Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1cc(Br)oc1C
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: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2cccc(F)c2)oc1C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.2 g), 3-fluorophenylboronic acid (1.7 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 15% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.1 g, 92%) as a white solid.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.[CH3:26][O:27][CH2:28][CH2:29][CH2:30][OH:31]>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([O:31][CH2:30][CH2:29][CH2:28][O:27][CH3:26])=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1
Reactant: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: COCCCO
Product: COCCCOc1ccc2c(C(=O)NCC3(O)CCC(F)(F)CC3)c(Cl)ccc2n1

Procedure:
The title compound was synthesized according to the procedure described in example 9 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide and 3-methoxy-propan-1-ol. 1H NMR (400 MHz, DMSO-d6): δ 8.74 (t, J=6.01 Hz, 1H), 8.03 (d, J=9.61 Hz, 1H), 7.77-7.80 (m, 1H), 7.69-7.71 (m, 1H), 7.10 (d, J=9.21 Hz, 1H), 4.68 (s, 1H), 4.45 (t, J=6.41 Hz, 2H), 3.47-3.50 (m, 2H), 3.38-3.39 (m, 2H), 3.25 (s, 3H), 2.01-2.04 (m, 4H), 1.90-2.00 (m, 2H), 1.67-1.72 (m, 4H). m/z: 443.2 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[CH2:11]([O:15][NH2:16])[CH:12]([CH3:14])[CH3:13]>>[CH2:11]([O:15][N:16]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)CON
Agent: Cl
Product: CC(C)CON=Cc1ccc(F)cc1

Procedure:
Reaction of 4-fluorobenzaldehyde with O-isobutyl-hydroxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a clear oil after chromatography on silica gel (elution toluene-ethyl acetate 95:5), (77% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 0.98 (6H, d, J=6.5 Hz, CH3), 2.07 (1H, m, CH), 3.95 (2H, d, J=7.18 Hz, OCH2), 7.08 (2H, m, aromatics), 7.59 (2H, m, aromatics), 8.08 (1H, s, CH). Anal. calcd for C11H14FNO: C, 67.67; H, 7.22; N, 7.17. Found: C, 67.71; H, 7.32; N, 7.38.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[NH:21][N:20]=[N:19][N:18]=2)[CH:5]=[CH:4][C:3]=1[C:22](=[O:24])[CH3:23].Cl.Cl[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[N:21]([CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[N:20]=[N:19][N:18]=2)[CH:5]=[CH:4][C:3]=1[C:22](=[O:24])[CH3:23]
Reactant: CCCc1c(OCCCCCc2nnn[nH]2)ccc(C(C)=O)c1O
Reactant: ClCc1cccnc1
Agent: Cl
Product: CCCc1c(OCCCCCc2nnnn2Cc2cccnc2)ccc(C(C)=O)c1O

Procedure:
1-[2-Hydroxy-3-propyl-4-[5-(1H-tetrazol-5-yl)pentyloxy]phenylethanone was allowed to reacted with 3-(chloromethyl)pyridine hydrochloride according to procedure A and the product was purified by high pressure liquid chromatography to give 1-[2-hydroxy-3-propyl-4-[5-[1-(3-pyridinyl)methyl-1H-tetrazol-5-yl]pentyloxy]phenyl]-ethanone, which is the N-1 isomer, and 1-[2-hydroxy-3-propyl-4-[5-[2-(3-pyridinyl)methyl]-2H-tetrazol-5-yl]pentyloxy]phenyl]ethanone, which is the N-2 isomer.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O.[C:12]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][C:20]([Cl:26])=[C:21]([O:24][CH3:25])[CH:22]=2)[NH:17][CH:16]=1)#[N:13].[OH-].[Na+]>O1CCCC1>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18]([NH:17][CH:16]=[C:15]2[CH2:14][CH2:12][NH2:13])=[CH:19][C:20]=1[Cl:26]
Reactant: COc1cc2c(CC#N)c[nH]c2cc1Cl
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cc2c(CCN)c[nH]c2cc1Cl
Yield: 83 %

