Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:31]([O-:33])=[O:32])=[CH:4][C:5]([Cl:30])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:18][O:19][C:20]=3[CH3:21])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.[CH3:34][O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.N1CCCCC1>CN(C1C=CN=CC=1)C.ClCCCl>[Cl:30][C:5]1[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:18][O:19][C:20]=3[CH3:21])=[O:15])[CH2:10][CH2:9]2)=[CH:7][C:2]([NH:1][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][C:36]([O:35][CH3:34])=[CH:37][CH:38]=2)=[C:3]([N+:31]([O-:33])=[O:32])[CH:4]=1
Reactant: COc1ccccc1-c1noc(C)c1C(=O)N1CCN(c2cc(N)c([N+](=O)[O-])cc2Cl)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: CN(C)c1ccncc1
Solvent: C1CCNCC1
Solvent: ClCCCl
Product: COc1ccc(C(=O)Nc2cc(N3CCN(C(=O)c4c(-c5ccccc5OC)noc4C)CC3)c(Cl)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 73.5 %

Procedure:
A mixture of (4-(5-amino-2-chloro-4-nitrophenyl)piperazin-1-yl)(3-(2-methoxyphenyl)-5-methylisoxazol-4-yl)methanone (16 mg, 0.034 mmol, Preparation L), 4-methoxybenzoyl chloride (12 mg, 0.068 mmol), DMAP (6 mg, 0.034 mmol), and BEMP (19 mg, 0.068 mmol) in DCE (1 mL) was heated at 80° C. for 3 h. Cooled down to RT, the mixture was treated with piperidine (0.3 ml) for 1 h and concentrated in vacuo. HPLC purification gave the title compound (15.7 mg, 0.025 mmol, 74.9% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2)CC1
Product: COc1cc(-c2cc(CN(c3ccc(Cl)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-chlorophenyl)amino]piperidine (621 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1>CO.[Pd]>[BrH:1].[BrH:1].[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([Cl:2])=[CH:27][CH:26]=3)[CH2:13][CH2:12]2)=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(OCCN2CCC(Cc3ccc(Cl)cc3)CC2)cc1
Agent: [Pd]
Agent: Br
Solvent: CO
Product: Nc1ccc(OCCN2CCC(Cc3ccc(Cl)cc3)CC2)cc1
Reaction time: 2.25 h
Yield: 125.6 %

Procedure:
A mixture of 4-(4-chlorobenzyl)-1-(2-(4-nitrophenoxy)ethyl)piperidine hydrobromide (500 mg, 1.10 mmol) and Pd/C (10%, 50 mg) in MeOH (25 mL) was shaken under H2 (20-30 psi, Parr) for 2.25 h and worked up to give a beige powder (350 mg, 63%): mp>130° C.; 1H NMR (DMSO-d6) 1.37-1.88 (m, 5 H), 2.45-3.75 (m, 8 H), 4.30-4.42 (m, 2 H), 7.04-7.38 (m, 8 H), 9.35-10.20 (m, 4 H); HRMS Calcd for C20H25ClN2O: 344.1655. Found: 344.1656.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:6]2[O:7][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[O:9][CH2:10][C@@H:5]2[CH2:4][C@H:3]1[N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].[CH:30]1[CH:35]=[CH:34][C:33]([O:36][C:37](Cl)=[S:38])=[CH:32][CH:31]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:37](=[S:38])([O:36][C:33]1[CH:34]=[CH:35][CH:30]=[CH:31][CH:32]=1)[O:1][C@@H:2]1[C@@H:6]2[O:7][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[O:9][CH2:10][C@@H:5]2[CH2:4][C@H:3]1[N:19]1[C:20](=[O:29])[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]1=[O:28]
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](N4C(=O)c5ccccc5C4=O)[C@H](O)[C@@H]3O2)cc1
Reactant: S=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C2OC[C@@H]3C[C@@H](N4C(=O)c5ccccc5C4=O)[C@H](OC(=S)Oc4ccccc4)[C@@H]3O2)cc1
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a stirred solution of 2-[(4aS,6R,7S,7aR)-7-hydroxy-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-1H-isoindole-1,3(2H)-dione (1.26 g, 3.19 mmol) in DCM (150. mL) was added DMAP (1.17 g, 9.54 mmol) and phenyl chlorothionoformate (0.661 mL, 4.78 mmol) under an atmosphere of argon. After 2 h, the mixture was concentrated in vacuo and the residue was purified via silica gel chromatography eluting with a gradient of 0 to 5% EtOAc in DCM to afford the title compound as a white amorphous solid (1.64 g, 97%). LC/MS: Rt=2.21 min, ES+ 532 (AA standard).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]([CH3:18])=[C:16]3[C:11]([C:12](=[O:27])[C:13]([C:22]([O:24]CC)=[O:23])=[CH:14][N:15]3[CH:19]3[CH2:21][CH2:20]3)=[C:10]([CH3:28])[C:9]=2[F:29])[CH2:4][CH2:3]1.[OH-].[Na+].C(O)C>O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]([CH3:18])=[C:16]3[C:11]([C:12](=[O:27])[C:13]([C:22]([OH:24])=[O:23])=[CH:14][N:15]3[CH:19]3[CH2:20][CH2:21]3)=[C:10]([CH3:28])[C:9]=2[F:29])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C)c(N3CCN(C)CC3)c(F)c(C)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(F)c(N2CCN(C)CC2)c(C)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 60.2 %

