Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][C:37]=1[F:45]>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:34])=[O:3])[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[CH:13]=2)=[CH:38][C:37]=1[F:45]
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(Cl)c(F)c2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-chloro-3-fluoro-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.88-0.99 (m, 6H), 1.58 (dt, J=13.21, 6.60 Hz, 1H), 1.77 (ddd, J=13.69, 7.21, 6.97 Hz, 1H), 2.07 (ddd, J=13.57, 7.83, 7.70 Hz, 1H), 3.82 (t, J=7.83 Hz, 1H), 7.33-7.43 (m, 2H), 7.45-7.50 (m, 1H), 7.52-7.58 (m, 2H), 7.61-7.69 (m, 1H), 7.71 (s, 4H); Calcd for C25H21ClF4O2 (M+H) 465.88, Found 465.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH2:20][CH:21]4[O:25][CH2:24][CH2:23][CH2:22]4)[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([O:27][CH3:28])[CH2:10][CH2:11][C:12](=[O:26])[CH2:13]4.B(Br)(Br)Br.[NH4+].[OH-]>C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH2:20][CH:21]4[O:25][CH2:24][CH2:23][CH2:22]4)[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([O:27][CH3:28])[CH2:10][CH2:11][C:12](=[O:26])[CH2:13]4
Reactant: COc1ccc2c(c1)[C@]13CCN(CC4CCCO4)[C@H](C2)[C@]1(OC)CCC(=O)C3
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CO[C@@]12CCC(=O)C[C@@]13CCN(CC1CCCO1)[C@@H]2Cc1ccc(O)cc13
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 3,14-dimethoxy-17-tetrahydrofurfurylmorphinan-6-one (9) (0.12 g, 0.31 mmol) in 10 ml of CHCl3 was added to a solution of BBr3 (0.65 g, 2.59 mmol) in 20 ml of chloroform under stirring. After 20 minutes, the product was treated with a mixture of ice (10 g), chloroform (10 ml) and NH4OH (10 ml). The resulting mixture was stirred at 0° C. for 30 minutes whereupon the layers were separated and the organic extract was washed with water. The aqueous layer was saturated with sodium chloride and re-extracted with ethyl acetate (3×15 ml). The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure to provide an oily solid. The material was purified by chromatography (twice) over silica gel using graded methanol/chloroform as the eluant to give a mixture of the R and S isomers, yield 0.028 g (24.3% theory).
Reaction SMILES: [CH2:1]([C:3]([CH2:12][CH3:13])=[CH:4][CH2:5][CH2:6][C:7]([CH3:11])(O)[CH:8]=[CH2:9])[CH3:2].N1C=CC=CC=1.P(Br)(Br)[Br:21]>CCCCCC>[Br:21][CH2:9][CH:8]=[C:7]([CH3:11])[CH2:6][CH2:5][CH:4]=[C:3]([CH2:12][CH3:13])[CH2:1][CH3:2]
Reactant: BrP(Br)Br
Reactant: C=CC(C)(O)CCC=C(CC)CC
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CCC(=CCCC(C)=CCBr)CC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
18.2 g. of 7-ethyl-3-methyl-1,6-nonadien-3-ol, 100 ml. of hexane and 1 ml. of anhydrous pyridine are cooled to -15° C. and treated dropwise in the course of 1.5 hours with a solution of 4 ml. of phosphorus tribromide in 50 ml. of hexane, the temperature being maintained at between -15° C. and -10° C. The mixture is stirred for a further 1.5 hours during which time it is allowed to warm up to room temperature slowly. For working up, the mixture is poured onto 50 ml. of ice-water, the organic phase separated and washed in turn with 20 ml. of 10% by weight aqueous sodium carbonate solution, 50 ml. of semi-saturated aqueous sodium chloride solution and 50 ml. of saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. There is obtained 1-bromo-7-ethyl-3-methyl-2,6-nonadiene which is used in the process without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH2:25][C:26]#[N:27])[C:5]2=3)[CH:14]=1>C1COCC1.CO.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH2:25][CH2:26][NH2:27])[C:5]2=3)[CH:14]=1
Reactant: Cc1cc2c3c(c1)c1c(OCC#N)cccc1n3C(c1ccccc1)CO2
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc2c3c(c1)c1c(OCCN)cccc1n3C(c1ccccc1)CO2
Temperature: 85 °C
Yield: 66.6 %

