Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)C.Cl.N1C=CC=CC=1C(Cl)=O.[CH2:34]([N:36]([C:45]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:46]=1[CH:53]1[CH2:62][CH2:61][C:60]2[C:55](=[CH:56][CH:57]=[C:58]([O:63][CH3:64])[CH:59]=2)[CH2:54]1)[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)=O)[CH3:35]>>[CH2:34]([N:36]([C:45]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:46]=1[CH:53]1[CH2:62][CH2:61][C:60]2[C:55](=[CH:56][CH:57]=[C:58]([O:63][CH3:64])[CH:59]=2)[CH2:54]1)[CH2:37][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)[CH3:35]
Reactant: CCN(C(=O)c1ccccn1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Agent: O=C(Cl)c1ccccn1
Product: CCN(Cc1ccccn1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Yield: 80.2 %

Procedure:
Synthesized from ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine and picolinoyl chloride hydrochloride according to an analogous synthetic method to Preparation Example 87, pyridine-2-carboxylic acid ethyl [5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amide (129 mg) was used according to an analogous synthetic method to Example 337 described below to provide ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]pyridin-2-ylmethylamine (100 mg). This compound (93 mg) was used according to an analogous synthetic method to Example 111 described below to provide the title compound (108 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18]>ClCCl.C1(C)C=CC=CC=1>[C:11]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH:20][C:21]([NH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1)=[O:22])(=[O:19])=[O:18]
Reactant: O=C=NS(=O)(=O)c1ccccc1-c1ccccc1
Reactant: COc1cc(C)nc(N)n1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 86.9 %

Procedure:
13.9 g of 2-amino-4-methoxy-6-methylpyrimidine were dissolved in 150 ml of dry dichloromethane. To this solution was added dropwise a solution of 28.5 g of 2-biphenylylsulfonyl isocyanate in 40 ml of toluene over an hour. During this addition, the internal temperature was maintained at room temperature. When the addition was finished, the mixture was stirred at room temperature for 10 hours to complete the reaction. After completion of the reaction, the mixture was concentrated to about half the volume by evaporating dichloromethane under reduced pressure. The resultant colorless crystals were filtered. The crystals were then washed with a small amount of ether and dried to obtain 34.6 g of N-2-biphenylylsulfonyl-N'-(4-methoxy-6-methylpyrimidin-2-yl) urea; m.p. 199°-202° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([NH:21][C@@H:22]1[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]1[OH:24])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>O.C1COCC1>[C@@H:22]1([N:21]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:33](=[O:36])[CH:34]=[CH2:35])[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]1[OH:24]
Reactant: C=CC(=O)Cl
Reactant: CCCCCCCCCCCCCCN[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)N(CCCCCCCCCCCCCC)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
A solution of 85 mmol (9 g) of sodium carbonate in 25 ml of water is added to a solution of 13.7 mmol (4 g) of N-tetradecyl-β-D-glucopyranosylamine in 190 ml of THF. A solution of 26 mmol (2.0 ml) of acryloyl chloride in 20 ml of THF is added dropwise over one hour. The THF is evaporated off and the acylamidosugar is then extracted with 300 ml of ethyl acetate. The organic phase is washed with a saturated solution of NaHCO3, dried over MgSO4 and evaporated at reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.Cl.[CH3:32][O:33][C:34]([CH:36]1[CH2:40][CH2:39][CH2:38][NH:37]1)=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl.O1CCCC1>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][N:37]3[CH2:38][CH2:39][CH2:40][CH:36]3[C:34]([O:33][CH3:32])=[O:35])[CH:8]=2)[N:3]=1
Reactant: COC(=O)C1CCCN1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: C1CCOC1
Product: COC(=O)C1CCCN1Cc1ccccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
500 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 5 ml of 1,2-dichloroethane and 5 ml of tetrahydrofuran. 314 mg of methylpyrrolidine-2-carboxylate hydrochloride are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 566 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:21]([I:22])=[CH:20][C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1.Cl[C:24]1[CH:33]=[CH:32][C:27]([C:28]([NH:30][CH3:31])=[O:29])=[CH:26][N:25]=1>CS(C)=O.O.ClCCl>[I:22][C:21]1[C:4]([O:3][C:24]2[CH:33]=[CH:32][C:27]([C:28]([NH:30][CH3:31])=[O:29])=[CH:26][N:25]=2)=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)c(I)cc2CC1
Reactant: CNC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(Oc2cc3c(cc2I)CCN(C(=O)OC(C)(C)C)CC3)nc1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% disp. in mineral oil, 240 mg, 6 mmol) was added to a stirred solution of 1,1-dimethylethyl 7-hydroxy-8-iodo-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (D41) (1.94 g, 5 mmol) in dimethyl sulfoxide (10 ml). After 10 minutes, 6-chloro-N-methyl-nicotinamide (D10) (850 mg, 5 mmol) was added and the reaction mixture was heated to 100° C. for 20 hours. After cooling to room temperature the reaction mixture was diluted with water and dichloromethane. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (1:1 ethyl acetate:hexanes) to afford the title product (D42).
Reaction SMILES: [C:1]([C:5]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:6]=1[O:7][CH:8]1[CH2:11][N:10]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=2)=[O:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][Mg]I>C(OCC)C>[C:1]([C:5]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:6]=1[O:7][CH:8]1[CH2:11][N:10]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])([CH3:28])[CH3:21])=[CH:16][CH:15]=2)=[O:13])[CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Mg]I
Reactant: CC(=O)c1ccc(C(=O)N2CC(Oc3ccc(F)cc3C(C)(C)C)C2)cc1
Solvent: CCOCC
Product: CC(C)(C)c1cc(F)ccc1OC1CN(C(=O)c2ccc(C(C)(C)O)cc2)C1
Temperature: 0 °C
Yield: 56.8 %