Procedure:
To ethyl 7-(4-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5, 8-dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (25 mg) are added 10% aqueous solution of sodium hydroxide (3 ml) and ethanol (3 ml), and the mixture is refluxed for 1 hour. After cooling, the reaction mixture is diluted with water and washed with dichloromethane. The aqueous layer is made acidic with acetic acid and then made weak alkaline with an aqueous sodium hydrogen carbonate. The resultant is extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure and to the residue is added diethyl ether. The precipitated crystals are filtered and recrystallized from ethanol to give 7-(4-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5, 8-dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (14 mg), as yellow crystals, m.p. 205°-206° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]([NH:10][C:11]([C:13]2[C:14]3[CH:21]=[N:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[C:15]=3[CH:16]=[N:17][CH:18]=2)=[O:12])[CH2:8][CH3:9])[CH2:3][CH2:2]1.C=O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:31][N:1]1[CH2:6][CH2:5][CH:4]([CH:7]([NH:10][C:11]([C:13]2[C:14]3[CH:21]=[N:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[C:15]=3[CH:16]=[N:17][CH:18]=2)=[O:12])[CH2:8][CH3:9])[CH2:3][CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCNCC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCN(C)CC1
Reaction time: 2 h

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (1-piperidin-4-yl-propyl)-amide (0.10 mg, 0.26 mmol) and 37% aqueous formaldehyde (157 μL, 2.1 mmol) in MeOH (3 mL) was added sodium triacetoxyborohydride (83 mg, 0.39 mmol). After 2 hours, the reaction was quenched with saturated aqueous sodium bicarbonate (5 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by reversed-phase HPLC chromatography (Sunfire PrepC18 OBD 5 mM 30×150 mm column) eluting with a gradient of 5-75% acetonitrile in water (0.1% TFA). The fractions from the column were concentrated to remove acetonitrile, made basic with saturated aqueous sodium carbonate and extracted with EtOAc. The organic layer was dried and concentrated to afford the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[C:5]=1[CH2:12][C:13]([O:15]CC1C=CC=CC=1)=[O:14])[CH:2]=[CH2:3].[OH-].[Na+]>O1CCOCC1.O>[CH2:1]([C:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[C:5]=1[CH2:12][C:13]([OH:15])=[O:14])[CH:2]=[CH2:3]
Reactant: C=CCC1=C(CC(=O)OCc2ccccc2)C(C)(C)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=CCC1=C(CC(=O)O)C(C)(C)CCC1
Temperature: 100 °C
Yield: 100.4 %

Procedure:
To a solution of benzyl 2-(2-allyl-6,6-dimethyl-cyclohexen-1-yl)acetate (1.5 g, 5.02 mmol) in dioxane (12 mL) and water (4 mL) was added NaOH (2M, 5.5 mL). The solution was heated to 100° C. for 30 h. The solution was concentrated in vacuo and water was added. The aqueous layer was extracted 2 times with ether and the organic layer was removed. Then, pH of the aqueous layer was adjusted to 1. The solution was extracted with ethyl acetate and washed with brine, dried and concentrated to give the desired product as a colourless oil (1.05 g, quant). 1H NMR (400 MHz, CDCl3) δ 5.77 (1H, dd, J=16.9, 10.3 Hz), 4.88-5.09 (2H, m), 3.13 (2H, s), 2.74 (2H, d, J=6.2 Hz), 1.96-2.08 (2H, m), 1.59-1.69, (2H, m), 1.43-1.57 (2H, m), 0.98-1.06 (6H, s) ppm.
