Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11]O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:15]>>[Cl:15][CH2:11][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2c(c1)OCCO2
Product: ClCc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
A mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)methanol (10.6 g) in SOCl2 (10 mL) was stirred at room temperature for 10 min and then poured into ice-water. The organic layer was separated and the aqueous phase was extracted with dichloromethane (50 mL×3). The combined organic layers were washed with NaHCO3 (sat solution), water and brine, dried over Na2SO4 and concentrated to dryness to obtain 6-chloromethyl-2,3-dihydro-benzo[1,4]dioxine (12 g, 88% over two steps), which was used directly in next step.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[F:20][C:21]([F:32])([F:33])[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccccc2OC(F)(F)F)C1
Yield: 76.7 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 2-trifluoromethoxyphenylboronic acid (188 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (190 mg, 76.6%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:19].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1.Cl[Si](C)(C)C.C(N(CC)CC)C>CN(C)C=O>[CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]([NH:33][C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[O:17])=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:19]
Reactant: Nc1nnn[nH]1
Reactant: Cc1sc2nc3ccc(C(=O)O)cn3c(=O)c2c1C
Agent: C[Si](C)(C)Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1sc2nc3ccc(C(=O)Nc4nnn[nH]4)cn3c(=O)c2c1C
Yield: 59.4 %

Procedure:
From 1 g (0.0036 mol) of 2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]-thieno[2,3-d]pyrimidine-7-carboxylic acid (Example 6), 0.83 g (0.0051 mol) of 1,1'carbonyldiimidazole (Aldrich Chemical Company) in 50 ml of dimethylformamide and 0.41 g (0.004 mol) of 5-aminotetrazole monohydrate (Aldrich Chemical Company), 1.5 ml (0.012 mol) of chlorotrimethylsilane (Aldrich Chemical Company), 3.0 ml (0.022 mol) of triethylamine in 40 ml of dimethylformamide, following the procedure of Example 11, there is obtained 0.73 g of 2,3-dimethyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno-[2,3-d]pyrimidine-7-carboxamide after slurrying in boiling glacial acetic acid, cooling and filtering the precipitate; mp 297°-300° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=O)[CH2:6][CH2:5]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[S:23])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)c(Cl)cc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C1CCc2cc(Br)c(Cl)cc2N1
Temperature: 100 °C

Procedure:
To a stirred solution of 6-bromo-7-chloro-3,4-dihydroquinolin-2(1H)-one (110-2; 2.95 g, 0.0113 mol) in toluene (50 mL) was added Lawesson's reagent (2.2 g, 0.00566 mol). Reaction mass was refluxed at 100° C. for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel (60-120 mesh) column chromatography using 7% ethyl acetate in hexane to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 7.64 (s, 1H), 7.24 (s, 1H), 2.93-2.89 (t, J=6.8 Hz, 2H), 2.80-2.76 (t, J=8.0 Hz, 2H); MS (M+1): 275.8.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18])=[O:5])C.Cl>C(O)(=O)C>[F:19][C:17]([F:18])([F:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[O:9][N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnoc1-c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cnoc1-c1ccccc1C(F)(F)F
Yield: 57.8 %

Procedure:
A mixture of 5-(2-trifluoromethyl-phenyl)-isoxazole-4-carboxylic acid ethyl ester (1.43 g, 5.01 mmol, 1.0 equiv), 6M HCl aqueous solution (34 mL) and acetic acid (20 mL) were heated to reflux for 5.5 hours. After cooling, the mixture was partitioned between water and ethyl acetate and separated. The organic phase was washed sequentially with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 745 mg (58%) of crude 5-(2-trifluoromethyl-phenyl)-isoxazole-4-carboxylic acid which was used without purification.
Reaction SMILES: N[C:2]1[C:7](CO)=C(C2CCCN(C(OC(C)(C)C)=O)C2)[CH:5]=[C:4]([C:23]2C(OCC3C=CC(OC)=CC=3)=CC=CC=2OCC2CC2)[N:3]=1.O1[CH2:48][CH2:47][CH2:46]C1>>[CH:47]([N:3]([CH:4]([CH3:23])[CH3:5])[CH2:2][CH3:7])([CH3:48])[CH3:46]
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(CO)c(N)n2)cc1
Reactant: C1CCOC1
Product: CCN(C(C)C)C(C)C

