropane were dissolved in 50 mL methanol and the reaction mixture was heated at 65° C. for 18 hr. After cooling to room temperature, methanol was removed under reduced pressure. The residue was poured into 2 L tert butylmethyl ether with stirring and then the mixture was allowed to stand for 6 hr. The white precipitate thus formed was filtered and was dried at 40° C. under vacuum for 24 hr yielding 68 g (3-chloropropyl)decylpiperidinium bromide as a light yellow solid.
Reaction SMILES: O1CCOCC1.C(O)(=O)C.[Cl:11][C:12]1[CH:35]=[CH:34][C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24](=[N:31][O:32][CH3:33])[C:25]([N:27]=[CH:28][NH:29][OH:30])=O)=[CH:14][CH:13]=1>CCOCC>[CH3:33][O:32][N:31]=[C:24]([C:25]1[O:30][N:29]=[CH:28][N:27]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][O:16][C:15]1[CH:34]=[CH:35][C:12]([Cl:11])=[CH:13][CH:14]=1
Reactant: CON=C(C(=O)N=CNO)c1ccccc1COc1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CON=C(c1ncno1)c1ccccc1COc1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 40.7 %

Procedure:
Dioxane (2 ml) and acetic acid (1.5 ml) were added to 2-(4-chlorophenoxymethyl)-N-hydroxyaminomethylene-α-methoxyiminophenylacetamide (0.36 g, 1 mmol), and the mixture was stirred at 120° C. for 4 hours. After completion of the reaction, ether (150 ml) was added, and the mixture was washed with saturated aqueous sodium bicarbonate solution (100 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 2-(4-chlorophenoxymethyl)phenyl 1,2,4-oxadiazol-5-yl ketone O-methyloxime (0.14 g, 40.8%) as colorless crystals.