Procedure:
To a mixture of 2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile (0.66 g, 1.86 mmol) in dry THF (120 mL) is added borane-methylsulfide complex (0.53 mL, 5.6 mmol). The mixture is refluxed at 85° C. for 18 h. The mixture is removed from heat and methanol is slowly added until gas evolution ceased. The solvents are removed under vacuum and methanol (5 mL) is added and again removed. The residue is dissolved in CH2Cl2/CH3OH (1:2 15 mL). Conc. HCl (2 mL) is added and the mixture heated at 65° C. for 1 h. The mixture is removed from heat and neutralized with aqueous potassium carbonate then partitioned between water and CH2Cl2. The organic layer is washed with water, dried over magnesium sulfate, and concentrated. Column chromatography (70 g silica get) using CH3OH/CH2Cl2 (4:96) as eluent gave 0.444 g (67%) of 2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][C:22]([CH2:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.C(OP([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])(OCC)=O)C.[H-].[Na+]>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][C:22]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([CH:29]=[CH:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:31][CH:32]=2)=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(NC(=O)Cc2ccc(C=O)cc2)c2ccccc2N2CCCCC2)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C=Cc1ccc(CC(=O)NC(c2ccc(C)cc2)c2ccccc2N2CCCCC2)cc1
Reaction time: 8 h

Procedure:
Four hundred twenty-seven milligrams (1 m mol) of 4-{N-[α-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl}-benzaldehyde were added to an ethereal solution of 450 mg (2 m mol) of ethyl diethylphosphonoacetate and 100 mg (2 m mol) of 50% sodium hydride. After the mixture had been stirred overnight, water was added, and the resulting mixture was extracted with chloroform and purified by column chromatography on silica gel by use of toluene/ethyl acetate (5:1) as eluant.
Reaction SMILES: [Na].[N+:2]([C:5]1[C:14]([NH:15]C(=O)C)=[C:13]([Cl:19])[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]=1[OH:20])([O-:4])=[O:3].Cl>CO>[N+:2]([C:5]1[C:14]([NH2:15])=[C:13]([Cl:19])[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]=1[OH:20])([O-:4])=[O:3]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c([N+](=O)[O-])c1O
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)c1cc(Cl)c(N)c([N+](=O)[O-])c1O
Temperature: 20 °C

Procedure:
Sodium (3.8 g, 0.17 m) is dissolved in 150 ml methanol and to this is added methyl 3-nitro-4-acetylamino-5-chlorosalicylate (5 g, 17 mmol) under nitrogen. This mixture is then heated to reflux overnight. The mixture is then cooled to 20° C. and poured into a rapidly stirring mixture of ice and 10% HCl (650 ml). The ppt. which forms is filtered, washed with H2O and dried to obtain methyl 3-nitro-4-amino-5-chlorosalicylate as a yellow powder which is used directly in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1>CN(C)C=O>[O:19]=[C:13]([N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)[CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C1CCC(=O)O1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CN(C)C=O
Product: O=C(O)CCC(=O)N1CCN(c2ccccn2)CC1
Yield: 64.7 %

