Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)[O-].[K+].[C:7]([O:11][C:12]([NH:14][C@H:15]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:16]([O-:18])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH:26]1([NH2+]C2CCCCC2)CCCCC1.C[Si](C=[N+]=[N-])(C)C>CCOCC>[CH3:26][O:17][C:16](=[O:18])[C@H:15]([NH:14][C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1
Reactant: C1CCC([NH2+]C2CCCCC2)CC1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)[O-])c1ccc(Cl)cc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOCC
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
A 0.5 N potassium bisulfate aqueous solution (7.9 mL) was added to a suspension of dicyclohexylammonium (R)-t-butoxycarbonylamino-(4-chloro-phenyl)acetate (605.6 mg, 1.30 mmol) in ether (16 mL), and the mixture was stirred for 10 minutes. Then, the aqueous layer was extracted with ether. The organic layer was washed with water and then brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in benzene (3.6 mL) and methanol (1.8 mL). A solution of trimethylsilyldiazomethane in ether (2 M, 0.71 mL, 1.43 mmol) was added dropwise under cooling with ice, and then the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=4/1) to give the title compound (378.9 mg, 97%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([OH:14])([C:10]([F:13])([F:12])[F:11])[CH2:6][C:7]([CH3:9])=[CH2:8])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4](=[O:15])[C:5]([OH:14])([C:10]([F:13])([F:12])[F:11])[CH2:6][C:7]([C:25]1[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=1[O:27][CH3:28])([CH3:9])[CH3:8])[CH3:2]
Reactant: COc1ccc(F)cc1
Reactant: C=C(C)CC(O)(C(=O)OCC)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)C(O)(CC(C)(C)c1cc(F)ccc1OC)C(F)(F)F
Temperature: 0 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
To a mixture of 5.9 g (26.1 mmol) of the above 2-hydroxy-4-methyl-2-trifluoromethylpent-4-enoic acid ethyl ester in 30 mL of 4-fluoroanisole was added in several portions 5.2 g (39.4 mmol) of aluminum chloride. The mixture became exothermic and turned black with the first addition and was cooled with an ice-water bath. The mixture was stirred for 3 days and was then poured into 200 mL of ice-cold 1N aqueous HCl and extracted with three 150 mL portions of EtOAc. The combined organic layers were washed with 50 mL of 1N aqueous hydrochloric acid, three 50 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with EtOAc-hexanes (1:9, then 2:8, then 3:7, then 4:6) to afford 6.6 g (71%) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester.
Reaction SMILES: C([O:5][C:6](=[O:31])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([N:14]([CH3:30])[NH:15][CH:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:13])(C)(C)C.Cl>CCOCC>[CH3:30][N:14]([C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:31])=[O:5])=[O:13])[NH:15][CH:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(CCc1ccccc1)NN(C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C(CCc1ccccc1)NN(C)C(=O)N1CCC[C@H]1C(=O)O
Yield: 86.1 %

Procedure:
A solution of 0.4 g of the product of Example 1 in 50 ml anhydrous ether was treated with dry HCl gas at 0° C. for two hours. Solvent was evaporated to dryness. Purification of the crude product through Dowex 50 X 2-100, resin gave 0.3 g of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:24][S:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1)(=[O:27])=[O:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:13][CH2:14][N:15]([CH:18]3[CH2:23][CH2:22][N:21]([C:32]([C:31]4[CH:30]=[CH:29][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:36][CH:35]=4)=[O:33])[CH2:20][CH2:19]3)[CH2:16][CH2:17]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCN(C2CCNCC2)CC1
Product: CS(=O)(=O)c1ccc(C(=O)N2CCC(N3CCC(S(=O)(=O)c4ccc(Cl)c(Cl)c4)CC3)CC2)cc1

Procedure:
The product of step 5 was coupled to 4-methanesulfonyl-benzoic acid following the procedure of Example 2 step c.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]1(=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[O:7]1.CCN(CC)CC>C1(C)C=CC=CC=1>[OH:5][CH2:4][CH2:3][CH2:2][N:1]1[C:6](=[O:7])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:15]
Reactant: NCCCO
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCO
Yield: 67 %

