Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:33])[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[N:28][CH:29]=[N:30][CH:31]=2)[CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:27]=[N:28][CH:29]=[N:30][CH:31]=4)[CH:21]=3)[CH2:18][C:17](=[O:33])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cncnc3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3cncnc3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-methyl-2-[3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M95) (0.44 g, 0.92 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (180 mg, 89%).
Reaction SMILES: [CH2:1]1[CH2:7][S:4](=[O:6])(=O)[O:3][CH2:2]1.[CH3:8][C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1>CCOCC.C(OCC)(=O)C>[S:4](=[CH:7][CH2:1][CH2:2][N:13]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:8])[CH2:14]1)(=[O:6])=[O:3]
Reactant: O=S1(=O)CCCO1
Reactant: Cc1cnccn1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC1=NC=CN(CCC=S(=O)=O)C1

Procedure:
16.0 g of 1,3-propane sultone was dissolved in 200 ml of 1:1 ether/ethyl acetate and 15.1 g of 2-methylpyrazine added. It was then stored and the solvent allowed to evaporate.
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([Li])CCC.[C:24]([N:34]1[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]1)([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>O1CCCC1>[C:28]1([CH2:27][O:26][C:24]([N:34]2[CH2:35][CH2:36][C:37]([OH:40])([C:15]3[CH:16]=[CH:17][C:12]([NH:11][C:1]([O:3][CH2:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:2])=[CH:13][CH:14]=3)[CH2:38][CH2:39]2)=[O:25])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(Nc1ccc(Br)cc1)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)cc1)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(carbobenzyloxy)-4-bromoaniline (5.00 g) in dry tetrahydrofuran (80 mL) at -78° C. under N2 is added n-butyllithium (21.4 mL, 1.6 M in hexanes) dropwise over five minutes. The resulting yellow solution is stirred at -78° C. for 30 minutes and is then treated with a solution of N-(carbobenzyloxy)-4-piperidone (3.99 g) in dry tetrahydrofuran (17 mL). The reaction mixture is stirred for three hours, during which the reaction temperature is allowed to rise to 0° C., and is quenched with saturated aqueous ammonium chloride (30 mL). The mixture is then diluted with water (100 mL), the layers are separated, the aqueous phase is extracted with diethyl ether, and the combined organic phase is washed with saline (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is chromato-graphed on silica gel (230-400 mesh, 350 g), eluting with ethyl acetate/hexane (25/75), and those fractions with an Rf =0.38 by TLC (ethyl acetate/hexane, 50/50) are pooled and con-centrated under reduced pressure to give the title compound, mp 156° C.-158° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[C:14]1([CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH:20]([N:11]1[N:12]=[N:13][C:9]([C:4]2[CH:5]=[C:6]([Br:8])[CH:7]=[C:2]([Br:1])[CH:3]=2)=[N:10]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: Brc1cc(Br)cc(-c2nnn[nH]2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cc(Br)cc(-c2nnn(C(c3ccccc3)c3ccccc3)n2)c1
Temperature: 100 °C
Yield: 85.1 %

Procedure:
A suspension of 5-(3,5-dibromophenyl)-1H-tetrazole (6.08 g, 20.00 mmol), diphenylmethanol (3.68 g, 20.00 mmol) and TsOH.H2O (0.38 g, 2.00 mmol) in toluene (50.0 mL) was heated to 100° C. until a clear solution was obtained. The solution was cooled to rt, and filtered. The filtration was concentrated, and the residue was purified by recrystallization in ether and hexane to afford 8.00 g (85%) of product as a white solid.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([C:21]1[CH:30]=[C:27]([O:28][CH3:29])[CH:26]=[C:23]([O:24][CH3:25])[CH:22]=1)([CH3:20])[CH3:19])=[O:16])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([O:13]C)=[O:12])[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].[OH-].[Na+].CC1C(C2(C3C(C)=CC(O)=C(C(C)C)C=3)OC(=O)C3C2=CC=CC=3)=CC(C(C)C)=C(O)C=1>O1CCOCC1.O>[NH:1]([C:15]([O:17][C:18]([C:21]1[CH:22]=[C:23]([O:24][CH3:25])[CH:26]=[C:27]([O:28][CH3:29])[CH:30]=1)([CH3:19])[CH3:20])=[O:16])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=[O:12])[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4]
Reactant: CC[C@H](C)[C@H](NC(=O)CNC(=O)OC(C)(C)c1cc(OC)cc(OC)c1)C(=O)OC
Agent: Cc1cc(O)c(C(C)C)cc1C1(c2cc(C(C)C)c(O)cc2C)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)CNC(=O)OC(C)(C)c1cc(OC)cc(OC)c1)C(=O)O