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-[2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-3-(hydroxymethyl)-4-pyridinyl]-1-piperidine-carboxylate (5.0 g, 8.478 mmol), which was obtained in the step (2) of Example 17-1, and diisopropylethyl amine (4.12 mL, 25.435 mmol) in tetrahydrofuran (200 mL) under argon atmosphere was added dropwise to a solution of triphosgene (1.258 g, 4.239 mmol) in tetrahydrofuran (100 mL). The mixture was allowed to warm to room temperature, and the stirring was continued for 3 hrs. After quenched by water, the mixture was extracted with ethyl acetate. The separated organic phase was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on Silica-gel (hexane/ethyl acetate=1/1) to give tert-butyl 3-(7-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1-piperidinecarboxylate as a white form (3.2 g, yield; 61%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][CH2:8][C@@H:7]1[C:12]([OH:14])=O.[NH2:18][CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:20]([OH:24])[C:21]([NH2:23])=[O:22].O[NH-].O=[N-]>>[NH2:23][C:21](=[O:22])[C:20](=[O:24])[CH:19]([NH:18][C:12]([C@H:7]1[CH2:8][CH2:9][C:10](=[O:11])[N:6]1[CH2:5][C:4]1[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=1)=[O:14])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1cccc(F)c1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1cccc(F)c1

Procedure:
Coupling of (R)-1-(3-fluoro-benzyl)-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:7][CH2:6]1)=O.O.[NH2:20][NH2:21]>C1(C)C=CC=CC=1>[C:13]1([CH3:18])[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:20][NH2:21])=[O:2])[CH2:6][CH2:7]1
Reactant: NN
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ccccc2C)CC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccccc1O[C@H]1CC[C@H](C(=O)NN)CC1
Temperature: 120 °C

Procedure:
A mixture of trans-4-o-tolyloxy-cyclohexanecarboxylic acid methyl ester (0.091 g, 0.36 mmol) and hydrazine hydrate (0.02 ml, 0.36 mmol) was heated at 120° C. for 22 h. After cooling to room temperature the reaction mixture was suspended in toluene. After evaporation of the solvent the residue was dried in high vacuo (1-2 mbar) to give the crude title compound (0.73 g, 81%) as white solid, which was used in the next step without further purification.
Reaction SMILES: [O:1]=[O+][O-].[F:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C@H:12]([CH3:15])[CH2:13][CH3:14])=[CH:7][C:6]=1[CH:16]=C.[BH4-].[Na+]>ClCCl.CO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C@H:12]([CH3:15])[CH2:13][CH3:14])=[CH:7][C:6]=1[CH2:16][OH:1]
Reactant: C=Cc1cc(O[C@H](C)CC)ccc1F
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC[C@@H](C)Oc1ccc(F)c(CO)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ozone was bubbled through a −78° C. solution of 1-fluoro-4-{[(1R)-1-methylpropyl]oxy}-2-vinylbenzene (0.81 g, 4.17 mmol) in dichloromethane (27.8 ml) and MeOH (13.90 ml) until the reaction color remained blue. The reaction stirred 10 min, and then was purged with N2 for 10 min. MeOH (25 mL) was added, followed by sodium borohydride (0.237 g, 6.25 mmol). The reaction warmed to rt. After 1 h, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on a silica gel cartridge (12% EtOAc/hexanes) to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]3[C:15](=[O:29])[N:16]([CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=4)[N:17]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Ca+2].[Br-:35].[Br-].[Br-].C[N+](C)(C)CC1C=CC=CC=1.C[N+](C)(C)CC1C=CC=CC=1.C[N+](C)(C)CC1C=CC=CC=1>ClCCl.CO>[Br:35][C:9]1[C:10]2[N:11]([C:15](=[O:29])[N:16]([CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=3)[N:17]=2)[C:12]([CH3:14])=[N:13][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)cc2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(-c2ccc(Cl)cc2)c(Br)c2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Temperature: 60 °C
Yield: 109.5 %

