Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N+:11]([O-])=O)[CH2:3][CH2:2]1.C([O-])=O.[NH4+]>CO.[Pd]>[CH:1]1([NH:4][C:5]2[C:6]([NH2:11])=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1NC1CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1ccccc1NC1CC1
Yield: 97.4 %

Procedure:
To a solution of N-cyclopropyl-2-nitroaniline (365 mg, 2.05 mmol) and ammonium formate (516 mg, 8.2 mmol) in methanol was added catalytic amount of palladium on carbon (5%). The mixture was heated to reflux under a nitrogen atmosphere overnight and filtered. The filtrate was concentrated and purified by biotage column chromatography to give N1-cyclopropylbenzene-1,2-diamine (296 mg)
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.[C:23]([CH2:31][CH2:32][C:33](O)=[O:34])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>O1CCOCC1>[O:30]=[C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:31][CH2:32][C:33]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)=[O:34]
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: Cc1ccc(N)cc1
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)CCC(=O)c2ccccc2)cc1
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
EDC (347 mg, 1.81 mmol) and HOBT (254 mg, 1.88 mmol) were added to mixture of p-toluidine (129 mg, 1.20 mmol) and 3-benzoylpropionic acid 27 (218 mg, 1.21 mmol) in 1,4-dioxane (3 mL) at room temperature. It was stirred for 20 minutes and then added triethylamine (0.5 mL, 3.59 mmol). The reaction mixture was stirred for 20 h at room temperature and the solvent was evaporated under vacuum. The residue was purified by flash silica gel column chromatography (hexane:ethyl acetate=3:1 to 2:1) yielded the compound 28 (252 mg, 78%). 1H-NMR (CDCl3, 300 MHz) δ 2.30 (s, 3H), 2.80 (t, J=6.3 Hz, 2H), 3.45 (t, J=6.3 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.47 (m, 2H), 7.58 (m, 1H), 7.99 (m, 1H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:6]([Cl:16])=[CH:7][C:8]([F:15])=[C:9]([CH:14]=1)[C:10](OC)=[O:11])(=[O:4])=[O:3].[Cl-].[Cl-].[Ca+2].[BH4-].[Na+]>C1COCC1.CCO>[Cl:16][C:6]1[CH:7]=[C:8]([F:15])[C:9]([CH2:10][OH:11])=[CH:14][C:5]=1[S:2]([NH2:1])(=[O:3])=[O:4]
Reactant: COC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1F
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(CO)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.2 %

Procedure:
To a solution of methyl 5-(aminosulfonyl)-4-chloro-2-fluorobenzoate (500 mg, 1.87 mmol) in THF/EtOH (20 mL, 1:1), CaCl2 (415 mg, 3.74 mmol) and NaBH4 (283 mg, 7.48 mmol) were added in one portion respectively. The reaction mixture was stirred at room temperature for 6 hours, quenched with water. 1 M aqueous citric acid (5 mL) was added to the mixture and extracted with EtOAc (3×100 mL). The extracts were combined, washed with brine, and dried (Na2SO4). The solvent was evaporated to afford the product (440 mg, 98%) as a white solid. MS (ES+) m/z 262 [M+Na]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[Cl-].[Li+].[CH2:14](C([Sn])=C(CCCC)CCCC)[CH2:15]CC>C1(C)C=CC=CC=1.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>[CH:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2)=[CH2:15]
Reactant: Brc1ccc2nccnc2c1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=Cc1ccc2nccnc2c1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
