Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[OH:18])[CH:3]=1.F[B-](F)(F)F.[CH3:24][O+](C)C.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[O:18][CH3:24])[CH:3]=1
Reactant: C[O+](C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1O[C@@H]1CCCC[C@H]1O
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Product: CO[C@@H]1CCCC[C@H]1Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R,R)-4-fluoro-2-(2-hydroxycyclohexyloxy)-nitrobenzene (0.200 g) dissolved in methylene chloride (10.0 ml) was added trimethyloxonium tetrafluoroborate (0.348 g). The mixture was stirred overnight at rt. Water was added; the organic phase was separated and evaporated to dryness to yield a brownish oil.
Reaction SMILES: [O:1]=[C:2]([CH3:6])[CH2:3][CH2:4][OH:5].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>O1CCCC1>[O:1]=[C:2]([CH3:6])[CH2:3][CH2:4][O:5][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)CCO
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)CCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To 400 ml of tetrahydrofuran in a reactor, 15.0 g (0.17 mol) of 3-oxo-1-butanol and 26.3 g (0.19 mol) of benzoyl chloride were dissolved, followed by drop-wise adding 20.6 g (0.20 mol) of triethylamine under ice-cooling. After the end of drop-wise addition, the reaction liquid was stirred at room temperature for 3 hours. Hydrochloric acid salt of triethylamine was filtered, followed by adding water to the filtrate and extracting with ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium carbonate, water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:5 to 1:3) to obtain 31.5 g (yield: 96%) of 3-oxobutylbenzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=[C:5]([C:19]([OH:21])=[O:20])[CH:4]=1.[N+](=[CH2:24])=[N-]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=[C:5]([C:19]([O:21][CH3:24])=[O:20])[CH:4]=1
Reactant: C=[N+]=[N-]
Reactant: COc1cc(C(=O)O)cc2c1C(=O)c1ccccc1CC2
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(c(OC)c1)C(=O)c1ccccc1CC2

Procedure:
4-Methoxy-10,11-dihydro-5-oxo-5H-dibenzo[a.d]cycloheptene-2-carboxylic acid (4.0 g) is dissolved in dimethylformamide (30 ml) and to the solution is added excess ethereal diazomethane. The mixture is evaporated to low volume, poured into water and extracted with ethyl acetate. The extract is washed, dried and evaporated to yield methyl 4-methoxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylate. 1.0 G of this compound is refluxed for 1 hour in carbon tetrachloride (50 ml) containing N-bromosuccinimide (0.635 g) while irradiating the mixture with a 100 watt incandescent lamp. The solution is cooled, filtered and evaporated. The residue is dissolved in dimethylformamide (10 ml) and 1,5-diazabicyclo[4.3.0]non-5-ene (1.0 ml) is added. The mixture is heated to 70° for 30 minutes then cooled and poured into water. The solution is extracted with ethyl acetate, and the extract washed, dried and evaporated to afford methyl 4-methoxy-5-oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylate. This material is refluxed for 3 hours in water (10 ml) and methanol (2.5 ml) containing sodium hydroxide (0.5 g). The cooled solution is acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The extract is dried and evaporated. The residue is recrystallized from aqueous methanol to afford 4-methoxy-5-oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid, mp 252°-253°.
Reaction SMILES: [C:1]1([NH:7]C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:14]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 230.7 %

Procedure:
830 mg (2.44 mmole) of the aniline compound obtained in step 1 was dissolved in 10 mL of pyridine, 0.340 mL (2.93 mmoles) of benzoylchloride was added, and the mixture was stirred overnight at room temperature. When the reaction had ended, the solvent was removed under reduced pressure. Ethyl acetate and 1N HCl aqueous solution were added to the residue. The mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure, yielding 1.11 g of N-benzoylaniline compound.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9](Cl)=[O:10])=[CH:3][CH:2]=1.[N-:13]=[N+:14]=[N-:15].[Na+].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O1CCOCC1.O.O1CCOCC1>[C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]([N:13]=[N+:14]=[N-:15])=[O:10])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C=CC(=O)Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C=CC(=O)N=[N+]=[N-])cc1
Temperature: 7.5 °C
Reaction time: 1.5 h