Procedure:
To a solution of 7-(4-chlorophenyl)-5-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (210 mg, 0.50 mmol) in dichloromethane (10 mL) and methanol (10 mL) at room temperature under argon was added calcium carbonate (50.0 mg, 0.50 mmol) and N,N,N-trimethyl-1-phenylmethanaminium tribromide (195 mg, 0.50 mmol). The resulting suspension was stirred and heated at 60° C. under argon for 1 h. Analysis by HPLC/MS indicated that the starting material had been consumed. The solvents were removed under reduced pressure, and water (25 mL) was added. After stirring at room temperature for 30 min, the solid product was collected by filtration and further washed with water (2×10 mL). After drying, the title compound (273 mg) was obtained as an off-white solid. HPLC/MS: retention time=3.84 min, [M+H]30 =500.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][C:4]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]2[C:18]([O:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:39]=3[O:40][CH3:41])=[C:19]([O:29][CH2:30][CH2:31][OH:32])[N:20]=[C:21]([C:23]3[N:24]=[CH:25][CH:26]=[CH:27][N:28]=3)[N:22]=2)(=[O:15])=[O:14])=[CH:11][CH:12]=1)([CH3:6])[CH3:5]>O>[CH3:6][C:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([N-:16][C:17]2[C:18]([O:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:39]=3[O:40][CH3:41])=[C:19]([O:29][CH2:30][CH2:31][OH:32])[N:20]=[C:21]([C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:22]=2)(=[O:14])=[O:15])=[CH:9][CH:8]=1)([CH3:3])[CH3:5].[Na+:2]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1Oc1c([N-]S(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydroxide powder (0.43 g) was added to a mixture of bosentan (5 g) in deionized water (20 mL) and the resultant mixture was heated to 55° C. The reaction mixture was stirred for 15 minutes at the same temperature. The reaction mixture was cooled to 25° C. and the mixture was further stirred for 5 hours. The solid obtained was filtered, washed with de-ionized water and dried in air for 12 hours at 55° C. to 60° C. to obtain the title compound.
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][CH2:6][C:5]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])(S(C3C=CC=CC=3)(=O)=O)[CH2:4]2)[O:2]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CC(C)=O>[OH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:5]1[CH2:6][CH2:7][CH2:8][C:3](=[O:2])[CH:4]=1
Reactant: O=S(=O)(c1ccccc1)C1(CCCCCCCCCCO)CCCC2(C1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: O=C1C=C(CCCCCCCCCCO)CCC1
Yield: 77.4 %

Procedure:
Paratoluenesulfonic acid (20 mg) was added to a solution of 193 mg of 1,1-(ethylenedioxy)-3-(10-hydroxydecyl)-3-(phenylsulfonyl)-cyclohexane in 3 ml of chloroform and 0.6 ml of acetone. To the resulting mixture was added 10 ml of a saturated aqueous solution of sodium bicarbonate, followed by extraction with dichloromethane. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane-ethyl acetate, whereby 86 mg of 3-(10-hydroxydecyl)-2-cyclohexen-1-one were obtained in the form of a colorless oil. Yield: 77%
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][CH2:11][CH3:12])[C:4](=[O:13])[CH:3]=1.[N:14]([O-])=[O:15].[Na+].C(O)(=O)C>C(O)C.O>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][CH2:11][CH3:12])[C:4](=[O:13])[C:3]=1[N:14]=[O:15]
Reactant: O=N[O-]
Reactant: CCCn1c(=O)cc(N)n(C)c1=O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCCn1c(=O)c(N=O)c(N)n(C)c1=O
Temperature: 25 °C
Yield: 50 %