Procedure:
To a solution of 3-aminopropan-1-ol (1.0 g, 13.1 mmol) and isobenzofuran-1,3-dione (2.0 g, 13.1 mmol) in toluene (25 mL, 3 mL/mmol) was added Et3N (2 mL, 13.1 mmol) and the reaction was heated at reflux for 24 h. Then reaction was quenched with water and extracted with EtOAc (2×40 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford 2-(3-hydroxypropyl)isoindoline-1,3-dione (1.8 g, 87%). Observed mass (M+1): 206.1. This material was taken to the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:3]1.[H][H]>CO.[Pt](=O)=O>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]([CH3:1])([CH3:20])[CH2:3][CH:4]([O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:5]1
Reactant: CC1(C)CC(Oc2ccc([N+](=O)[O-])cc2)CC(C)(C)C1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: CC1(C)CC(Oc2ccc(N)cc2)CC(C)(C)C1

Procedure:
Under atmospheric pressure, 8.3 g of 4-(3,3,5,5-tetramethylcyclohexyloxy) nitrobenzene in 500 ml of methanol are hydrogenated in the presence of 400 mg of platinum dioxide until the uptake of hydrogen has ended. The catalyst is filtered off, the solution is then concentrated using a rotary evaporator and the residue, a brownish oil which slowly solidifies, is used for the further reactions without any further purification.
Reaction SMILES: Cl.FC(F)(F)C([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]5[O:39][CH:38]=[N:37][CH:36]=5)[CH:30]=4)[N:23]=3)=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:8]=1)=O.[Li+].[OH-]>C1COCC1.O>[NH2:6][C:7]1[CH:8]=[C:9]([C:13]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]5[O:39][CH:38]=[N:37][CH:36]=5)[CH:30]=4)[N:23]=3)=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Yield: 98 %

Procedure:
A solution of 2,2,2-trifluoro-N-{3-[3-(2-{[3-(1,3-oxazol-5-yl)phenyl]amino}-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}acetamide hydrochloride (0.68 g, 1.26 mmol) and LiOH (69 mg, 1.64 mmol) in THF (15 mL) and water (5 mL) was stirred for 6 h at 50° C. The reaction was extracted with DCM. The combined organic phases were dried over MgSO4 and evaporated down to give the title compound as a tan solid, (0.55 g, 98% yield). 1H NMR (400 MHz, d6-DMSO): δ 9.73 (s, 1H), 8.82 (d, J=6.7 Hz, 1H), 8.60 (d, J=8.9 Hz, 1H), 8.42 (s, 1H), 8.29 (d, J=5.3 Hz, 1H), 8.24 (s, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.61 (s, 1H), 7.35-7.44 (m, 3H), 7.10-7.19 (m, 2H), 6.83 (s, 1H), 6.69-6.73 (m, 2H), 6.58 (d, J=5.3 Hz, 1H), 5.30 (bs, 2H) ppm. ES-LC/MS m/z=446 [M+H]+.
Reaction SMILES: [N:1]1([C:6](=O)[CH2:7][CH:8]2[CH2:16][CH2:15][CH2:14][C:13]3[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=[CH:10][C:9]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[N:1]1([CH2:6][CH2:7][CH:8]2[CH2:16][CH2:15][CH2:14][C:13]3[NH:12][CH:11]=[CH:10][C:9]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CCCC3CC(=O)N2CCCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1cc2c([nH]1)CCCC2CCN1CCCC1