Procedure:
3-p-Tolyl-acryloyl chloride (22.3 g, 123.3 mmol) in dioxane (50 mL) is slowly added to an ice cooled solution of sodium azide (16 g, 246.6 mmol) in water/dioxane (50 mL, 1/1, v/v) so as to maintain the temperature between 5-10° C. The mixture is stirred for 1.5 hours then poured over 300 g of ice. The resulting white solid is filtered and washed with additional water. The solid (20.72 g, 110.7 mmol) was dried over P2O5 under vacuum overnight and used in the next step without further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:11]=[CH:10][NH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:16])[CH3:15]>C1COCC1.CN(C=O)C>[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:9]3[CH:10]=[CH:11][C:7]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])=[CH:8]3)(=[O:35])=[O:36])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(NC1CC1)c1cc[nH]c1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)NC4CC4)c3)ccc2n1CC1CCOCC1
Yield: 51.3 %

Procedure:
Following the same procedure in Example 29, using N-cyclopropyl-1H-pyrrole-3-carboxamide (49 mg, 0.33 mmol) (see following step B for preparation), sodium hydride (100 mg, 60%, 2.5 mmol) and 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (122 mg, 0.33 mmol) in THF (6 mL) and DMF (0.5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:4) on silica gel to give 82 mg (51%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.50-0.56 (m, 2 H), 0.69-0.76 (m, 2 H), 1.40-1.57 (m, 4 H), 1.59 (s, 9 H), 2.29 (m, 1 H), 2.67-2.76 (m, 1 H), 3.24-3.34 (m, 2 H), 3.84-3.93 (m, 2 H), 4.41 (d, J=7.42 Hz, 2 H), 6.64 (dd, J=3.32, 1.56 Hz, 1 H), 7.27 (dd, J=3.32, 2.34 Hz, 1 H), 7.78-7.82 (m, 1 H), 7.90 (d, J=9.0 Hz, 1 H), 7.94 (dd, J=8.6, 1.5 Hz, 1H), 8.25 (d, J=1.56 Hz, 1 H); MS (ESI) (M+H)+=484.7; Anal. Calcd for C25H32N4O4S+1.10 TFA+0.10H2O (611.88): C, 53.40; H, 5.49; N, 9.16. Found: C, 53.44; H, 5.53; N, 9.18.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].[CH2:7]([O:9][CH:10]=[CH2:11])[CH3:8].CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C(OCC)C>[CH2:7]([O:9][CH:10]([O:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH3:11])[CH3:8]
Reactant: C=COCC
Reactant: COC(=O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(C)OCC(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
A solution of methyl glycolate (0.193 g, 2.15 mmol) in THF (21 ml) was treated with ethylvinyl ether (EVE) (1.03 ml, 10.7 mmol) and a catalytic amount of p-TsOH (41 mg). After stirring for 15 min at 0° C., the mixture was diluted with ethyl ether, washed with saturated NaHCO3 aqueous solution, brine, dried (Na2SO4) and evaporated to give methyl (1-ethoxyethoxy)acetate (0.306 g, 87%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1>>[CH2:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:25][CH:17]1[NH:16][C:2]1[C:3]2[C:10]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NC1Cc2ccccc2C1
Reactant: Clc1ncnc2scc(-c3cccs3)c12
Product: c1csc(-c2csc3ncnc(NC4Cc5ccccc5C4)c23)c1
Yield: 100 %

Procedure:
Using 4-chloro-5-(2-thienyl)thieno[2,3-d]pyrimidine (50 mg, 0.20 mmol) and 2-aminoindan (110 mg, 0.80 mmol), a similar procedure to Example 1 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (70 mg, 0.20 mmol) having the following physical properties:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:27])=[N:5][C:6]([CH2:9][S:10](/[CH:13]=[CH:14]/[C:15]2[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=2[O:25][CH3:26])(=[O:12])=[O:11])=[CH:7][CH:8]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([NH:27][S:29]([CH3:28])(=[O:31])=[O:30])=[N:5][C:6]([CH2:9][S:10](/[CH:13]=[CH:14]/[C:15]2[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=2[O:25][CH3:26])(=[O:11])=[O:12])=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(N)n2)c(OC)c1
Solvent: c1ccncc1
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(NS(C)(=O)=O)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 5 %