A mixture of 6-Bromoquinoxaline (1.05 g, 5.02 mMol), tetrakis(triphenylphosphine)palladium (0.232 g, 0.2 mMol), and lithium chloride (0.639 g, 15.1 mMol) in dry toluene (50 mL) under nitrogen was treated with tributylvinyl tin (4.4 mL, 15.1 mMol) and heated to one hundred degrees for three hours. After cooling to room temperature the mixture was partitioned between ethyl acetate (200 mL) and water (100 mL). The aqueous layer was discarded and the organics washed with brine (2×100 mL), dried with magnesium sulfate, filtered, and concentrated to dryness on a rotary evaporator. Purification by flash column chromatography on silica gel using 10% ethyl acetate in dichloromethane as eluant yielded 680 mg (87% yield) of 6-vinylquinoxaline as a light orange solid. 1H NMR (DMSO-d6): δ=8.92 (dd, 2H, J=14.1, 1.9 Hz), 8.10 (m, 3H), 7.03 (dd, 1H, J=17.7, 10.9 Hz), 6.15 (dd, 1H, J=17.7, 0.4Hz), 5.52 (d, 1H, J=11.1 Hz). LC/MS (Method A), rt=1.14 mins., purity=99%, calculated mass=156, [M+H]+=157.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([CH3:13])[CH:4]=1)[CH3:2]>[OH-].[Na+]>[CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:13])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)OC)c(C)c1
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccc(C(=O)O)c(C)c1
Temperature: 60 °C

Procedure:
Methyl 4-ethyl-2-methylbenzoate (example 10c) (2.37 g) was dissolved in aq. NaOH (1M, 40 mL) and the solution heated at 60° C. overnight. The mixture was washed with hexanes and the aqueous layer was acidified with 6N HCl to pH 2. The title product was obtained as a white precipitate, following filtration and drying (2.17 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[C:23]4[C:29](O)=[O:30])[N:14]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>C1COCC1>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[C:23]4[C:29]([N:65]3[CH2:70][CH2:69][O:68][CH2:67][CH2:66]3)=[O:30])[N:14]=2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Nc1ccc(Oc2ccnc(Nc3ccc4[nH]nc(C(=O)O)c4c3)n2)c2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(Nc3ccc4[nH]nc(C(=O)N5CCOCC5)c4c3)n2)c2ccccc12
Temperature: 25 °C

Procedure:
To a solution of the carboxylic acid described above (460 mg, 80% pure, 0.90 mmol) in THF (6.0 mL) at RT was added HATU (613 mg, 1.61 mmol) and DIPEA (0.340 μL, 1.97 mmol). After 10 min the resulting mixture was treated with morpholine (0.141 mL, 1.61 mmol) and after a further 16 hr at RT additional portions of HATU (170 mg, 0.45 mmol), DIPEA (80 μL, 0.45 mmol) and morpholine (39 μL, 0.45 mmol) were added. The resulting mixture was maintained at RT for a further 24 hr and was then partitioned between saturated aq. NaHCO3 (20 mL) and EtOAc (20 mL). The organic phase was separated and was washed sequentially with 1M hydrochloric acid (20 mL), water (2×30 mL) and brine (2×30 mL) and was then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, 0-100% [10% MeOH in EtOAc] in isohexane, gradient elution) to afford the title compound, Intermediate B18, as a dark purple solid (165 mg, 82% pure, 24%); Rt 1.55 min (Method 2, acidic); m/z 482 (M+H)+ (ES+). The material was used in subsequent reactions without additional purification.