Procedure:
To a stirred suspension of 1-(4-(3-(2-tert-butyl-4-fluorophenoxy)azetidin-1-carbonyl)phenyl)ethanone (0.14 g, 0.37 mmol) in diethyl ether (2.0 mL) was added methyl magnesium iodide (0.25 mL, 3.0 M in diethyl ether, 0.75 mmol) dropwise at room temperature. The resulting reaction mixture was heated to reflux for 1.5 h. After this reaction mixture was cooled to 0° C., diluted with diethyl ether, quenched with 1 N hydrochloric acid (2 ml) and the reaction mixture was stirred until the solids disappeared. The organic layer was separated and washed with water (2×2.0 mL), dried (Na2SO4), filtered and the filtrate was directly purified by flash column chromatography (silica gel, 50:50 ethyl acetate/heptane) to provide (3-(2-tert-butyl-4-fluorophenoxy)azetidine-1-yl)(4-(2-hydroxypropan-2-yl)phenyl)methanone (0.081 g, 57%) as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:10]([N:12]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]#[N:28])[CH:25]=3)[NH:20][CH:19]=2)[CH2:13]1)=O)C.O.[OH-].[Na+]>O1CCCC1>[CH3:10][N:12]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][NH2:28])[CH:25]=3)[NH:20][CH:19]=2)[CH2:13]1
Reactant: CCOC(=O)N1CCC(Cc2c[nH]c3ccc(C#N)cc23)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(Cc2c[nH]c3ccc(CN)cc23)C1
Temperature: 20 °C
Yield: 72 %

Procedure:
A suspension containing 158 mmol of lithium aluminum hydride in 150 ml of tetrahydrofuran is added at 20° C. to 15.8 mmol of the compound of Example 20 in 50 ml of tetrahydrofuran. The combined mixture is maintained for 9 hours at 20° C. and then hydrolyzed with 30 ml of water and 12 ml of 10% sodium hydroxide solution. After filtration and evaporation, the expected product is obtained in the form of an oil.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:35]=[CH:34][C:33]([N:36]([CH3:40])[C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=1>>[C:37]([N:36]([CH3:40])[C:33]1[CH:34]=[CH:35][C:30]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH2:16][NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]3)[CH:18]=2)=[CH:31][CH:32]=1)(=[O:39])[CH3:38]
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)N(C)c1ccc(Br)cc1
Product: COc1ccc(-c2ccc(N(C)C(C)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (650 mg, 1.04 mmol) is coupled to aryl bromide 62 (238 mg, 1.04 mmol) using Method A to give the title compound.
Reaction SMILES: Cl.Cl.[OH:3][CH:4]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C@@H:8]1[CH2:21][C:22]([O:24]C)=[O:23].[OH-].[Na+]>O1CCOCC1>[OH:3][CH:4]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C@@H:8]1[CH2:21][C:22]([OH:24])=[O:23]
Reactant: COC(=O)C[C@H]1CN(CCSc2cccs2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CCSc4cccs4)C[C@@H]3CC(=O)O)c2c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 95.5 %

Procedure:
A mixture of 0.22 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetate dihydrochloride in 5 cm3 of dioxane, to which had been added 0.683 cm3 of 5N aqueous sodium hydroxide solution, was stirred for 20 hours at a temperature in the region of 60° C. After evaporating under reduced pressure (5 kPa) at a temperature in the region of 40 ° C., the residue obtained was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45 μ; diameter 1 cm; silica volume 20 cm3), elution was carried out with a chloroform/methanol/aqueous ammonia (12/3/1 by volume) mixture. Fractions 1 to 3 were combined and concentrated under the above conditions. A product was obtained, which product was dried in an oven to constant weight under reduced pressure (10 Pa) at a temperature in the region of 40° C. 0.179 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin4-yl)propyl]-1-[2-(2-thienylthio)-ethyl]piperidine-3-acetic acid was obtained in the form of a white foam which was a mixture of two diastereoisomers.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1.[CH3:22][O:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:25]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:22][O:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[N:11]=[CH:10][CH:9]=2)[CH:27]=1)=[O:25]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: FC(F)(F)c1ccc2nccc(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(-c2ccnc3ccc(C(F)(F)F)cc23)c2ccccc12
Temperature: 100 °C
Reaction time: 20 h
Yield: 84.6 %