Procedure:
To a mixture of (E)-3-methoxy-6-((2,4,6-trimethoxystyrylsulfonyl)methyl)pyridin-2-amine (333 mg, 0.84 mmol) in dry pyridine (20 mL) cooling on an ice bath methanesulfonyl chloride (0.3 mL, 2 mmol) was added dropwise. The mixture was stirred at room temperature for 20 hours. After evaporated to dryness, the residue was purified by silica gel chromatography, eluting with PE/EtOAc (1:1 v/v) to afford 20 mg of the title compound as white powder. 1H-NMR (DMSO-d6): δ 3.26 (s, 3H, OCH3), 3.82 (s, 3H, CH3), 3.85 (s, 9H, 3×OCH3), 4.45 (s, 2H, CH2), 6.30 (s, 2H, Ph-H), 7.14 (d, 1H, J=15.6 Hz, CH), 7.15 (d, 1H, J=8.8 Hz, Py-H), 7.41 (d, 1H, J=8.4 Hz, Py-H), 7.56 (d, 1H, J=15.6 Hz, CH), 9.73 (s, 1H, NH).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[OH:23][C:24]1([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1>>[OH:23][C:24]1([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH2:25][CH2:26][CH:27]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=4)[NH:11][N:10]=3)[CH2:4]2)[CH2:28][CH2:29]1
Reactant: O=C1CCC(O)(c2cccnc2)CC1
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Product: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(O)(c3cccnc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in the previous step) and 4-hydroxy-4-pyridin-3-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25](Cl)=[O:26]>ClCCl>[NH2:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([C:25]([C:24]3[C:23]([Cl:22])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:32])=[O:26])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(C2CCNCC2)c1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1cccc(C2CCN(C(=O)c3c(Cl)cccc3Cl)CC2)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 46.9 %

Procedure:
To an ice-cooled solution of 4-(3-aminophenyl)-piperidine hydrochloride (250.2 mg, 1.0 mmol) and triethylamine (1 mL) in dichloromethane (6 mL) is added 2,6-dichlorobenzoic chloride (0.15 mL, 1.0 mmol). The reaction mixture is stirred at 0° C. for 6 hours. After removal of solvent, the residue is purified on a silica gel chromatography with ethyl acetate-hexanes to provide a white solid (163.9 mg, 46.9% yield, ES+(m/z) 349.1 [M+H]).
Reaction SMILES: [F-].[K+].[CH3:3][O:4][CH:5]([O:12][CH3:13])/[CH:6]=[CH:7]\[C:8]([O:10][CH3:11])=[O:9].[C:14]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=[O:17]>C(O)(C)(C)C>[C:21]([O:20][C:14]([CH:15]([C:16](=[O:17])[CH3:18])[CH:6]([CH:5]([O:12][CH3:13])[O:4][CH3:3])[CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)/C=C\C(OC)OC
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)CC(C(OC)OC)C(C(C)=O)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 48 h