Procedure:
A solution of 1-(2-pyridyl)piperazine (1.63 g) and succinic anhydride (1.1 g) in dimethylf ormamide (5 ml) was stirred for 24 hours at room temperature. The reaction mixture was reduced under reduced pressure and the concentrate was recrystallized from ethanol to give the titled compound (1.7 g) as a pale yellow crystal.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5C(=[CH:16][CH:17]=[CH:18][CH:19]=5)C=4C[CH2:12][N:11]3[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:4][C:3]=2[O:2]1.C[C:31]([CH3:34])([O-:33])[CH3:32].[K+].O=O>CN(C=O)C>[CH2:23]([N:11]1[CH2:12][C:34]2[C:31](=[O:33])[C:32]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[NH:21][C:22]=2[CH:10]1[C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(CN2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Reactant: CC(C)(C)[O-]
Agent: O=O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3,4-Methylenedioxyphenyl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline (0.79 g, 2.0 mmol) (prepared as in Example 1) was dissolved in dry DMF (15 mL). Potassium t-butoxide (0.56 g, 5.0 mmol) was added, followed by oxygen, bubbled in via syringe needle. The mixture was maintained at room temperature for one hour and then poured onto a mixture of 1N HCl (5 mL), water (35 mL) and ethyl acetate (35 mL). A fluffy yellow precipitate was collected, the organic layer removed, and the aqueous solution extracted with ethyl acetate (15 mL). The extracted layer was agitated and set aside overnight. The following day an additional quantity of product (as a precipitate) was collected. Drying of the combined solids yielded the product as a yellow powder.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][NH:6][C:7](=[O:33])[C:8]1[CH:13]=[CH:12][C:11]([S:14](=[O:32])(=[O:31])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])=[CH:10][CH:9]=1)C.O.CO>O1CCCC1>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][C:4]([OH:34])=[O:3])=[O:33])=[CH:9][CH:10]=1)(=[O:31])=[O:32]
Reactant: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a stirred solution of {4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-benzoylamino}-acetic acid ethyl ester (7.68 g, 14.67 mmol) in a mixture of tetrahydrofuran (36 mL), water (18 mL) and methanol (18 mL) lithium hydroxide monohydrate (3.09 g, 73.64 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated, the residue was dissolved in water, acidified with 1M hydrochloric acid, the precipitated solid was filtered off, washed with water and dried to yield 6.76 g (93%) of the title compound as a yellowish solid. MS (EI) 496.2 (MH+).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH3:5][O:6][CH:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]3[CH2:17][CH2:18][O:19][C:10]([C:11]=23)=[CH:9][N:8]1[O:20][CH3:21].[OH-].[Na+]>O1CCOCC1>[C:1]([CH2:2][CH2:3][CH:14]1[CH2:15][C:16]2[CH:7]([O:6][CH3:5])[N:8]([O:20][CH3:21])[CH:9]=[C:10]3[O:19][CH2:18][CH2:17][CH:12]([C:11]=23)[CH2:13]1)#[N:4]
Reactant: C=CC#N
Reactant: COC1C2=C3C(=CN1OC)OCCC3CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC1C2=C3C(=CN1OC)OCCC3CC(CCC#N)C2
Reaction time: 24 h

Procedure:
A solution of acrylonitrile (12 ml) and 1,2,3a,4,5,6-hexahydro7,8-dimethoxypyrano[2,3,4-de]isoquinoline (11 g), described in Example 56, in dioxane (80 ml) and 10 % NaOH solution (2.5 ml) is heated and stirred on the steam bath for 24 hr. The mixture is evaporated and the residue is dissolved in a mixture of ether and a little chloroform. The solution is extracted with 2N HCl and the extracts are washed (brine), dried and evaporated. The residue is crystallized from ether and then from benzene-hexane to give the title compound, m.p. 105° - 107° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17]C)=[O:16])=[CH:11][C:10]=1[CH2:19][O:20][CH3:21])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][C:10]=1[CH2:19][O:20][CH3:21])[CH3:2]
Reactant: CCc1ccccc1-c1ccc(C(=O)OC)cc1COC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccccc1-c1ccc(C(=O)O)cc1COC
Reaction time: 12 h
Yield: 78.9 %

Procedure:
To a solution of methyl 2′-ethyl-2-(methoxymethyl)-1,1′-biphenyl-4-carboxylate (12 g, 0.0422 mol) in THF (150 mL) and water (30 mL), was added lithium hydroxide monohydrate (5.31 g, 0.1266 mol) in portions. After 12 h at RT, the reaction mixture was concentrated and the aqueous phase was acidified using conc. HCl and extracted with EtOAc. Then the organic layers were washed with water and brine solution. The solvents were dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as a white solid (9 g, 80%). 1H NMR (DMSO-d6, 300 MHz) δ 12.9 (1H, bs), 8.08 (1H, s), 7.88-7.90 (1H, m), 7.34-7.35 (2H, m), 7.21-7.25 (2H, m), 7.03-7.05 (1H, m), 4.04-4.13 (2H, m), 3.16-3.18 (3H, s), 2.29-2.38 (1H, m), 2.19-2.24 (1H, m), 0.92-0.95 (3H, m). LC/MS (Method A): 269.0 (M−H)−. HPLC (Method B) Rt 5.06 min (Purity: 97.4%).
Reaction SMILES: P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.[C:28]1([C:34]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1>[C:28]1([C:34]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1c[nH]cn1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: c1ccncc1
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Yield: 82.6 %