Procedure:
Pyrrolidin-1-yl-2-[1-(toluene-4-sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-yl]-ethanone (840 mg) was reduced using lithium aluminum hydride (4 eq.) in THF (80 mL) at reflux for 5 hours to give 480 mg of mainly 4-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-indole as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[CH3:28].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:27][CH3:28])[C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)OC(C)(C)C)[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a solution of (S)-benzyl 3-(tert-butoxycarbonylamino)piperidine-1-carboxylate (500 mg, 1.49 mmol) in DMF (5 mL) was added NaH (60% suspension in mineral oil, 120 mg, 1.64 mmol) and the reaction mixture was stirred for 1 h. To the reaction mixture was added ethyl bromide (0.12 mL, 1.64 mmol) and the reaction mixture was stirred for 4 h. The reaction mixture was diluted with ice-cooled water and the solution was extracted with EtOAc, the EtOAc layer was dried over Na2SO4 and concentrated in vacuo to give the crude product that was purified by column chromatography (silica gel, gradient, EtOAc in hexanes) to give (300 mg, 55%) of the titled compound. 1H NMR (400 MHz, CDCl3): δ 7.36-7.30 (m, 5H), 5.18-5.12 (m, 2H), 4.18-4.13 (m, 2H), 3.68-3.62 (m, 1H), 3.22-3.17 (m, 2H), 3.01-2.85 (m, 1H), 2.68-2.59 (m, 1H), 1.89-1.81 (m, 1H), 1.78-1.73 (m, 2H), 1.55 (s, 9H), 1.54-1.48 (m, 1H), 1.08 (t, J=6.4 Hz, 3H). ES-MS: m/z [M+1]=363.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:7][CH2:6]1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.O>C1(C)C=CC=CC=1>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][O:3][CH2:4][CH:5]1[CH2:7][CH2:6]1
Reactant: BrCCCCBr
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: BrCCCCOCC1CC1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
2.8 g of a 60% suspension of sodium hydride in mineral oil are added in portions to a solution of 5.0 g of hydroxymethylcyclopropane in 25 ml of toluene at room temperature. The mixture is then heated at 100° C. for 2 hours. After this, it is allowed to reach room temperature and a solution of 14.9 g of 1,4-dibromobutane in 15 ml of toluene is added. The mixture is left to stir at 100° C. for a further 15 hours. Then, at room temperature, 10 ml of water are added, the phases are separated, and the toluene is removed in a rotary evaporator. The product is isolated by vacuum distillation.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@@:7]([C:16]([F:19])([F:18])[F:17])([OH:15])[C:6]=2[CH:5]=[C:4]([OH:20])[CH:3]=1.C1(C)C=CC(S(O[CH2:31][CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@@:7]([C:16]([F:18])([F:19])[F:17])([OH:15])[C:6]=2[CH:5]=[C:4]([O:20][CH2:31][CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[CH:3]=1
Reactant: Oc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)CCOc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Temperature: 70 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
Under a nitrogen atmosphere, (9R)-4-chloro-9-(trifluoromethyl)-9H-fluorene-2,9-diol (55.5 g) was dissolved in N,N-dimethylformamide (550 ml), 3-hydroxy-3-methylbutyl toluene-4-sulfonate (49.6 g) and potassium carbonate (39.5 g) were added, and the mixture was stirred at an oil bath temperature of 70° C. overnight. To the reaction mixture was added a solution of 3-hydroxy-3-methylbutyl toluene-4-sulfonate (4.0 g) in N,N-dimethylformamide (5 ml), and the mixture was further stirred at the same temperature for 9.5 hr. The reaction mixture was ice-cooled, water (800 ml) was added, and the mixture was extracted with ethyl acetate (900 ml). The obtained organic layer was washed with water (500 ml, 3 times) and saturated brine (500 ml). The obtained organic layer was dried over anhydrous sodium sulfate, the insoluble material was filtered off, and the solvent in the filtrate was evaporated. The obtained residue was purified by silica gel column chromatography (a mixture of hexane and ethyl acetate was used as an elution solvent, first eluted with a mixture of (hexane:ethyl acetate) at a mixing ratio 3:1, and then with the mixture at a mixing ratio 2:1, and further with the mixture at a mixing ratio 3:2) to give the title compound (49.5 g).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[C:10]1([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][CH2:18]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:18][CH2:17][CH:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: CCOC(CN)OCC
Reactant: BrCCC(c1ccccc1)c1ccccc1
Product: CCOC(CNCCC(c1ccccc1)c1ccccc1)OCC
Yield: 60.8 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-1, 2,2-diethoxyethanamine (5.82 ml, 40 mmol) was reacted with 3,3-diphenylpropyl bromide (5.50 g, 20 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: n-hexane:ethyl acetate=90:10 to 80:20) to obtain the title compound (3.98 g, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[O:18][CH3:19].C([Li])(C)(C)C.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br>O1CCCC1>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:18][CH3:19])[CH:5]=1)[S:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1
Reactant: COc1ccc(CSc2ccc(C)cc2)cc1OC
Reactant: BrCCCCCBr
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(CCCCCBr)Sc2ccc(C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 13.72 g of 1,2-dimethoxy-4-[[(4-methylphenyl)thio]methyl]benzene in 200 mL of tetrahydrofuran (dried over 3A sieves), under nitrogen, is cooled to -78° C. and 30 mL of 1.7M t-butyl lithium is added. After 30 minutes, the solution is transferred, via a canula, into a stirred solution of 14.0 mL of 1,5-dibromopentane in 25 ml of tetrahydrofuran, under nitrogen at -78° C. The reaction is slowly warmed to room temperature, and the reaction is quenched by the addition of 4 mL of acetone. The reaction is concentrated in vacuo and the residual material is dissolved in ethyl acetate and is washed with brine. Drying (sodium sulfate) and solvent removal affords 33.22 g of oil. The residue is purified via chromatography on silica gel with gradient elution progressing from hexane to chloroform to methyl alcohol to afford 10.82 g of the desired product as a tan gum. MS(FAB): m/z 299(M-TolSH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:22][CH3:23]>CC(C)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:22][CH3:23])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of 4-(4-bromophenyl)-phenol (4.06 g, 16.3 mmol) in acetone (30 mL) at room temperature, was added 4.5 eq K2CO3 (4.0M, 18 mL, 73.3 mmol) in water and 4.0 eq Iodoethane (5.26 mL, 65.2 mmol). The reaction mixture was stirred overnight, and heated to reflux for 6 hrs. The product was crystallized out of the solution, and filtered. The crude product was recrystallized from hexane to provide ethyl 4-(4-bromophenyl) phenyl ether (4.1 g, 91%) as an white crystal.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[CH:16](OS(C)(=O)=O)[C:17]1[CH:28]=[CH:27][CH:26]=[CH:25][C:18]=1[CH2:19]OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:34]([N:41]1[CH2:19][C:18]2[C:17](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]1[C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CS(=O)(=O)OCc1ccccc1C(OS(C)(=O)=O)c1cc(F)ccc1OCc1ccccc1
Reactant: NCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(OCc2ccccc2)c(C2c3ccccc3CN2Cc2ccccc2)c1
Temperature: 70 °C