Procedure:
10 g (23.56 mmoles) of Ddz-Gly-Ile-OMe are dissolved in a mixture of 24 ml of dioxane and 8 ml of water and are titrated with 1 N NaOH against thymolphthalein as the indicator. The consumption depends on the ethyl acetate content but is more than 23 ml. After neutralization with citric acid, the dioxane is distilled off. The residue is taken up in water and brought to pH 3 with 2 N citric acid at 0° C. The oil which precipitates is extracted with ethyl acetate. The aqueous phase is again acidified to pH 3 if necessary and is extracted with ethyl acetate. The combined ethyl acetate extracts are extracted by shaking once with water, dried over Na2SO4 and concentrated. The residue is dried in a high vacuum. The substance becomes amorphous.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH2:4][CH2:5][CH3:6]>C(Cl)(Cl)Cl>[Br:1][C:9]1[S:8][C:7]([CH2:3][CH2:4][CH2:5][CH3:6])=[CH:11][CH:10]=1
Reactant: CCCCc1cccs1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCCCc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Bromine, 5 ml (15.63 g or 0.0977 mol), was added to a solution of 15.2 g (0.108 mol) of 2-butylthiophene in 400 ml of chloroform. Following the addition, the mixture was stirred for 10 minutes at room temperature and was then washed with 10% aqueous sodium carbonate solution. The organic layer was separated, dried and evaporated and the remaining oil was distilled under high vacuum to yield a colorless oil. Nmr (CDCl3): 0.89 ppm (t, 3, J=7.5 Hz, CH3). 1.2-1.7 (m, 4, CH2CH2), 2.7 (t, 2, J=7.5 Hz, CH2). 6.47 (d, 1, J=4 Hz. C4-H), 6.78 (d, 1, J=4 Hz. C3-H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[N:21]=[C:20]([CH:22]=O)[CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:22][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:15])[N:21]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1cccc(C=O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1cccc(CN2CCC(NC(=O)OC(C)(C)C)CC2)n1
Yield: 112.4 %

Procedure:
In 15 ml of dichloroethane, 315 mg of 4-t-butoxycarbonylaminopiperidine, 320 mg of 6-methyl-2-pyridinecarbaldehyde and 100 mg of acetic acid were dissolved. To the solution 575 mg of sodium triacetoxyborohydride was added at room temperature, followed by an hour's stirring at the same temperature. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and removed of the solvent by reduced pressure distillation. The residue was purified by silica gel column chromatography (chloroform/methanol=100/1 to 50/1), to give 540 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=[C:5]2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[N:32]1([CH2:31][CH2:30][NH:29][C:11]([C:9]2[CH:10]=[C:5]3[N:4]=[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=5[N:19]=4)[N:2]([CH3:1])[C:6]3=[N:7][CH:8]=2)=[O:13])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)cnc21
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCN3CCOCC3)cnc21
Yield: 29.3 %

Procedure:
3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (28 mg) was prepared by following General Procedure F starting from 3-methyl-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (75 mg), 4-(2-aminoethyl)morpholine (26 mg), HBTU (83 mg), and DIEA (48 uL). LC/MS: m/z 466.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (bs, 1H), 8.48 (bs, 1H), 8.09 (s, 1H), 7.94 (d, 1H), 7.81-7.66 (m, 1H), 7.51 (d, 1H), 7.35 (d, 1H), 3.83-3.23 (m, 11H), 2.51-2.48 (m, 4H).
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[N:12]1([C:17]([S-:19])=[S:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.[NH4+].C(O)(=O)C>CO>[N:12]1([C:17]([S:19][CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[S:18])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: S=C([S-])N1CCCC1
Reactant: O=[N+]([O-])C=Cc1ccccc1
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])CC(SC(=S)N1CCCC1)c1ccccc1
Temperature: 10 °C
Yield: 77 %