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].N1C=CC=CC=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][C:28]2=[O:33])=[CH:23][CH:22]=1.[Cl-].[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([C@H:45]2[CH2:49][CH2:48][CH2:47][NH2+:46]2)=[O:44])=[CH:38][CH:37]=1.C(N(C(C)C)C(C)C)C>ClCCl>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]([C@H:45]2[CH2:49][CH2:48][CH2:47][N:46]2[C:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][C:28]3=[O:33])=[CH:25][CH:26]=2)=[O:3])=[O:44])=[CH:40][CH:41]=1
Reactant: O=C(Nc1ccc(Cl)cc1)[C@H]1CCC[NH2+]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)cc1)[C@H]1CCCN1C(=O)Nc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.01 g (5.00 mmol) of 4-nitrophenyl chloroformate and 0.404 ml (5.00 mmol) of pyridine are added to a solution of 961 mg (5.00 mmol) of 4-(4-aminophenyl)morpholin-3-one in 10 ml of dichloromethane, and the mixture is stirred at room temperature for 1 hour. 1.31 g (5.00 mmol) of (R)-2-(4-chlorophenylcarbamoyl)pyrrolidinium chloride and 2.55 ml (15.0 mmol) of N-ethyldiisopropylamine are added to the suspension. The reaction mixture is stirred at room temperature for 12 hours and then evaporated, and the residue is chromatographed on a silica-gel column, giving 2-N-[(4-chlorophenyl)]-1-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(R)-pyrrolidine-1,2-dicarboxamide as a yellowish solid, ESI 443.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]2[NH:8][C:9](=[S:11])[O:10][C@H:6]2[CH2:5][C@H:4]([CH2:12][OH:13])[C@H:3]1[OH:14].[CH3:15]I.[OH-].[Na+]>CCO>[F:1][C@H:2]1[C@H:7]2[N:8]=[C:9]([S:11][CH3:15])[O:10][C@H:6]2[CH2:5][C@H:4]([CH2:12][OH:13])[C@H:3]1[OH:14]
Reactant: OC[C@H]1C[C@@H]2OC(=S)N[C@@H]2[C@H](F)[C@@H]1O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSC1=N[C@@H]2[C@H](F)[C@H](O)[C@@H](CO)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To a solution of (3aS,4S,5R,6R,7aS)-4-fluoro-5-hydroxy-6-(hydroxymethyl)hexahydrobenzo[d]oxazole-2(3H)-thione (490 mg, 2.22 mmol) in EtOH (8 mL) was added MeI (630 mg, 4.43 mmol) and 5 N NaOH (0.58 mL, 2.9 mmol). The mixture was stirred at room temperature for 2 h. The solvents were evaporated to give the crude product. This was purified by SiO2 column, eluted with 10%-20% MeOH in DCM to give (3aS,4S,5R,6R,7aS)-4-fluoro-6-(hydroxymethyl)-2-(methylthio)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazol-5-ol (370 mg, 71%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 4.78 (ddd, J=52.1 Hz, 3.8 Hz, 1.6 Hz, 1H), 4.64-4.68 (m, 1H), 4.03 (ddd, J=25.8 Hz, 7.6 Hz, 3.9 Hz, 1H), 3.91 (dd, J=10.9 Hz, 3.7 Hz, 1H), 3.61-3.71 (m, 2H), 2.48 (s, 3H), 2.17-2.30 (m, 2H), 1.95-2.02 (m, 1H), 1.65-1.72 (m, 1H).