Procedure:
To a solution of (±)-methanesulfonic acid 2-[(2-benzyloxy-5-fluoro-phenyl)-methanesulfonyloxy-methyl]-benzyl ester (650 mg, 1.31 mmol, 1.0 eq.) in DMF (15 mL), benzylamine (0.19 mL, 1.71 mmol, 1.3 eq.) and DIPEA (0.69 mL, 3.94 mmol, 3.0 eq.) were added in sequence. The mixture was heated at 70° C. for 2 days. The reaction mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was filtered and then purified by prep. HPLC (column: Water X-Bridge, 30×75 mm, 10 um, UV/MS, basic conditions) and concentrated in vacuo to give (±)-2-benzyl-1-(2-benzyloxy-5-fluoro-phenyl)-2,3-dihydro-1H-isoindole.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].CC(C)=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O>[Cl:1][CH2:2][CH2:3][C:4]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C(CCCl)Nc1ccccc1

Procedure:
A mixture of 3-chloropropionyl chloride (300 ml) and acetone (600 ml) is added dropwise to a refluxing mixture of aniline (575 ml) and acetone (600 ml). The reaction mixture is refluxed for one hour, cooled in an ice bath, and poured into a mixture of 6N HCl (500 ml) and water (3.5 l). The resulting solid is filtered, washed with water, and dried, yielding the desired product, M.P. 114°-115.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:14]1[N:18]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C:17]2[CH:29]=[CH:30][CH:31]=[CH:32][C:16]=2[N:15]=1.ClC1C=CC=C(C(OO)=[O:41])C=1.C(=O)([O-])O.[Na+]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([C:14]1[N:18]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[C:17]2[CH:29]=[CH:30][CH:31]=[CH:32][C:16]=2[N:15]=1)=[O:41]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccccc1)n1c(Sc2ccccc2-c2ccccn2)nc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)n1c(S(=O)c2ccccc2-c2ccccn2)nc2ccccc21
Reaction time: 3 h