Procedure:
A solution 7.6 g. (0.2 mole) of lithium aluminum hydride in 200 ml. of tetrahydrofuran was stirred under nitrogen while a solution of 5.2 ml. (9.8 g., 0.1 mole) of 100 percent sulfuric acid in 40 ml. of tetrahydrofuran was added. A solution of 6.0 g. (27 mmoles) of 3-cyanomethyl-5-methoxy-6-chloroindole in 40 ml. of tetrahydrofuran then was added over a 30-minute period. The reaction was allowed to proceed for another hour with stirring. The mixture then was poured into ice followed by 20 percent sodium hydroxide solution. The resulting mixture was extracted with several portions of chloroform. The extracts were washed with sodium chloride solution, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was boiled in ether, and a small amount of pentane was added. The mixture was cooled, and the crystalline product collected by filtration. After drying, 5.04 g. (83 percent) of 5-methoxy-6-chlorotryptamine were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1([CH2:23][CH3:24])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]([NH:20]C=O)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19]>Cl.CO>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1([CH2:23][CH3:24])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]([NH2:20])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3NC=O
Agent: Cl
Solvent: CO
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3N
Yield: 49.9 %

Procedure:
1,8-Diethyl-4-formylamino-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid methyl ester 10 (5.5 g, 0.01 mol) in 1N methanolic HCl (4.2 mL) and methanol (18 mL) was stirred at 25° C. for 72 hours, then concentrated in vacuo, diluted with water and extracted with ethyl acetate. The aqueous phase was basified with concentrated NaHCO3 solution and extracted with ether to afford the product (1.58 g, 50%), m.p. 230° C. (dec.) after recrystallization from ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Cl:24])C(=O)C1>CC#N>[Cl:24][C:9]1[C:10]([C:13]([F:14])([F:15])[F:16])=[N:11][NH:12][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: Fc1cccc(-c2cc(C(F)(F)F)n[nH]2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Fc1cccc(-c2[nH]nc(C(F)(F)F)c2Cl)c1

Procedure:
Following protocol L, 5-(3-fluorophenyl )-3-trifluoromethyl-1H-pyrazole was treated with NCS in CH3CN to yield the title compound.
Reaction SMILES: [CH2:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]1=[O:16])[CH:2]=[CH2:3].[CH:17](=[O:21])/C=C/C>>[CH3:15][O:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:16])[N:4]([CH2:1]/[CH:2]=[CH:3]/[CH:17]=[O:21])[CH2:13][CH2:12]2
Reactant: C/C=C/C=O
Reactant: C=CCN1CCc2cc(OC)ccc2C1=O
Product: COc1ccc2c(c1)CCN(C/C=C/C=O)C2=O

Procedure:
The title compound 44 is prepared according to the procedure reported in step C of Example 8 with amide 43 (222.4 mg, 1.03 mmol) and crotonaldehyde (4.12 mmol, 4 equiv) as reactants. Brown solid. (Yield 242.5 mg, 96%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:12](=[O:26])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:27])[N:5]=1)[CH3:3].Cl[C:29]1[C:30]2[CH:37]=[CH:36][NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:32]1[C:31]2[NH:35][CH:36]=[CH:37][C:30]=2[C:29]([NH:1][C@H:2]([C:4]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:23])([F:25])[F:24])[CH:15]=3)[C:12](=[O:26])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[Cl:27])[N:5]=2)[CH3:3])=[N:34][CH:33]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: C[C@H](N)c1nc2cccc(Cl)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: C[C@H](Nc1ncnc2[nH]ccc12)c1nc2cccc(Cl)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 28 h
Yield: 14.6 %