Procedure:
6-Amino-1-methyl-3-propyl-2,4(1H,3H)pyrimidinedione (V. Papesch and F. F. Schroeder, J.Org.Chem. 1951, 16 1879) (5.53 g, 27.5 mmol) was dissolved in hot 95% ethanol (20 ml)-water (120 ml). Sodium nitrite (2.32 g) and glacial acetic acid (2.4 ml) were added. The resulting mixture was allowed to cool to room temperature. Orange-pink crystals were filtered off and dried at 50° C. under vacuum to give purple crystals of 6-amino-1-methyl-5-nitroso-3-propyl-2,4 (1H,3H)-pyrimidinedione (2.92 g, 80%); mp 250°dec.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH2:5]Br.[CH3:17][C:18]([C:20]1[CH:28]=[CH:27][C:25]([OH:26])=[C:22]([O:23][CH3:24])[CH:21]=1)=[O:19].CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH2:5][O:26][C:25]1[CH:27]=[CH:28][C:20]([C:18](=[O:19])[CH3:17])=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a N2 purged flask was added 2,4-bis-trifluoromethyl benzyl bromide (2.21 g, 7.20 mmol), acetovanillone (1.32 g, 7.92 mmol), and DMF (15 mL). To the reaction solution was added fine mesh K2CO3 (3 equiv, 21.6 mmol). The reaction was allowed to stir at 70° C. for 1 h, then at 60° C. for 14 h. The reaction solution was then diluted with EtOAc (150 mL), filtered through a Buchner funnel, washed with sat'd NH4Cl (70 mL×2) washed with sat NaCl (50 mL), dried over Na2SO4, and then filtered and concentrated in vacuo to provide a crude product (2.8 g, 99% yield).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([C:12]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH3:14])[CH:9]=[CH:8][N:7]=1.[OH-].[Na+].Cl>CO>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH:13]([CH3:14])[C:12]([C:10]1[CH:9]=[CH:8][N:7]=[C:6]([O:5][CH2:4][C:3]([OH:28])=[O:2])[CH:11]=1)([OH:27])[C:23]([F:25])([F:26])[F:24]
Reactant: COC(=O)COc1cc(C(O)(C(C)c2ccc(Cl)cc2Cl)C(F)(F)F)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccnc(OCC(=O)O)c1)C(F)(F)F
Temperature: 55 °C
Reaction time: 2 h

Procedure:
{4-[2-(2,4-Dichloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-pyridin-2-yloxy}-acetic acid methyl ester (Example 120, 190 mg) was dissolved in MeOH (3 mL), and treated with 1N NaOH (0.87 mL). The reaction mixture was stirred at 55° C. (Bath temperature) for 2 h. The reaction mixture was then cooled down to r.t., pH adjusted to pH2 by addition of 1N aqueous HCl, and the MeOH evaporated in vacuo. The resulting suspension was then extracted twice with ethyl acetate, the combined organic phases washed with brine, dried over MgSO4 and concentrated in vacuo, leading to the title compound as light yellow amorphous solid (180 mg). MS (m/e)=424.1 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[CH:22]=O.O>CO>[CH3:18][C:19]1[CH:26]=[C:25]([CH:24]=[C:21]([CH3:22])[CH:20]=1)[CH2:27][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4]
Reactant: Cc1cc(C)cc(C=O)c1
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Solvent: CO
Solvent: O
Product: Cc1cc(C)cc(CN[C@@H](C)[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.8 %