Reaction SMILES: [CH:1]([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C:19]1[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][C:25](OCC)=[O:26])=[O:17])([CH3:3])[CH3:2].[NH3:34].CO.C(Cl)Cl>CO>[CH:1]([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C:19]1[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][C:25]([NH2:34])=[O:26])=[O:17])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCCOc1ccccc1NC(=O)CCCCCCCCCCCSC(C)C
Reactant: N
Solvent: CO
Solvent: ClCCl
Product: CC(C)SCCCCCCCCCCCC(=O)Nc1ccccc1OCCCC(N)=O

Procedure:
To a stirred solution of (7) (20 mg, 0.041 mM) in methanol (10 mL) is added methanol saturated with ammonia (5 mL) and the stoppered mixture allowed to stir at ambient temperatures until TLC analysis shows little or no (D) remains. Concentration of the reaction mixture followed by preparative thin layer chromatography (silica gel; 3% methanol/methylene chloride as eluant) yields product 9 (11 mg) as a waxy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[CH:9]=[C:10]([SH:14])[C:11]([OH:13])=[O:12].[OH-].[K+]>O>[C:11]([C:10]1[S:14][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH:9]=1)([OH:13])=[O:12]
Reactant: O=C(O)C(S)=Cc1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2c(Cl)cccc2s1
Temperature: 25 °C

Procedure:
A suspension of (Z)-3-(2,6-dichlorophenyl-2-mercapto-2-propenoic acid (72.4 g) and water (362 ml) was stirred at room temperature. Further, potassium hydroxide (40.8 g) was added, and the mixture was heated under reflux for 4 hours. After the mixture was allowed to cool, the mixture was stirred for 1 hour while cooling with ice. The precipitated crystals ((Z)-3-(2,6-dichlorophenyl-2-mercapto-2-propenoic acid potassium salt) were collected by filtration and washed with cold water. After the crystals were suspended in water, 35% concentrated hydrochloric acid (32 ml) was added (pH=1), and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration and dried to obtain 2-carboxy-4-chlorobenzo[b]thiophene.
Reaction SMILES: [C:1]([S@@:5](/[N:7]=[CH:8]/[CH2:9][CH2:10][C@@:11]1([C:26]([O:28][CH3:29])=[O:27])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:6])([CH3:4])([CH3:3])[CH3:2].[F:30][C:31]1[CH:32]=[C:33]([Mg]Br)[CH:34]=[C:35]([F:37])[CH:36]=1>C1(C)C=CC=CC=1.C1COCC1>[C:1]([S@@:5]([NH:7][C@H:8]([C:33]1[CH:32]=[C:31]([F:30])[CH:36]=[C:35]([F:37])[CH:34]=1)[CH2:9][CH2:10][C@@:11]1([C:26]([O:28][CH3:29])=[O:27])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@]1(CC/C=N/[S@@](=O)C(C)(C)C)CCCN1C(=O)OCc1ccccc1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)[C@]1(CC[C@H](N[S@@](=O)C(C)(C)C)c2cc(F)cc(F)c2)CCCN1C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 1-benzyl 2-methyl (2R)-2-((3E)-3-{[(S)-tert-butylsulfinyl]imino}propyl)pyrrolidine-1,2-dicarboxylate from Step B (1.56 g, 3.70 mmol) in toluene (30 mL) at −78° C. was added 3,5-difluorophenylmagnesium bromide (14.8 mL of a 0.5 M solution in THF, 7.41 mmol) dropwise. The reaction mixture was stirred for 30 min at −78° C., 3.5 h at −10° C., and then at ambient temperature for 1.5 h. The mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—95:5 to 0:100, to give the title compound. MS: m/z=537 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11](O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:61]=[N+:62]=[N-:63])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([N:61]=[N+:62]=[N-:63])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N=[N+]=[N-])CC1
Temperature: -10 °C
Reaction time: 6 h

Procedure:
To a cooled (−10° C.) and stirred solution under Ar of (trans-4-hydroxy-cyclohexyl)carbamic acid tert-butyl ester (10.0 g) (H. Noguchi, T. Aoyama, T. Shioiri, Heterocycles 2002, 58, 471-504) and PPh3 (18.3 g) in THF (250 ml) was added diethyl azodicarboxylate (12.1 g). After 5 min a solution of diphenylphosphoryl azide (19.2 g) in THF (250 ml) was slowly added from a dropping funnel. The reaction mixture was stirred 6 h at −10° C. and stirring was continued over night at RT. After dilution with Et2O the mixture was washed with H2O. The aqueous layer was washed with one more portion of Et2O. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. Chromatography (silica, CH2Cl2 to CH2Cl2/5% MeOH) afforded 12.0 g (quant.) of product still contaminated by side products. This material was used as this in the following step. Light yellow semisolid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[CH:3][CH:2]=1.[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[O:15])[CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1ccncc1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1ccncc1)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Yield: 19.3 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-4-ylcarbamate (360 mg, 1.33 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (360 mg, 1.47 mmol) and diisopropylethylamine (0.256 ml, 1.47 mmol) in dimethyl sulfoxide (4.4 ml) was stirred at 70° C. for 8 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 93.7 mg (19.2%) of the desired product as a solid.