Procedure:
1.04 g (7.5 mmol) of potassium carbonate and 0.695 g (3 mmol) of 4-chloro-6-(trifluoromethyl)quinoline are added to 0.525 g (3 mmol) of 3-methoxycarbonyl-1H-indole in 10 cm3 of dimethylformamide under an argon atmosphere. After stirring at a temperature in the region of 100° C. for 20 hours, the reaction mixture is cooled and diluted with 100 cm3 of ethyl acetate and 100 cm3 of water. The organic phase is separated off by settling and washed with twice 100 cm3 of water and 100 cm3 of saturated aqueous sodium chloride solution and then it is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa), resulting in an orange-coloured oil. This oil is triturated in 20 cm3 of isopropyl ether and the resulting precipitate is filtered off, giving 0.94 g of 3-methoxycarbonyl-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole in the form of a yellow powder. Mass spectrum (EI): m/e 370 (M+•), m/e 339.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[C:6]1([S:12][CH:13]([S:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]2[C:19]([O:20][Si](C(C)(C)C)(C)C)=[CH:18][CH2:17][CH2:16][CH2:15]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[C:6]1([S:12][CH:13]([S:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]2[CH2:15][CH2:16][CH2:17][CH:18]([CH:13]([S:12][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[S:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:19]2=[O:20])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)OC1=CCCCC1C(Sc1ccccc1)Sc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C1C(C(Sc2ccccc2)Sc2ccccc2)CCCC1C(Sc1ccccc1)Sc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
400 mg (1.18 mmol) of 1,1′,1″-(methanetriyltrisulphanediyl)tribenzene are dissolved in 25 ml of dichloromethane, and the mixture is cooled to −78° C. 1.41 ml (1.41 mmol) of tin(IV) tetrachloride solution (1 M in dichloromethane) and 520 mg (1.18 mmol) of (({6-[bis(phenylsulphanyl)methyl]-cyclohex-1-en-1-yl}oxy)(tert-butyl)dimethylsilane) are added in succession, and the mixture is stirred at −78° C. for 1 h. The reaction mixture is poured into ice-water and extracted with dichloromethane. After washing with water, the organic phase is dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate) gives 341 mg of 2,6-bis[bis(phenylsulphanyl)methyl]cyclohexanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1>ClCCl.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9]=[O:10])=[C:6]([OH:8])[CH:7]=1
Reactant: OCc1ccc(Cl)cc1O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
2,3-Dichloro-5,6-dicyano-1-4-benzoquinone (DDQ, 9.92 g, 43.7 mmol) was added to a solution of 5-chloro-2-hydroxymethylphenol in dichloromethane (65 mL) and tetrahydrofuran (15 mL). The reaction mixture was stirred at room temperature for 4 h. Then, the solvent was evaporated under vacuum and the crude was purified by chromatography on silica to afford the title compound (72%):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10](=O)[C:11](=[N:19]O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]=[CH:6][CH:7]=1.[CH3:22][CH2:23][O:24][C:25]([CH2:27][C:28]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=O)=[O:26].C([O-])(=O)C.[Na+]>[Zn].C(O)(=O)C>[C:15]([O:14][C:12]([C:11]1[NH:19][C:28]([CH2:27][C:25]([O:24][CH2:23][CH3:22])=[O:26])=[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:10]=1[CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)CCc1cccc(Cl)c1
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1[nH]c(C(=O)OC(C)(C)C)c(CCc2cccc(Cl)c2)c1C(=O)OCC
Reaction time: 1.5 h
Yield: 30.9 %