Procedure:
Under nitrogen, to (S)-2-(1-aminoethyl)-5-chloro-3-(3-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (80 mg, 0.20 mmol, 1.0 equiv) in t-BuOH (0.2 mL) at 23° C. was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (34 mg, 0.22 mmol, 1.1 equiv) and diisopropylethylamine (70 μL, 0.40 mmol, 2.0 equiv). After stirring for 28 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 15 mg of the title compound (15% yield).
Reaction SMILES: [O:1]=[C:2]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:26][NH:27][O:28][CH3:29].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.CN(C)C=O.O1CCCC1>[O:9]=[C:7]([N:27]([O:28][CH3:29])[CH3:26])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:1]
Reactant: COc1ccc(NC(=O)CCCCC(=O)O)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)CCCCC(=O)N(C)OC)cc1
Yield: 22.3 %

Procedure:
6-Oxo-6-(4-methoxyphenylamino)hexanoic acid (509 mg), tetrahydrofuran (12 mL) and dimethylformamide (0.1 mL) were cooled to 0°-5° C. Oxalyl chloride (0.23 mL) was added and the reaction was allowed to stir for fifteen minutes before the addition of N,O-dimethylhydroxylamine hydrochloride (221 mg). After twenty minutes, pyridine (0.8 mL) was added and reaction was warmed to 20°-25° C. Saturated sodium bicarbonate solution (100 mL) was added and the reaction was extracted with dichloromethane (2×30 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to afford a brown oil which was purified by chromatography eluting with 95:5 ethyl acetate:hexanes. The resulting white solid was recrystallized from ethyl acetate:hexanes to give the title compound as white crystals (133 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH3:38].CO>>[NH2:38][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Reactant: N
Solvent: CO
Product: Nc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.150 g, 0.265 mmol) and 7N ammonia in methanol (5.67 mL, 39.7 mmol), the title compound was obtained as a white solid (93 mg, 64% yield). MS (ESI): 548 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)=[O:9]>CO.O1CCOCC1.CCOCC>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)=[O:9]
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: c1c[nH]cn1
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Cc1ncc[nH]1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 68.32 g (1.004 mol) of imidazole dissolved in 150 ml of methanol at 0° C. (ice-bath) is added dropwise a solution of 2-bromo-2'-acetonaphthone (50 g, 0.201 mol) in 100 ml of dioxane and 25 ml of ether, while keeping the temperature at 0° C. After about 3 hours at 0° C., the mixture is allowed to warm to room temperature where it is stirred for 20 hours. The mixture is then filtered and added to 500 ml of water, extracted 3 times with 500 ml of chloroform, dried over magnesium sulfate, and evaporated under reduced pressure. The brown oil that remaines is crystallized with a small amount of ethyl acetate and hexane and collected by filtration. The solid is heated in ethyl acetate and filtered hot then concentrated enough to recrystallized the produce as a light tan solid. Yield: 31.07 g (65%); m.p. 125°-126° C. (Found: C, 76.03; H, 5.25; N, 11.81. C15H12N2O requires: C, 76.25; H, 5.12; N, 11.86).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]3([C:32]4[C:33]([O:38][CH2:39][CH3:40])=[N:34][CH:35]=[CH:36][CH:37]=4)[C:27]4[C:22](=[CH:23][C:24]([F:30])=[C:25]([C:28]#[N:29])[CH:26]=4)[NH:21][C:20]3=[O:31])=[O:17])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1.[CH3:41][O:42][C:43]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][C:44]=1[S:51](Cl)(=[O:53])=[O:52]>CN(C)C=O>[CH3:3][N:4]1[CH2:5][CH2:6][CH:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]3([C:32]4[C:33]([O:38][CH2:39][CH3:40])=[N:34][CH:35]=[CH:36][CH:37]=4)[C:27]4[C:22](=[CH:23][C:24]([F:30])=[C:25]([C:28]#[N:29])[CH:26]=4)[N:21]([S:51]([C:44]4[CH:45]=[CH:46][C:47]([O:49][CH3:50])=[CH:48][C:43]=4[O:42][CH3:41])(=[O:53])=[O:52])[C:20]3=[O:31])=[O:17])[CH2:12][CH2:11]2)[CH2:8][CH2:9]1
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: CCOc1ncccc1C1(OC(=O)N2CCN(C3CCN(C)CC3)CC2)C(=O)Nc2cc(F)c(C#N)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ncccc1C1(OC(=O)N2CCN(C3CCN(C)CC3)CC2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2cc(F)c(C#N)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
9.2 mg (0.19 mmol) of sodium hydride (50% dispersion in mineral oil) were added to a solution of 50 mg (0.10 mmol) of 5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate in 2 ml of anhydrous dimethylformamide under a nitrogen atmosphere and while cooling in an ice bath. The mixture was stirred at 0° C. for 10 min and then 29 mg (0.12 mmol) of 2,4-dimethoxyphenylsulfonyl chloride were added, and stirring was continued at room temperature for 30 min. The reaction mixture was poured into ice-water and then extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by chromatography on silica gel (Redisep cartridge, mobile phase gradient from 0 to 20% methanol in dichloromethane). 34 mg of the title compound were obtained as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:2].[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[O:21]=[C:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[S:16][C:1]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: COC(=O)c1cccc(C#N)c1
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(-c2nc(=O)c3ccccc3s2)c1
Temperature: 145 °C
Reaction time: 22 h
Yield: 29.1 %