Procedure:
Into a 500-ml reactor are placed 40 g of potassium fluoride, 40 ml of dry tert-butanol, 123 g of methyl cis-4,4-dimethoxy-2-butenate and 36 g of tert-butyl acetoacetate. The mixture is heated at 100° C. with stirring on an oil bath for two days. On completion of the reaction, the tert-butanol is distilled off from the mixture. The residue is dissolved in ethyl acetate, and the solution washed with an aqueous solution of common salt and then dried. The solvent is removed from the product. The resulting residue is purified by a silica gel column and distilled at reduced pressure, giving methyl 4-tert-butoxycarbonyl-3-dimethoxymethyl-5-oxohexanoate (compound (5), R1 =t-Bu, R2 =R3 =CH3) in a yield of 95.4%, b.p. 72°-76° C./0.014 mm Hg.
Reaction SMILES: [CH:1]([Si:4]([C:11]#[CH:12])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.O=O.[Br:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1>O1CCCC1.[Cu](I)I.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>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:12]#[C:11][Si:4]([CH:5]([CH3:6])[CH3:7])([CH:1]([CH3:3])[CH3:2])[CH:8]([CH3:10])[CH3:9])=[CH:25][CH:24]=1
Reactant: Brc1ccc(I)cc1
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: O=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)[Si](C#Cc1ccc(Br)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
11.6 mL triisopropylsilylacetylen and 14.4 mL triethylamine followed by 0.2 g copper iodide and 0.73 g bis-(triphenylphosphine)-palladium dichloride are added under argon to an oxygen-free solution of 15.0 g 4-bromo-1-iodo-benzene in 150 mL dry tetrahydrofuran. The solution is stirred for 16 h at ambient temperature and then filtered through Celite and evaporated down. The residue is purified by chromatography on silica gel (cyclohexane).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[NH:5][C:6](=[O:14])[CH:7]=[C:8]([S:12][CH3:13])[C:9]=1[C:10]#[N:11].Br[CH2:16][C:17]([NH2:19])=[O:18].Cl>CN(C=O)C>[C:10]([C:9]1[C:8]([S:12][CH3:13])=[CH:7][C:6](=[O:14])[NH:5][C:4]=1[S:3][CH2:16][C:17]([NH2:19])=[O:18])#[N:11]
Reactant: CSc1cc(=O)[nH]c(S)c1C#N
Reactant: NC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(=O)[nH]c(SCC(N)=O)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
NaH (2.60 g, 65.0 mmol) was added to a solution of 2-mercapto-4-methylsulfanyl-6-oxo-1,6-dihydro-pyridine-3-carbonitrile (12.5 g, 63 mmol) in DMF (300 mL) cooled in an ice water bath. The mixture was stirred for 30 min then 2-bromoacetamide was added (8.80 g, 64 mmol) as a solid in one portion. The mixture was slowly warmed to room temperature and stirred for 15 h then poured onto ice water. The mixture was acidified with 2N HCl, filtered, and the resulting precipitate was washed with diethyl ether then hexanes to provide 11.3 g (70%) of 2-(3-cyano-4-methylsulfanyl-6-oxo-1,6-dihydro-pyridin-2-ylsulfanyl)-acetamide as a tan solid.
Reaction SMILES: [CH2:1]([N:3]([CH3:17])[S:4]([C:7]1[CH:8]=[N:9][C:10]([Sn](C)(C)C)=[CH:11][CH:12]=1)(=[O:6])=[O:5])[CH3:2].[NH2:18][C:19]1[C:24]([C:25]2[S:33][C:28]3[C:29](=[O:32])[NH:30][CH2:31][C:27]=3[CH:26]=2)=[CH:23][C:22](Br)=[CH:21][N:20]=1>>[NH2:18][C:19]1[N:20]=[CH:21][C:22]([C:10]2[CH:11]=[CH:12][C:7]([S:4]([N:3]([CH2:1][CH3:2])[CH3:17])(=[O:6])=[O:5])=[CH:8][N:9]=2)=[CH:23][C:24]=1[C:25]1[S:33][C:28]2[C:29](=[O:32])[NH:30][CH2:31][C:27]=2[CH:26]=1
Reactant: CCN(C)S(=O)(=O)c1ccc([Sn](C)(C)C)nc1
Reactant: Nc1ncc(Br)cc1-c1cc2c(s1)C(=O)NC2
Product: CCN(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3cc4c(s3)C(=O)NC4)c2)nc1
Yield: 36.5 %