Procedure:
A mixture of pyridine (15 ml), triphenyl phosphite (1.55 g, 5 mmole), imidazole (0.68 g, 10 mmole) and triphenylmethanol (2.08 g, 8 mmole) was refluxed for 3 hours. The reaction mixture was treated in the same manner as in Example 11 to give 2.05 g of 1-triphenylmethylimidazole as colorless needles. Yield, 82.7%. M.P., 218°-221° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.[N-:31]=[N+:32]=[N-:33].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH:31]1[C:27]([C:26]2[CH:25]=[CH:24][C:23]([CH2:22][N:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:10]4([CH2:14][O:13][C:12]5[CH:15]=[C:16]6[C:20](=[CH:21][C:11]4=5)[CH2:19][CH2:18][O:17]6)[C:2]3=[O:1])=[CH:30][CH:29]=2)=[N:28][N:33]=[N:32]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1N(Cc2ccc(-c3nnn[nH]3)cc2)c2ccccc2C12COc1cc3c(cc12)CCO3
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A round bottom flask was charged with 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzonitrile (0.50 g, 1.27 mmol), sodium azide (0.21 g, 3.17 mmol), and triethylamine hydrochloride (0.45 g, 3.17 mmol) in toluene (20 mL). The reaction mixture was refluxed under argon for 24 h. After cooling to ambient temperature, the product was extracted with water. 36% hydrochloric acid was added dropwise to the aqueous layer. The solid was filtrated and dried under reduced pressure to afford 1′-[4-(1H-tetrazol-5-yl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.38 g, 58%); 1H NMR (300 MHz, CDCl3) δ8.02 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.22 (t, J=7.6 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.05-6.94 (m, 2H), 6.47 (s, 1H), 6.40 (s, 1H), 5.01 (ABq, 2H), 4.79 (ABq, 2H), 4.53-4.38 (m, 2H), 3.03-2.82 (m, 2H); 13C NMR (75 MHz, CD3OD) δ177.6, 161.6, 161.2, 142.5, 140.1, 132.6, 129.1, 128.6, 127.9, 124.2, 123.6, 120.8, 120.4, 119.4, 109.8, 92.9, 80.3, 72.5, 57.4, 43.3, 28.8; MS (ES+) m/z 437.9 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C>[Si:19]([O:18][CH2:17][CH2:16][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1cc([N+](=O)[O-])cn1
Temperature: 50 °C
Yield: 273.2 %

Procedure:
To a mixture of 4-nitropyrazole (904 mg, 8 mmol) and potassium carbonate (3.3 g, 24 mmol) in DMF (10 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (0.6 mL, 2.9 mmol) and the mixture was heated to 50° C. for 2 h. Further (2-bromoethoxy)(tert-butyl)dimethylsilane (1.4 mL, 6.7 mmol) was added and the mixture was heated to 50° C. for 4 h. The solvent was removed in vacuo and the residue was partitioned between DCM (10 mL) and water (10 mL). The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography, eluting with iso-hexane/ethyl acetate (100/0 to 0/100), to give the title compound (2.15 g, 99%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 8.08 (s, 1H), 4.24 (t, J=4.9 Hz, 2H), 3.95 (t, J=4.9 Hz, 2H), 0.84 (s, 9H), −0.04 (s, 6H). LC-MS (ESCI): m/z=272 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[C:9]([F:15])=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=2)=[C:6]([N+:16]([O-:18])=[O:17])[C:5]([CH3:19])=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH2:24]([S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27])[CH3:25].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[CH2:24]([S:26]([C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]([C:20]([F:23])([F:21])[F:22])[C:5]([CH3:19])=[C:6]([N+:16]([O-:18])=[O:17])[C:7]=2[C:8]2[C:9]([F:15])=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:27])=[O:28])[CH3:25]
Reactant: Cc1cnc(F)c(-c2c(Cl)cc(C(F)(F)F)c(C)c2[N+](=O)[O-])c1
Reactant: CCS(=O)(=O)c1cccc(B(O)O)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1cccc(-c2cc(C(F)(F)F)c(C)c([N+](=O)[O-])c2-c2cc(C)cnc2F)c1
Temperature: 25 °C
Yield: 78.3 %