Procedure:
A mixture of methyl 3-cyanobenzoate (967 mg, 6.00 mmol), methyl thiosalicylate (1.51 g, 8.98 mmol), triethylamine (1.5 ml, 11 mmol) and xylene (6 mL) was stirred at 145° C. for 22 hours under a nitrogen flow. After the reaction mixture was allowed to cool, the crystals were taken by filtration and recrystallized from methanol to give the title compound (519 mg, 29%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26]>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2)(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1S(=O)(=O)c1ccccc1Cl

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-chlorobenzene sulfonyl chloride were used for a similar reaction and treatment as Example 169, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=2)[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]1C=CC=CC=1.CO.C[Si](C=[N+]=[N-])(C)C>CCCCCC>[C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=2)[C:10]([O:12][CH3:16])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccnc(-c2ccccc2)c1
Reactant: c1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1ccnc(-c2ccccc2)c1
Reaction time: 6 h

Procedure:
Preparation H1, Step 2: A solution of 2-phenylisonicotinic acid (459 mg, 2.30 mmol) in 9:1 benzene/methanol (20 mL) was cooled to 0° C., and treated with the dropwise addition of a 2.0 M hexane solution of (trimethylsilyl)diazomethane (1.15 mL, 2.30 mmol). The mixture was allowed to come to room temperature and stirred for 6 h. Analysis by TLC indicated incomplete reaction, so the mixture was treated with additional (trimethylsilyl)diazomethane solution (230 μL, 0.23 mmol), and the reaction was stirred for an additional 2 h. TLC of the mixture remained unchanged. The solvent was stripped, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The layers were separated, the organic phase was washed 2× with saturated sodium bicarbonate, the combined aqueous phases were extracted with ethyl acetate, and the combined organic phases were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified over silica gel, eluting with 20% ethyl acetate/heptane, to yield 372 mg of methyl 2-phenylisonicotinate as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.83 (d, J=5.27 Hz, 1 H), 8.29 (s, 1 H), 8.04 (d, J=7.03 Hz, 2 H), 7.77 (d, J=3.52 Hz, 1 H), 7.51-7.42 (m, 3 H), 3.98 (s, 3 H).
Reaction SMILES: C(#[N:3])C.[Cl:4][C:5]1[C:6]([F:14])=[N:7][C:8]([F:13])=[C:9]([F:12])[C:10]=1F.N>O>[NH2:3][C:10]1[C:9]([F:12])=[C:8]([F:13])[N:7]=[C:6]([F:14])[C:5]=1[Cl:4]
Reactant: Fc1nc(F)c(Cl)c(F)c1F
Reactant: CC#N
Agent: N
Solvent: O
Product: Nc1c(F)c(F)nc(F)c1Cl
Reaction time: 0.5 h