Procedure:
Phenylmethyl 2-[2-(pyridyl)-phenyl thio]benzimidazole-1-carboxylate (0.41 mmole) in dry dichloromethane (10 ml) was treated at 0° with a solution of m-chloroperbenzoic acid (0.48 mmole) in dichloromethane (5 cm3). The mixture was stirred for 3 hours at between 0° and 10° and then poured into aqueous sodium hydrogen carbonate. The organic phase was separated, dried (MgSO4), filtered and evaporated to give a pale brown foam. The foam was taken up into dichloromethane and flash chromatographed (4/1 CH2Cl2 /60:80 petroleum ether) to give the title compound as a yellow gum.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)[N:10]=[CH:9][C:8]=1[C:23]([O:25]CC)=[O:24])([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:20])([F:22])[F:21])[CH:13]=2)[N:10]=[CH:9][C:8]=1[C:23]([OH:25])=[O:24])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)c(C(F)(F)F)c2)c1C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1c(C(=O)O)cnn1-c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 82.7 %

Procedure:
A solution of Sodium hydroxide (6.67 mL, 13.34 mmol) was added in one portion to a stirred solution of ethyl 5-tert-butyl-1-(4-chloro-3-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylate (Intermediate#120) (1 g, 2.67 mmol) in methanol (20 mL). The resulting suspension was stirred at 80° C. for 6 hours. The resulting mixture was evaporated to remove the methanol, washed with ether (20 mL). The reaction mixture was acidified with 2M HCl, extracted with ethyl acetate(2×30 mL) The organic layers were combined and washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered and evaporated to afford pure 5-tert-butyl-1-(4-chloro-3-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylic acid (0.766 g, 83%).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:26])[CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][CH2:9][C@H:8]([NH:17]C(OC(C)(C)C)=O)[C:7]1=[O:25]>C(Cl)Cl>[ClH:1].[CH3:2][O:3][C:4](=[O:26])[CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][CH2:9][C@H:8]([NH2:17])[C:7]1=[O:25]
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CN1C(=O)[C@@H](N)CNc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Anhydrous HCl was bubbled into a solution of (3S)-2-oxo-3-tert-butoxycarbonylamino-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-acetic acid methyl ester (600a/103, 4.0 g, 11.4 mmol) in 20 ml of CH2Cl2 for 20 min then stirred for 1 h at RT. The reaction was evaporated to give (3S)-2-oxo-3-amino-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-acetic acid methyl ester hydrochloride as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1C(O)=O.Cl.C(O)(C)C>O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Nc1c(C(=O)O)cnn1-c1ncc(Cl)cc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Nc1ccnn1-c1ncc(Cl)cc1Cl
Yield: 92.4 %

Procedure:
16.5 g (0.06 mole) of 5-amino-1-(3,5-dichloropyrid-2-yl)-pyrazole-4-carboxylic acid are slowly heated to 80° C. in a mixture of 150 ml of water, 75 ml of concentrated hydrochloric acid and 20 ml of isopropanol and the reaction mixture is stirred at this temperature until the evolution of gas has ended. The clear solution formed is evaporated to dryness, the residue is suspended in methylene chloride, the suspension is neutralized with aqueous sodium carbonate solution, the organic phase is separated off and the aqueous phase is extracted twice more with methylene chloride. The combined organic phases are dried over sodium sulphate and freed from the solvent in vacuo. 12.7 g (92% of theory) of 5-amino-1-(3,5-dichloropyrid-2-yl)-pyrazole are obtained as an oil. 1H-NMR (CDCl3 /TMS as the internal standard): δ=4.55; 5.55; 7.43; 7.88; and 8.30 ppm.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([O:8]C)[CH:5]=[CH:6][CH:7]=1.Br[CH:11]([CH3:24])[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=O>>[CH3:24][C:11]1[S:1][C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][C:7]=2[C:12]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=1
Reactant: CC(Br)C(=O)c1ccc(C(F)(F)F)cc1
Reactant: COc1cccc(S)c1
Product: Cc1sc2cc(O)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to examples 26.1-26.3, 3-Mercaptoanisole and 2-Bromo-1-(4-trifluoromethyl-phenyl)-propan-1-one were converted to yield 2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-ol as colorless amorphous solid, MS: 308 (M).