Procedure:
A mixture of 3-(6-chloro-3-methyl-2-nitro-4-(trifluoromethyl)phenyl)-2-fluoro-5-methylpyridine (6.0 g, 17.2 mmol), 3-ethylsulfonylphenylboronic acid (4.79 g, 22.4 mmol), bis(dibenzylidineacetone)Pd(0) (1.48 g, 2.6 mmol), tricyclohexylphosphine (1.45 g, 5.2 mmol), Cs2CO3 (14.0 g, 43 mmol), and dioxane (60 mL) was heated at reflux for 4.5 hr. After completion the reaction was cooled to room temperature, filtered, rinsed with dioxane, and concentrated in vacuo. The resulting oil was reconstituted in EtOAc (75 mL) washed with H2O (1×30 mL) and brine (1×30 mL), dried (MgSO4), and concentrated in vacuo. Purification by silica gel chromatography (4:1 hexanes/EtOAc) gave 6.5 g (78%) of the title compound as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ 8.15 (s, 1H), 8.04 (s, 1H), 7.90-7.93 (m, 1H), 7.80-7.82 (m, 1H), 7.60-7.70 (m, 3H), 3.1-3.2 (m, 2H), 2.49 (s, 3H), 2.25 (s, 3H), 0.85 (t, 3H). MS (ES) [m+H] calc'd for C22H18F4N2O4S, 483; found 483.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20]CC)=O)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:25](OCCCC)(=O)[CH:26]=C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:25][CH2:26][C:18](=[O:20])[C:13]3=[CH:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OCCCC
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1CCn2c1cc1cc(OCc3ccccc3)ccc12
Temperature: 70 °C
Reaction time: 0.83 h
Yield: 33.9 %

Procedure:
Ethyl 5-(benzyloxy)-1H-indole-2-carboxylate (25 g, 85 mmol) was dissolved in toluene (125 mL) and 60% sodium hydride in mineral oil (7.79 g, 195 mmol) was added portionwise. The reaction was stirred for 50 min and butyl acrylate (26.6 mL, 186 mmol) was added. The reaction was stirred at room temperature for 1.5 h and additional butyl acrylate (20 mL) was added. After stirring for 30 min, the solution was warmed to 70° C. and stirred for 1 h. The reaction was cooled to room temperature and sodium hydride (4.0 g) was added. The reaction was warmed to 70° C. causing the reaction to reflux. The heat source was removed and butyl acrylate (15 mL) was added and heating at 70° C. was resumed. After 30 min, the heat source was removed and the reaction was left to stir for 16 h. Water (25 mL) was added followed by 1.0 M HCL (250 mL) and 12 M HCL (50 mL). The aqueous layer was removed and the toluene was washed two times with water (100 mL). The toluene layer was concentrated under reduced pressure and the concentrate was taken up in acetic acid (120 mL) and water (12 mL). The reaction mixture was heated under reflux and stirred for 24 h. The reaction mixture was cooled to room temperature and water (200 mL) was added. The aqueous mixture was diluted with ethyl acetate and washed with water and brine. The ethyl acetate layer was filtered through a pad of Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by crystallization from methanol to provide the title compound (8.0 g). LCMS m/z=278.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.20 (t, J=6.6 Hz, 2H), 4.41 (t, J=6.2 Hz, 2H), 5.11 (s, 2H), 6.91 (s, 1H), 7.13 (dd, J=9.0, 2.4 Hz, 1H), 7.19 (d, J=2.4 Hz, 1H), 7.30-7.42 (m, 4H), 7.44-7.49 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@@H:3]1[O:15][CH3:16].[Cl:17][C:18]1[N:19]=[C:20]([C:25](O)=[O:26])[NH:21][C:22]=1[CH2:23][CH3:24].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:17][C:18]1[N:19]=[C:20]([C:25]([NH:1][C@@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@@H:3]2[O:15][CH3:16])=[O:26])[NH:21][C:22]=1[CH2:23][CH3:24]
Reactant: CO[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OC)nc1Cl
Yield: 72 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl (3S,4R)-4-amino-3-methoxypiperidine-1-carboxylate obtained in Example (56a) (224.4 mg, 0.96 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid synthesized by the method described in Example (1d) (140 mg, 0.80 mmol), WSC hydrochloride (440 mg, 2.29 mmol) and HOBT (110 mg, 0.81 mmol), to obtain 222.4 mg of the title compound as a white solid (72%).