Reaction SMILES: C(=O)([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([N:14]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH:7]=1)OCC.[Li+].[OH-]>CO>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([N:14]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH:7]=1
Reactant: CCOC(=O)Oc1ccc(OC)c(N(CCN2CCOCC2)S(C)(=O)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(O)cc1N(CCN1CCOCC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
To a solution of ethyl 4-methoxy-3-(N-(2-morpholinoethyl)-methylsulfonamido)-phenyl carbonate (0.250 g, 0.621 mmol) in MeOH (5 ml), LiOH 1M (1.242 ml, 1.242 mmol) was added, and the mixture was stirred at RT for 4 hours. The volatiles were removed under vacuum, and the solid residue was partitioned between EtOAc and a diluted aqueous solution of HCl (pH=5). The organic layer was dried over Na2SO4, the solvent was evaporated and the crude was purified by chromatography on silica gel column (DCM:MeOH=10:0.2) affording N-(5-hydroxy-2-methoxyphenyl)-N-(2-morpholinoethyl)methanesulfonamide (0.180 g, 0.545 mmol, 88% yield, MS/ESI+ 331.0 [MH]+).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH3:32][S:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=[O:39])=[CH:36][C:35]=1[C:42]([F:45])([F:44])[F:43]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:38]([C:37]2[CH:40]=[CH:41][C:34]([S:33][CH3:32])=[C:35]([C:42]([F:45])([F:44])[F:43])[CH:36]=2)[OH:39])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccc(C=O)cc1C(F)(F)F
Reactant: COc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cnc2c(c1)cc(C(O)c1ccc(SC)c(C(F)(F)F)c1)n2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a −78° C. suspension of 1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridine (3.17 g, 11 mmol) in dry tetrahydrofuran (50 mL) was added n-butyllithium in n-hexane (1.6 M, 6.9 mL, 11 mmol) dropwise. The mixture was stirred at −78° C. for 30 min before adding 4-methylsulfanyl-3-trifluoromethyl-benzaldehyde (2.65 g, 12 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched by adding brine (20 mL). The mixture was extracted with ethyl acetate (300 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (20% ethyl acetate/hexanes) afforded (1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-methanol as colorless oil (5.08 g, 91%): LC/MS m/e calcd for C23H20F3N2O4S2 [M+H]+ 509.07, observed 509.0.
Reaction SMILES: N#N.[CH3:3][O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1Br.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]>C1(C)C=CC=CC=1.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>[CH3:3][O:4][C:5]([C:6]1[C:7]([C:18]2[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=2)=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:13]
Reactant: COC(=O)c1ccccc1Br
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccccc1-c1cc(OC)c(OC)c(OC)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
(The following reaction is done in an N2 atmosphere.) To a solution of Methyl-2-bromobenzoate (53) (922 mg, 4.29 mmol) in toluene (11 mL) is added Pd(PPh3)4 (297 mg, 0.26 mmol) and Na2CO3.10H2O (3.43 g, 12.00 mmol) in water (3.8 mL). Degas the resulting mixture is carefully (5 times alternating vacuum and flushing with N2). Add a solution of 3,4,5-Trimethoxyphenylboronic acid (54) (1.00 g, 4.72 mmol) in toluene (10 mL) by syringe, degas the resulting mixture again carefully and stir the resulting mixture overnight at 100° C. Partition the mixture between brine/EtOAc (1+1), separate layers, extract the aqu. layer with EtOAc (3×), wash the combined organic layer with brine and dry with Na2SO4. Purify the crude product by flash chromatography (silica gel, EtOAc/CyH 1+7, later 1+5) to obtain 3′,4′,5′-Trimethoxy-biphenyl-2-carboxylic acid methyl ester (55) as a yellow solid (1.30 g, 99%). 1H NMR (400 MHz, CDCl3): 3.65 (s, 3H); 3.84 (s, 6H); 3.87 (s, 3H); 6.52 (s, 2H); 7.35-7.42 (m, 2H); 7.50 (t, 1H, J=8.0 Hz); 7.73 (d, 1H, J=8.0 Hz).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[CH3:13][CH:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][NH2:16].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH3:13][CH:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][N:16]1[CH2:10][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]1=[O:12]