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:21][CH3:22])=[C:18]([Pb+3])[CH:19]=1.[CH:23]12[CH2:30][CH:27]([CH2:28][CH2:29]1)[C:26](=[O:31])[CH2:25][C:24]2=[O:32].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:21][CH3:22])=[C:18]([CH:25]2[C:26](=[O:31])[CH:27]3[CH2:30][CH:23]([CH2:29][CH2:28]3)[C:24]2=[O:32])[CH:19]=1
Reactant: CCc1ccc(Br)cc1[Pb+3]
Reactant: O=C1CC(=O)C2CCC1C2
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1ccc(Br)cc1C1C(=O)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-bromo-2-ethylphenyllead triacetate (16.34 g, 28.80 mmol) in chloroform (160 ml) is added bicyclo[3.2.1]octane-2,4-dione (3.61 g, 26.10 mmol) and 4-dimethylaminopyridine (16.63 g, 131 mmol), and the reaction mixture is stirred at room temperature for 5 minutes. Next toluene (40 ml) is added, and the mixture is stirred at 80° C. for 1 hour (pre-heated oil bath). The reaction mixture is allowed to cool to room temperature, quenched with 1M hydrochloric acid, and the organic phase separated. The aqueous phase is further washed with dichloromethane (×2), and again the phases are separated. All organics are combined then evaporated under reduced pressure to give a crude oil, which is purified by flash column chromatography on silica gel (30% to 50% ethyl acetate/iso-hexane eluant ratio, then 10% methanol/dichloromethane eluant ratio). The resulting gum is then recrystalised from dichloromethane/hexane to afford 3-(5-bromo-2-ethylphenyl)bicyclo[3.2.1]octane-2,4-dione as a cream coloured solid.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][CH:12]2[O:16][C:15](=[O:17])[CH2:14][CH2:13]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C.O>C1(C)C=CC=CC=1>[OH:17][CH:15]1[CH2:14][CH2:13][CH:12]([CH2:11][O:10][S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:18])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[O:16]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(=O)O2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2CCC(O)O2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a suspension of (±)-dihydro-5-(p-toluensulfonyloxymethyl)-2(3H)-furanone (example 57) (5.20 g, 19.26 mmol) in anhydrous toluene (125 mL) at -78° C. was added DIBAL (1.5M in toluene, 13.5 mL, 20.22 mmol) dropwise. The solution was allowed to stir at -78° C. for 2 h. Water was then added to the mixture and the reaction mixture was brought to rt. The mixture was filtered through Celite and the organic layer was collected, dried (MgSO4) and concentrated to give the title compound as a 1:1 mixture of cis and trans isomers (4.2 g, 80%).