Procedure:
β-Nitrostyrene (7.5 grams, 0.050 mole) was added to a cooled (10° C.) stirred slurry of ammonium 1-pyrrolidinecarbodithioate (8.2 grams, 0.050 mole) in methanol (50 ml.). The temperature of the mixture fell to 5° C., then rapidly climbed to 10° C. The cooling bath was removed and the reaction temperature rose slowly to 22° C. Acetic acid (3.0 grams, 0.05 mole) was added, the slurry was cooled to 10° C. and the solid was filtered off, washed with water, and dried in air. The crude product melted at 108° - 116° C. and weighed 11.4 grams (77% yield). Repeated recrystallizations from cool acetone-methanol, hot acetone-2-propanol, and cool methylene chloride-toluene-hexane solutions gave pure α-(nitromethyl)benzyl 1-pyrrolidinecarbodithioate melting at 116° - 120° C. (sintering at 113° C.).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]([C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=1)[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([NH2:31])=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=2)=[CH:20][CH:19]=1)([F:13])[CH3:12]>C1COCC1>[F:10][C:11]([C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=1)[O:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:25]3=[N:31][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=2)=[CH:22][CH:23]=1)([F:13])[CH3:12]
Reactant: Cc1cnc(N)c(-c2ccc(Oc3cccc(C(C)(F)F)c3)cc2)c1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=CN2CCS(=O)(=O)N=C2C(c2ccc(Oc3cccc(C(C)(F)F)c3)cc2)=C1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 96 mg) in THF (dry) (10 ml) was added 2-chloroethanesulfonyl chloride (0.101 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(3-(1,1-difluoroethyl)phenoxy)phenyl)-5-methylpyridin-2-amine (164 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. Water, EtOAc and THF were added and the mixture was extracted. Silica-gel was added to the organic phase and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo to give 9-{4-[3-(1,1-difluoroethyl)phenoxy]phenyl}-7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide as a white solid. Platinum(IV) oxide (30 mg) was added to a solution of the prepared 9-{4-[3-(1,1-difluoroethyl)phenoxy]phenyl}-7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide in THF (dry) (15 mL) and MeOH (15 ml). The mixture was stirred at room temperature under hydrogen for 3 hr. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc, to remove catalytic poison). Platinum(IV) oxide (30 mg) was added and the mixture was stirred at room temperature under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (47.6 mg) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:6]2[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:5]=2[S:4][N:3]=1.[Na].[CH3:13][OH:14]>>[CH3:13][O:14][C:2]1[C:6]2[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:5]=2[S:4][N:3]=1
Reactant: O=C1CCCc2snc(Cl)c21
Reactant: CO
Agent: [Na]
Product: COc1nsc2c1C(=O)CCC2

Procedure:
A mixture of 3-chloro-4,5,6,7-tetrahydro-1,2-benzisothiazol-4-one 24a (600 mg) and a solution of sodium (506 mg) in methanol (22 mL) was stirred at 90° C. for 1 h. The reaction mixture was evaporated and water (20 mL) was added to the residue. Extractions with methylene chloride (3×30 mL), drying and evaporation gave an oil. Column chromatography on silica gel (eluent: toluene-ethyl acetate 4:1) gave the title compound (251 mg). Mp 45-46° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[NH2-].[Na+].[CH3:12][CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1>O1CCCC1>[CH3:9][O:8][C:3]1[CH:4]=[C:5]([CH:15]2[CH2:14][CH:13]([CH3:12])[CH2:18][CH2:17][C:16]2=[O:19])[CH:6]=[CH:7][CH:2]=1
Reactant: CC1CCC(=O)CC1
Reactant: COc1ccccc1Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(C2CC(C)CCC2=O)c1