Procedure:
To a solution of the amine (4) (131 mg, 0.50 mmol) and 3,5-dimethylbenzaldehyde (90 μL, 0.65 mmol) in methanol (5 mL) was added borane-pyridine complex (160 μL, 1.50 mmol) at 40° C. and the resulting mixture was stirred for 1.5 hours. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with a mixed solvent (ethyl acetate:methanol=10:1) and subsequent washing of the organic layer with saturated brine. The organic layer was dried and concentrated and the obtained crude product was purified by amine silica gel column chromatography (eluent; chloroform:methanol=7:1) to obtain the desired amine (9) as a white solid (62 mg, Yield: 33%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].C(N(CC)CC)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(OCC)(=O)C>O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:1][C@@H:2]2[CH2:6][CH2:5][CH2:4][C@H:3]2[CH2:7][OH:8])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: N[C@@H]1CCC[C@H]1CO
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(N[C@@H]1CCC[C@H]1CO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a solution of trans-2-aminocyclopentylmethanol (prepared according to LaPlae et al., J. Org. Chem., 66:5629-5632 (2001)) (1.05 g, 7.5 mmol) and triethylamine (1.25 mL, 9.0 mmol) in 25 mL tetrahydrofuran was added 4-chlorobenzenesulfonyl chloride (1.90 g, 9.0 mmol). The reaction was stirred at room temperature for 2 h, then diluted into 100 mL ethyl acetate and extracted with brine (50 mL). The organic layer was concentrated and purified by flash chromatography on a 40 g silica gel column using a gradient of 20 to 80% ethyl acetate in hexane over 30 min to give 4-chloro-N-(trans-2-hydroxymethylcyclopentyl)benzenesulfonamide (1.61 g, 74%). 1H NMR (400 MHz, CDCl3) δ ppm 7.77-7.85 (2H, m), 7.42-7.52 (2H, m), 5.10 (1H, d, J=6.29 Hz), 3.70 (1H, ddd, J=10.64, 5.22, 5.04 Hz), 3.41-3.53 (1H, m), 3.21-3.33 (1H, m), 1.70-1.98 (4H, m), 1.44-1.68 (3H, m), 1.31-1.44 (1H, m). LC/MS R.T.=2.33 min; [M+H]+=290.06.
Reaction SMILES: [C:1]([N:4]1[C:8]2=[CH:9][C:10]3[C:11]([C:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH:17]=4)=[CH:12][NH:13][C:14]=3[CH:15]=[C:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>[Pd].CO.CN(C=O)C.C(O)(=O)C>[C:1]([N:4]1[C:8]2=[CH:9][C:10]3[C:11]([CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[CH:12][NH:13][C:14]=3[CH:15]=[C:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc3[nH]cc(C4=CCN(C)CC4)c3cc21
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)N1CCc2cc3[nH]cc(C4CCN(C)CC4)c3cc21
Reaction time: 42 h

Procedure:
A mixture of 1-acetyl-7-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole (D4, 1.10 g, 3.7 mmole), 10% palladium on carbon (0.20 g) in MeOH (50 ml), DMF (10 ml) and glacial acetic acid (0.5 ml) was shaken under hydrogen at 50 psi/344.8 kPa for 42 hours. The mixture was filtered through Celite (Diatomaceous Earth) and the filtrate evaporated to dryness. The residue was dissolved in water (10 ml) and the pH adjusted to 8 with solid potassium carbonate. The precipitate was collected by filtration washed with water and dried in vacuo to leave the title compound as a buff powder (0.60 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](\[O:19][CH3:20])/[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][C:11]=1I)[CH2:2][CH2:3][CH3:4].[CH2:21]([NH:28][C:29](=[O:41])[N:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)[CH3:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](\[O:19][CH3:20])/[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][C:11]=1[C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([N:30]([CH3:31])[C:29]([NH:28][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:41])[CH:33]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(/C=C(\OC)C(=O)OC)ccc1I
Reactant: CCCCCCCNC(=O)N(C)c1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2OCCCC)c1
Temperature: 90 °C
Yield: 86.2 %

Procedure:
0.4 g (1 mmol) of methyl (Z)-3-(3-butoxy-4-iodophenyl)-2-methoxyacrylate prepared as described in Example 24c, 0.4 g (1.33 mmol) of 3-(3-heptyl-1-methylureido)phenylboronic acid and 1 mL (2 mmol) of potassium phosphate are dissolved in 10 mL of dimethylformamide. After bubbling nitrogen through the reaction mixture for 10 minutes, 2 mg (0.01 mmol) of palladium (II) acetate and 7 mg (0.02 mmol) of 2-(dicyclohexylphosphine)biphenyl are added. The reaction mixture is heated at 90° C. for 1 hour 30 minutes with vigorous stirring. After cooling, the reaction is worked up by addition of water and extraction with ethyl acetate. The organic phases are combined, washed with water and with saturated sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The crude product obtained is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture to give 0.44 g (85%) of methyl (Z)-3-[2-butoxy-3′-(1-methyl-3-heptylureido)biphenyl-4-yl]-2-methoxyacrylate in the form of an orange oil.