Reaction SMILES: C([Li])(C)(C)C.I[C:7](=[CH2:16])[CH2:8][C@@H:9]1[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10]1.[S:17]([Cl:20])(Cl)=[O:18].CC[O:23]CC>>[CH3:14][C:11]1([CH3:15])[O:10][C@H:9]([CH2:8][C:7]([S:17]([Cl:20])(=[O:18])=[O:23])=[CH2:16])[CH2:13][O:12]1
Reactant: C=C(I)C[C@@H]1COC(C)(C)O1
Reactant: O=S(Cl)Cl
Reactant: CCOCC
Agent: [Li]C(C)(C)C
Product: C=C(C[C@@H]1COC(C)(C)O1)S(=O)(=O)Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl lithium is added to a solution of (R)-4-(2-iodoallyl)-2,2-dimethyl-1,3-dioxolane in ether at −78° C. and the mixture stirred at −78° C. for 30 mins. A solution of thionyl chloride in ether is then added, the mixture warmed to room temperature and concentrated under reduced pressure. The residue is dissolved in chloroform, filtered and dried under reduced pressure.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1.Br[C:16]1[C:24]2[C:19](=[CH:20][C:21]([S:25]([N:28](CC3C=CC(OC)=CC=3OC)[C:29]3[S:33][N:32]=[CH:31][N:30]=3)(=[O:27])=[O:26])=[CH:22][CH:23]=2)[N:18]([CH3:45])[CH:17]=1>>[CH3:45][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[C:21]([S:25]([NH:28][C:29]3[S:33][N:32]=[CH:31][N:30]=3)(=[O:26])=[O:27])[CH:20]=2)[C:16]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=2)=[CH:17]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: Cn1cc(-c2cccc(OC(F)(F)F)c2)c2ccc(S(=O)(=O)Nc3ncns3)cc21

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using (3-(trifluoromethoxy)phenyl)boronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 1-methyl-N-(1,2,4-thiadiazol-5-yl)-3-(3-(trifluoromethoxy)phenyl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.89 (s, 3 H) 7.22 (d, J=8.25 Hz, 1 H) 7.54-7.58 (m, 3 H) 7.71 (d, J=8.02 Hz, 1 H) 7.87-7.92 (m, 3 H) 7.98 (s, 1 H). m/z (ESI) 454.0 (M+H)+.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[O:10][C:11]3([CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)[CH2:12][C:5]=12.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO>O1CCOCC1.O>[C:20]1([S:26][C:4]2[CH:9]=[CH:8][N:7]=[C:6]3[O:10][C:11]4([CH:17]5[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]5)[CH2:13]4)[CH2:12][C:5]=23)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Clc1ccnc2c1CC1(CN3CCC1CC3)O2
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: c1ccc(Sc2ccnc3c2CC2(CN4CCC2CC4)O3)cc1
Temperature: 25 °C
Yield: 51.8 %

Procedure:
Sodium hydride (151 mg, 3.77 mmol) was added to a solution of 97 mg (0.387 mmol) of 4′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine], 0.40 mL (3.91 mmol) of thiophenol and 0.10 mL of methanol in 15 mL of dioxane, under a nitrogen atmosphere. The reaction was refluxed for 4 days, cooled to ambient temperature, diluted with 30 mL of water, and extracted with chloroform (3×30 mL). The combined organic extract was dried over anhydrous magnesium sulfate, concentrated in vacuo and the residue flash chromatographed on neutral silica gel using a 98:2 mixture of ammoniated chloroforn/methanol to give 65 mg (52%) of the title compound as a colourless oil: electrospray MS (m/z, relative intensity) 325 ([MH]+).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:21])=[C:4]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH2:23]([O:21][C:3]1[C:2]([F:1])=[CH:17][C:16]([N+:18]([O-:20])=[O:19])=[CH:15][C:4]=1[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:12])[CH3:10])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1O)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CN(Cc1cc([N+](=O)[O-])cc(F)c1OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