Procedure:
Employing the general procedure of T. Kametani, et al., J. Chem. Soc. (C), 1971, 1047, 187 g o-chloroanisole was added to a mixture of 215 g of sodium amide, 3 liters of anhydrous tetrahydrofuran and 400 g of 4-methylcyclohexanone. The reaction was refluxed for 18 hours then quenched with saturated ammonium chloride. Concentration of the organic phase, dilution with water, extraction with ether and distillation of the residue from concentrating the ether extracts gave 90 g, b.p. 135° (0.07 mm), of product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:14]([Sn](CCCC)(CCCC)C=C)[CH2:15]CC.CCOC(C)=O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:14]([C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[CH2:15]
Reactant: CCOC(=O)Cc1cccc(Br)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1cccc(CC(=O)OCC)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a mixture of ethyl 2-(3-bromophenyl)acetate (1.5 g, 6.1 mmol) in anhydrous DMF (15 mL) was added tributyl(vinyl)stannane (2.1 mL, 7.4 mmol) and tetrakis(triphenylphosphine) palladium (400 mg, 0.5 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 110° C. for 8 hours. Followed a standard aqueous/EtOAc workup. Purified by silica gel column chromatography (petroleum:ether/ethyl acetate=15:1) (640 mg, yield 54%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([C:18]=1[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[CH:16][C:15]([Cl:28])=[CH:14][CH:13]=2)=[O:9].I[CH3:30]>CO.O1CCCC1>[CH3:30][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([C:18]=1[S:19]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:20])=[O:21])=[CH:16][C:15]([Cl:28])=[CH:14][CH:13]=2)=[O:9]
Reactant: O=C(NCc1ncc[nH]1)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Reactant: CI
Solvent: CO
Solvent: C1CCOC1
Product: Cn1ccnc1CNC(=O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a partial suspension of N-[(imidazol-2-yl)methyl] 3-phenylsulfonyl-5-chloroindole-2-carboxamide (Example 35) (42 mg, 0.1 mmol) in 1:1 methanol/tetrahydrofuran (4 mL) was added iodomethane (0.05 mL, 0.8 mmol). The reaction was stirred for three days at room temperature. The solvents were removed under reduced pressure, aq. NaHCO3 added and the product extracted into ethyl acetate/methanol. The organic layer was dried (Na2SO4), filtered, and the solvents evaporated. The residue was purified by chromatography and the product eluted with 3% methanol/chloroform. Appropriate fractions were combined, the solvents evaporated, and the residue triturated with methylene chloride to give pure product.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[S:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[O:24][CH2:23][C:13]3([C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:22])[C:11]=2[CH:12]=1)(=[O:5])=[O:4].[OH-].[Na+].Br[CH2:30][C:31]1[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1>CN(C)C=O.C(OCC)(=O)C>[F:26][C:2]([F:1])([F:25])[S:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[O:24][CH2:23][C:13]3([C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH2:30][C:31]4[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=4)[C:14]3=[O:22])[C:11]=2[CH:12]=1)(=[O:5])=[O:4]
Reactant: O=C1Nc2ccccc2C12COc1ccc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C12COc1ccc(OS(=O)(=O)C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.1 %

Procedure:
To a mixture of 2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-5-yl trifluoromethanesulfonate (0.42 g, 1.10 mmol) and sodium hydroxide (0.07 g, 1.65 mmol) in N,N-dimethylformamide (5.00 mL) was added 2-(bromomethyl)-5-(trifluoromethyl)furan (0.50 g, 2.20 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h and diluted with ethyl acetate (200 mL). After washing with aqueous saturated sodium chloride (2×20.0 mL), the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/3) to give the title compound (0.47 g, 80%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.34 (t, 1H), 7.18-6.94 (m, 5H), 6.74 (dd, 1H), 6.55 (dd, 1H), 6.40 (d, 1H), 5.09-4.72 (m, 4H); MS (ES+) m/z 534.4 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].[CH:17]([CH:19]=[CH2:20])=[O:18]>O1CCOCC1>[OH:10][C:7]1[CH:8]=[CH:9][C:2]2[O:1][CH2:20][C:19]([CH:17]=[O:18])=[CH:4][C:3]=2[CH:6]=1
Reactant: O=Cc1cc(O)ccc1O
Reactant: C=CC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=CC1=Cc2cc(O)ccc2OC1