Procedure:
Crude t-butyl 5-(m-chlorophenyl)-2-hydroximino-3-oxopentanoate (43 g., 0.15 mol) and diethyl acetonedicarboxylate (28 ml, 30.3 g, 0.15 mol) are placed in a 1 liter round bottom flask and 250 ml of glacial acetic acid added. With stirring, 25 g (0.30 mol) anhydrous sodium acetate is added followed by 26 g Zn dust (94% fine, 0.364 mol) in a portionwise manner so that the exotherm does not bring the reaction to reflux. When addition is complete, the reaction is heated on a steam bath for one hour. The hot solution is then decanted from the residual zinc into 3 liters of ice water, and the resulting mixture is stirred vigorously until the oil solidifies. The mixture is then allowed to stand for 1.5 hours, and the solid is filtered. The solid is washed with water, dried in vacuo and recrystallized to give 21.5 g (31%) of ethyl 5-(t-butoxycarbonyl)-4-[2-(m-chlorophenyl)ethyl]-3-ethoxycarbonylpyrrole-2-acetate, M.P. 131°- 132°.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:17][CH:16]3[C:18]([O:20]CC)=[O:19])=[CH:11][CH:10]=2)[O:3]1.[Li+].[OH-]>C1COCC1.O>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:23])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:17][CH:16]3[C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)[O:5]1
Reactant: CCOC(=O)C1CC1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(c2ccc(C3CC3C(=O)O)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ester from step 2 in THF-H2O (0.2M) was added LiOH (3 eq, 2M) and the mixture was stirred at rt for 18 h. The organic solvent evaporated, aqueous was acidified with HCl 1N and the acid extracted with EtOAc (3×). The organic was washed with brine, dried and solvent evaporated to afford the title carboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:19][C:20]1[CH:21]=[C:22]([NH:27]C(=O)OC(C)(C)C)[CH:23]=[CH:24][C:25]=1[OH:26]>CN(C)C=O>[F:19][C:20]1[CH:21]=[C:22]([NH2:27])[CH:23]=[CH:24][C:25]=1[O:26][C:2]1[CH:7]=[N:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c(F)c1
Reactant: CCS(=O)(=O)c1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(Oc2ccc(N)cc2F)cn1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
10.9 g of 5-chloro-2-ethanesulfonyl-pyridine and 1.6 g of cesium carbonate were added to a dimethylformamide (150 ml) solution of 10.0 g of tert-butyl (3-fluoro-4-hydroxy-phenyl)-carbamate obtained in Example 196 (step 1), and the reaction liquid was stirred at 100° C. for 3 hours. The solvent was evaporated away under reduced pressure, diluted with chloroform, washed with aqueous saturated sodium bicarbonate, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/9) to obtain a crude product. The resulting crude product was dissolved in 4 N hydrochloric acid/dioxane, and stirred at room temperature for 1 hour. The solvent was evaporated away under reduced pressure, diluted with chloroform, washed with water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/9) to obtain the entitled compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH2:28][CH2:27][CH2:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O1CCCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:24]1([C:2]2[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[S:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=2)[CH2:28][CH2:27][CH2:26][CH:25]=1
Reactant: OB(O)C1=CCCC1
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)/C=C/c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)/C=C/c1ccc(C2=CCCC2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 68.7 %

Procedure:
2-[[(E)-2-(4-Bromophenyl)ethenylsulfonylamino]benzenesulfonamide (75 mg, 0.18 mmol), cyclopenten-1-ylboronic acid (40.2 mg, 0.36 mmol), (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (14.79 mg, 0.02 mmol) and sodium carbonate (38.1 mg, 0.36 mmol) were suspended in N,N-dimethylformamide (2 mL) and the reaction mixture was stirred under an atmosphere of argon at 90° C. for 16 hours. The reaction mixture was diluted with tetrahydrofuran and filtered through Celite. The solvent was removed in vacuo and the residue was purified by preparative HPLC. The residue was purified a second time by column chromatography, using gradient mixtures of ethyl acetate/heptane as eluent (0%-100% ethyl acetate) to give 50 mg (69% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:42])[C:18]([N:20]([CH2:24][CH2:25][N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27][C:28]#[C:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[CH:21]([CH3:23])[CH3:22])=[O:19])[CH:9]2[C:12]([O:14]CC)=[O:13])=[CH:4][C:3]=1[O:43][CH3:44].[OH-].[K+].Cl>O1CCOCC1.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:42])[C:18]([N:20]([CH2:24][CH2:25][N:26]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:27][C:28]#[C:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[CH:21]([CH3:22])[CH3:23])=[O:19])[CH:9]2[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[O:43][CH3:44]
Reactant: CCOC(=O)C1c2cc(Br)c(OC)cc2CCN1C(=O)C(=O)N(CCN(CC#Cc1cccs1)C(=O)OC(C)(C)C)C(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(CCN(CC#Cc1cccs1)C(=O)OC(C)(C)C)C(C)C)CC2
Temperature: 45 °C
Reaction time: 5 h

Procedure:
A solution of 250 mg of 10j in 6 ml of dioxane was mixed with a solution of 120 mg of KOH in 1 ml of water and the reaction mixture was stirred for 5 h at 45° C. The mixture was diluted with 20 ml of water and acidified to pH3 with 0.5N HCl. The product was extracted into ethyl acetate. The organic layer was washed twice with water, dried and concentrated, to give 220 mg of amorphous 10k.