Procedure:
To 100 ml of acetonitrile was dissolved 20.5 g of 3-chloro-2,4,5,6-tetrafluoropyridine, and 30 ml of 25% aqueous solution of ammonia was added in three portions while the mixture was stirred and cooled with water, and the stirring was continued for another 30 minutes. The solution was concentrated under reduced pressure. After adding 200 ml of chloroform to the solid residue, the solution was washed with 50 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the precipitate was collected by filtration to obtain 16.6 g of the title compound as colorless flake crystals.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11](Cl)([Cl:13])=[O:12]>C1C=CC=CC=1>[C:1]1([S:7][CH2:8][CH2:9][O:10][C:11]([Cl:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cl
Reactant: OCCSc1ccccc1
Solvent: c1ccccc1
Product: O=C(Cl)OCCSc1ccccc1

Procedure:
A solution of 2-phenylthioethanol (3 g, 19 mmol) in benzene (5 mL) was added dropwise, at room temperature, to a solution of phosgene (1 mL, 1.9 M toluene, 1.9 mmol). After stirring for 3 h the excess phosgene and solvents were removed under vacuum to give 2-phenylthioethyl-chloroformate as a yellow oil which was used without further purification. A solution of alcohol 24 (27 mg, 45 μmol) and DMAP (38 mg, 0.31 mmol)in CH2Cl2 (5 mL) was treated, at 0° C., with 2-phenylthioethyl-chloroformate (38 mg, 0.18 mmol) and the mixture was stirred for 4 h. The reaction mixture was poured into brine (10 mL), extracted with CH2Cl2 (3×5 mL), dried (Na2SO4), concentrated, and purified by preparative TLC (20% EtOAc in benzene) to give carbonate 26 (30.7 mg, 88%):pale yellow oil; Rf =0.69 (20% EtOAc in benzene); [α]25D -150 (c0.20, CH2Cl2); IR (neat) νmax 2954, 2876, 1738, 1721, 1492, 1458, 1257, 1164 cm-1 ; 1H NMR (500 MHz, CDCl3) 7.41-7.40 (m, 2 H, Ph), 7.40-7.27 (m, 2 H, Ph), 7.26-7.19 (m, 1 H, Ph), 6.10 (rid, J=3.27, 9.02 Hz, 1 H, C=CHCH2), 5.87 (d, J=9.71 Hz, 1 H, CH=CHC≡CCH), 5.77 (b d, J=9.71 Hz, 1 H, CH=CHC≡CCH), 5.77 (b s, 1 H, CHOSi), 4.88 (dd, J=3.33, 13.52 Hz, 1 H, CHHOCO), 4.79 (dd, J=9.04, 13.54 Hz, 1 H, CHHOCO), 4.28-4.23 (m, 2 H, OCOCH2CH2SPh), 4.10-4.07 (m, 1 H, ehtylene ketal), 3.99-3.91 (m, 2 H, ethylene ketal), 3.88-3.84 (m, 1 H, ethylene ketal), 3.18 (dd, J=7.23, 7.40 Hz, 2 H, OCOCH2CH2SPh), 2.48 (d, J=13.24 Hz, 1 H, CHH-eq), 2.11 (d, J=13.25 Hz, 1 H, CHH-ax), 1.00-0.96 (m, 18 H, 2 x (Si(CH2CH3)3)), 0.79-0.67 (m, 12 H, 2 x (Si(CH2CH3)3)); 13C NMR (125 MHz, CDCl3) δ154.70, 138.17, 129.81, 129.07, 126.58, 124.11, 122.91, 122.46, 105.72, 68.04, 65.75, 65.52, 65.22, 63.71, 52.34, 31.95, 29.70, 7.07, 6.72, 6.16, 4.53; FAB HRMS (NBA/Csl) m/e 914.2180, (M+Cs+) calcd for C40H55NO9SSi:914.2190.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20]C(=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([F:38])[CH:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:27][C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([F:38])[CH:29]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: COC(=O)c1ccc(CBr)cc1F
Product: COC(=O)c1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1F

Procedure:
Use a method similar to the Example 428, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and methyl 4-bromomethyl-2-fluorobenzoate, to give the desired intermediate as a white solid.