Procedure:
The starting material is prepared as follows: 2,5-Dihydroxybenzaldehyde (25.0 g, 0.18 mol) is dissolved in 375 ml of 1,4-dioxane. To this is sequentially added potassium carbonate (50.0 g, 0.36 mol) and acrolein (15.22 g, 0.27 mol). The mixture is heated at reflux overnight, cooled, and partitioned between water and ether. The aqueous layer is removed and extracted twice with ether. The combined organic layers are dried (MgSO4) and evaporated. Trituration of the residue with dichloromethane, followed by filtration and drying, yields 6-hydroxy-2H-1-benzopyran-3-carboxaldehyde, m.p. 163°-165° C., as a yellow crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([CH2:13][OH:14])[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([O:14][CH2:13][CH:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:9]([O:11][CH3:12])=[O:10])(=[O:26])[CH3:25]
Reactant: COC(=O)C(CO)C(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(COC(C)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 97.5 %

Procedure:
methyl 2-(tertbutoxycarbonyl)-3-hydroxypropanoate (29) (2.2 g, 10.0 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by CH2Cl2 (40 mL). Next, DIEA (2.1 mL, 12.0 mmol, 1.2 equiv.) and acetic anhydride (1.2 mL, 13.0 mmol, 1.3 equiv.) were added to the reaction mixture and the solution was stirred at rt. The reaction solution was stirred for a total of 21 h. The solution was transferred to a separatory funnel with CH2Cl2 (75 mL), washed with 1% HCl (2×50 mL), and sat. NaCl (2×50 mL). The organic layers were dried over Na2SO4, concentrated on a rotary evaporator, and dried under vacuum to give 2.4 g (91%) of 30 as a clear oil which crystallized to a white solid upon standing. Rf=0.37 (25% EtOAc/hexanes); mp=61-62° C.; IR (KBr) 3327, 2985, 1742, 1683, 1533, 1348, 1241, 1166, 1071, 1038 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.33 (br d, J=8.0 Hz, 1H, carbamate-NH), 4.58 (m, 1H, Boc-NH—CH), 4.44 (dd, J=11.0, 3.5 Hz, 1H, CH—CH2), 4.33 (dd, J=11.0, 3.5 Hz, 1H, CH—CH2), 3.78 (s, 3H, OCH3), 2.06 (s, 3H, O═C—CH3), 1.46 (s, 9H, t-butyl-CH3).; 13C NMR (125 MHz, CDCl3) δ 170.6, 170.5, 155.3, 80.5, 64.5, 53.0, 52.9, 28.4, 20.8; LRMS (ESI-MS m/z): Mass calcd for C11H19NNaO6 [M+Na]+, 284.26. Found 284.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[C:23]1([C:29]2[C:30]3[C:35]([C:36]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[C:37]4[C:42]=2[CH:41]=[C:40](B(O)O)[CH:39]=[CH:38]4)=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[C:23]1([C:29]2[C:30]3[C:35]([C:36]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[C:37]4[C:42]=2[CH:41]=[C:40]([C:2]2[CH:3]=[CH:4][C:5]([N:8]5[C:12]6[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=6[N:10]=[C:9]5[C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:6][CH:7]=2)[CH:39]=[CH:38]4)=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Reactant: Brc1ccc(-n2c(-c3ccccc3)nc3ccccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2c3ccccc3c(-c3ccccc3)c3cc(-c4ccc(-n5c(-c6ccccc6)nc6ccccc65)cc4)ccc23)cc1
Yield: 92.1 %

Procedure:
1.0 g (2.9 mmol) of 1-(4-bromophenyl)-2-phenyl-1H-benzimidazole, 1.2 g (3.2 mmol) of 9,10-diphenylanthracene-2-boronic acid, and 0.067 g (0.058 mmol) of tetrakis(triphenylphosphine)palladium were dissolved into 20 mL of 1,2-dimethoxyethane. Then, 10 mL of a 2 M aqueous solution of sodium carbonate were added, and the whole was refluxed under heating for 8 hours in an argon atmosphere. After the completion of the reaction, the resultant was filtered, and the resultant solid was washed with water, methanol, and toluene to obtain 1.6 g of a greenish white solid (90% yield). Mass spectral analysis confirmed that the solid was a target product. The solid had an m/e of 598 with respect to a molecular weight of 598.24.