Reactant: CC(CN)Cc1ccccc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(Cc1ccccc1)CN1Cc2ccccc2C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.460 g, 2.0 mmol), 2-methyl-3-phenyl-propylamine (0.298 g, 2.0 mmol), and K2CO3 (0.500 g, 3.6 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(2-methyl-3-phenyl-propyl)-2,3-dihydro-isoindol-1-one (0.265 g, 50%). 1H NMR (300 MHz, CDCl3): δ (ppm) 0.93 (d, 3H), 2.19 (m, 1H), 2.46 (m, 1H), 2.73 (m, 1H) 3.56 (d, 2H), 4.36 (dd, 2H), 7.14-7.56 (m, 8H), 7.86 (d, 1H). GC-MS: m/z 265 (M)+.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.[O:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[N:16]1[CH2:25][C:26](Cl)=[N:27][OH:28]>C(Cl)(Cl)Cl>[CH2:3]([C:2]1[O:28][N:27]=[C:26]([CH2:25][N:16]2[C:15](=[O:14])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:24])[CH:1]=1)[CH2:4][CH2:5][CH3:6]
Reactant: O=C1c2ccccc2C(=O)N1CC(Cl)=NO
Reactant: C#CCCCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCc1cc(CN2C(=O)c3ccccc3C2=O)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
1-Hexyne (5.16 g, 62.9 mmol) and triethylamine (6.36 g, 62.9 mmol) were sequentially added to a suspension of 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-hydroxyethanimidoyl chloride (5.0 g, 21 mmol) in chloroform (80 mL). The solution was stirred overnight at room temperature, washed sequentially with 0.5 M hydrochloric acid and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with 3:1 to 1:1 hexane:ethyl acetate) to provide 2.14 g of 2-[(5-butylisoxazol-3-yl)methyl]-1H-isoindole-1,3(2H)-dione as a white, crystalline solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].S(=O)(=O)(O)O>>[C:14]([O:13][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 55 °C
Reaction time: 1 h

Procedure:
A mixture of 5-nitrosalicyclic acid (5 g), acetic anhydride (13 ml) and sulfuric acid (0.3 ml) was heated at 55° C. for 10 minutes. After the solution was removed from the hot water bath and stirred at room temperature for 1 hour it was poured into water (200 ml). The mixture was stirred for 10 minutes and filtered. The solid was stirred with water (100 ml), filtered by suction and air dried to give the title compound, m.p. ca, 165°-168° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si](C(C)(C)C)(C)C)[CH2:9][C@H:8]1[CH:20]=[C:21]([CH3:25])[C:22](=[O:24])[CH3:23])=[O:6])[CH:2]=[CH2:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH:20]=[C:21]([CH3:25])[C:22](=[O:24])[CH3:23])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=C(C)C(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C=C(C)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(2-methyl-3-oxo-1-butenyl)-pyrrolidine (9.9 g) in tetrahydrofuran (99 ml) was added lM solution of tetrabutylammonium fluoride in tetrahydrofuran (32.3 ml) at 0° C. After stirring at room temperature for 1 hour, the reaction mixture was poured into a mixture of ethyl acetate (200 ml) and water (100 ml). The aqueous layer was separated and extracted with ethyl acetate. The combined organic layer was washed twice with 1N hydrochloric acid (25 ml) and then with saturated aqueous sodium bicarbonate, water and brine successively, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (100 ml) eluting with a mixture of n-hexane and ethyl acetate (1:1-1:2 V/V) to give (2S,4R)-1-allyloxycarbonyl-4-hydroxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (5.65 g).