17D (2.500 g, 8.33 mmol) and (bromomethyl)benzene (1.483 mL, 12.49 mmol) were dissolved in acetone (40 mL). Cesium carbonate (5.43 g, 16.65 mmol) was added, and the reaction mixture was stirred at 50° C. for 4 h. The reaction mixture was filtered, the filter cake was washed with acetone (3×25 mL). Organic fractions were combined, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (0-50% EtOAc/hexanes). Fractions were combined and concentrated under reduced pressure to give 17E (2.789 g, 7.14 mmol, 86% yield) as a white solid. MS (ESI) m/z: 391.0 [M+1]+. 1H NMR: (400 MHz, CDCl3) δ ppm 7.94 (1H, d, J=11.54 Hz), 7.77-7.90 (1H, m), 7.39 (5H, s), 5.31 (2H, br. s.), 4.25-4.50 (2H, m), 2.78 (3H, s), 1.35-1.55 (9H, m).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-])=O)(=[O:4])=[O:3].O.NN>C(O)C.CO.[Pd]>[NH2:14][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:5]=1[S:2]([CH3:1])(=[O:4])=[O:3])[C:9]([OH:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(=O)O)cc1N
Yield: 70 %

Procedure:
4-methylsulfonyl-3-nitrobenzoic acid (0.90 g, 3.7 mmol) was dissolved in 10 mL ethanol. To it were added hydrazine monohydrate (0.46 mL, 15 mmol) and catalytic amount of 10% Pd/C. The mixture was refluxed for 1.5 hour, diluted with methanol, filtered through celite and concentrated in vacuuo to afford 3-amino-4-methylsulfonylbenzoic acid (>70%). ES-MS: (M+H)+216.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:17][CH:18]=1)[C:5]([OH:15])([C:10]#[C:11][CH:12]1[CH2:14][CH2:13]1)[C:6]([F:9])([F:8])[F:7].C(N(C(C)C)CC)(C)C.Br[CH:39]([CH2:43][CH2:44][Br:45])[C:40](Cl)=[O:41]>C(Cl)Cl>[Br:45][CH2:44][CH2:43][CH:39]1[O:15][C:5]([C:10]#[C:11][CH:12]2[CH2:13][CH2:14]2)([C:6]([F:7])([F:8])[F:9])[C:4]2[CH:3]=[C:2]([Cl:1])[CH:18]=[CH:17][C:16]=2[N:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:40]1=[O:41]
Reactant: COc1ccc(CNc2ccc(Cl)cc2C(O)(C#CC2CC2)C(F)(F)F)cc1
Reactant: O=C(Cl)C(Br)CCBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2C(=O)C(CCBr)OC(C#CC3CC3)(C(F)(F)F)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a solution of 1.64 g of 3-chloro-6-(4-methoxyphenyl)methylamino-α-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol and 2.0 mL of diisopropylethylamine in 30 mL of dry methylene chloride was added 1.6 g of 2,4-dibromobutyryl chloride. After stirring at room temperature overnight, the mixture was poured onto water and extracted with ether. The ether layer was washed with aqueous sodium bicarbonate, dried, and evaporated to an oil. This material was subjected to column chromatography over silica gel (elution with 5-10% ethyl acetate in hexanes) affording 1.13 g of the title compound as a mixture of diastereomers.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)CCl.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][C:23]([C:30]([F:33])([F:32])[F:31])=[N:22]2)=[CH:17][CH:16]=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[F:33][C:30]([F:31])([F:32])[C:23]1[CH:24]=[C:25]([C:26]([F:27])([F:28])[F:29])[N:21]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])=[CH:20][CH:19]=2)[N:22]=1
Reactant: O=C(O)C1CCCCC1
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1)C1CCCCC1
Reaction time: 0.25 h

Procedure:
A mixture of cyclohexanecarboxylic acid (0.10 g, 0.8 mmol) and EDC (0.077 g, 0.4 mmol) in CH2Cl2 (1.5 mL) was stirred for 15 minutes. 1(4′-Aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.059 g, 0.2 mmol) was added followed by dimethylaminopyridine (0.01 g, 0.1 mmol). After 3 hours the mixture was diluted with CH2Cl2 (50 mL), washed with 10% NaHCO3 (2×50 mL), brine (3×25mL), and dried over anhydrous Na2SO4. Evaporation of the solvent gave the above-named compound as a solid that crystallized from benzene (0.075 g, 92%): mp 178-180° C.; 1H NMR (CDCl3) δ 1.35 (3H, m), 1.66 (2H, m), 1.75 (1H, m), 1.85 (2H, m), 2.0 (2H, m), 2.3 (1H, m), 7.08 (1H, s), 7.45 (1H, d, J=8.5 Hz), 7.75 (2H, d, J=8.5 Hz).