Procedure:
General method D was applied to N-ethyl-N-methyl-6-(trimethylstannyl)pyridine-3-sulfonamide (218 mg, 0.6 mmol) and 2-(2-amino-5-bromopyridin-3-yl)-4H-thieno[2,3-c]pyrrol-6(5H)-one (186 mg, 0.6 mmol) to give 6′-amino-N-ethyl-N-methyl-5′-(6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)-[2,3′-bipyridine]-5-sulfonamide as a yellow solid (94 mg, 38% yield) after purification by preparatory reverse phase HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (d, J=1.5 Hz, 1H), 8.87 (d, J=2.3 Hz, 1H), 8.44 (s, 1H), 8.26 (d, J=2.3 Hz, 1H), 8.10-8.20 (m, 2H), 7.43 (s, 1H), 6.65 (s, 2H), 4.35 (s, 2H), 3.30 (s, 4H), 3.09 (dd, J=14.3, 7.0 Hz, 2H), 2.72 (s, 3H), 1.06 (t, J=7.0 Hz, 3H); MS (EI) m/z=430 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].CS([C:15]1[S:19][N:18]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:16]=1)(=O)=O.C(O)(=O)C>O1CCCC1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][C:15]2[S:19][N:18]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:16]=2)=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)c1cc(C(F)(F)F)ns1
Reactant: CC(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(Cc1cc(C(F)(F)F)ns1)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
The oil of a 4.0 g (100 mmol) portion of 60 percent in mineral oil sodium hydride was removed by triple extraction with hexane and was replaced with 100 mL of tetrahydrofuran. 4-Chloroacetophenone (4.33 g, 28 mmol) was added and the mixture was heated at reflux with stirring for 1 hr and then allowed to cool. 5-Methylsulfonyl-3-(trifluoromethyl)isothiazole (4.57 g, 19.8 mmol) dissolved in a small amount of tetrahydrofuran was added and the mixture was heated at reflux with stirring for 3 hr and then allowed to cool. The mixture was next acidified with 60 mL of 10 percent aqueous acetic acid and the layers that formed were separated. The aqueous layer was extracted with 2×100 mL of ether and the organic fractions were combined, washed with aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a residue. This residue was washed with hexane and crystallized from a 1:1 mixture of dichloromethane and hexane to obtain 3.19 g (53 percent of theory) of the title compound as a solid melting at 109°-110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][NH2:16])[CH2:7][O:8]2.C(N(CC)CC)C.[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][NH:16][S:27]([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:7][O:8]2
Reactant: CCCN(CCN)C1COc2cccc(OC)c2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCNS(=O)(=O)c1ccc(C)cc1)C1COc2cccc(OC)c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
4 mmol of the compound prepared in Example 14 are dissolved in 30 ml of dichloromethane cooled in ice. 11.4 mmol of triethylamine are added dropwise, followed by 4 mmol of tosyl chloride dissolved in dichloromethane. The mixture is left stirring for 30 minutes at room temperature. The solvent is then evaporated off and the expected product is obtained after purification by chromatography on a silica column (elution solvent: dichloromethane).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].C([Li])(C)(C)C.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.P(=O)(O)(O)O>C1COCC1.CCCCC>[CH3:11][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:2]([B:17]([OH:22])[OH:18])[C:3]=2[CH:4]=[CH:5]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cn1ccc2c(Br)cccc21
Agent: O=P(O)(O)O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cn1ccc2c(B(O)O)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of Intermediate 67 (4.90 g) in anhydrous THF (30 ml) was cooled to −78° C. under argon gas atmosphere, then added dropwise with a 1.62 M solution of t-butyllithium in pentane (28.8 ml) over 30 minutes, and stirred for 30 minutes. This reaction mixture was added dropwise with (iPrO)3B (10.77 ml) over 10 minutes, stirred for 1 hour, then warmed to room temperature, and further stirred for 2.5 hours. The reaction mixture was poured into 1.2 N aqueous phosphoric acid (250 ml) containing ice, and extracted with diethyl ether (200 ml×3). The organic layer was extracted with 0.4 N aqueous sodium hydroxide (150 ml×3), and the aqueous layer was made acidic with 5 N hydrochloric acid under ice cooling, and extracted with diethyl ether (200 ml×3) again. The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was washed with hexane to obtain the title compound (Intermediate 68, 3.17 g).
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[OH:19][C:20]([CH3:26])([CH3:25])[C:21]([NH:23][NH2:24])=[O:22]>>[OH:19][C:20]([CH3:26])([CH3:25])[C:21]([NH:23]/[N:24]=[C:9]1\[C:7](=[O:8])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:16]2[C:11]\1=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)=[O:22]
Reactant: CCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Reactant: CC(C)(O)C(=O)NN
Product: CCCCCN1C(=O)/C(=N\NC(=O)C(C)(C)O)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin obtained in Example 39(A) and 2-hydroxy-2-methylpropanohydrazide according to the synthetic method E. NMR (CDCl3): δ 0.91 (t, 3H), 1.36 to 1.39 (m, 4H), 1.59 (s, 6H), 1.87 (m, 3H), 2.63 (s, 1H), 3.68 (t, 2H), 3.87 (s, 3H), 6.41 (d, 1H), 6.61 (dd, 1H), 7.73 (d, 1H), 13.71 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH:3]([OH:14])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O.S(=O)(=O)(O)O.[H][H]>C1COCC1.[Pd]>[NH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][CH:3]([OH:14])[C:2]([CH3:15])([CH3:1])[CH3:16]
Reactant: [H][H]
Reactant: CC(C)(C)C(O)Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CC(C)(C)C(O)Cc1ccccc1N

Procedure:
3 g (13.4 mmol) of 3,3-dimethyl-1-(2-nitrophenyl)butan-2-ol are stirred in 50 ml of THF with 2.06 g of 65 percent sulfuric acid and 0.214 g of palladium/carbon (10%) at 90° C. under 10 bar of hydrogen pressure for 16 hours. Subsequently, the solution is filtered with suction through Celite and the filtrate is concentrated by rotary evaporation. After dissolution in ethyl acetate, washing with saturated sodium bicarbonate solution, and removal and concentration of the organic phase under reduced pressure, 2.2 g (75% of theory) of a solid are obtained. Purity (GC-MS): 88%.