Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[NH:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.[Br:21][CH:22]([CH2:26][Br:27])[C:23](Cl)=[O:24]>C(N(CC)CC)C>[C:1]1([CH:7]2[N:11]([C:23](=[O:24])[CH:22]([Br:21])[CH2:26][Br:27])[CH2:10][CH:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(Br)CBr
Reactant: c1ccc(C2CNC(c3ccccc3)O2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C(Br)CBr)N1CC(c2ccccc2)OC1c1ccccc1
Reaction time: 0.5 h

Procedure:
Four and five tenths grams of 2,5-diphenyl oxazolidine was dissolved in 50 ml. of methylene chloride and 5 g. of 2,3-dibromopropionyl chloride was added and the mixture stirred in an ice bath, while 2.1 g. of triethylamine was added dropwise. After standing for about 30 minutes, the mixture was washed with water, separated and dried over magnesium sulfate and stripped under vacuum. There was obtained a yield of 7.1 g. of an oil, the title compound, ND30 = 1.5734.
Reaction SMILES: C([O:9][CH2:10][C:11]1[CH:16]=[C:15]([F:17])[N:14]=[C:13]([F:18])[CH:12]=1)(=O)C1C=CC=CC=1.C[O-].[Na+].[Cl-].[NH4+]>CO>[F:18][C:13]1[CH:12]=[C:11]([CH2:10][OH:9])[CH:16]=[C:15]([F:17])[N:14]=1
Reactant: O=C(OCc1cc(F)nc(F)c1)c1ccccc1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OCc1cc(F)nc(F)c1
Reaction time: 0.33 h
Yield: 98.4 %

Procedure:
To a stirred solution of (2,6-difluoropyridin-4-yl)methyl benzoate (10.29 g, 41.325 mmol) in anhydrous methanol (80 mL) at room temperature, was added sodium methoxide (2.23 g, 41.325 mmol). After stirring for 20 min., excess ammonium chloride was added to the reaction mixture and stirring was continued for 30 min. The mixture was then evaporated in vacuo and the residue was dissolved in methanol-MC (1:9), filtered, and the filtrate was evaporated in vacuo to give a crude product. The crude product was purified by silica gel column chromatography (eluent, EA:hexane (1:2 to 2:1)) to afford 5.9 g (98%) of (2,6-difluoropyridin-4-yl)methanol as a white solid. m.p. 66-67° C. 1H NMR (200 MHz, CDCl3) δ 2.19 (1H, t, J=5.8 Hz), 4.81 (2H, d, J=5.8 Hz), 6.84 (2H, s).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][NH:18]CC3C=CC(OC)=CC=3OC)=[N:15][CH:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31].C([SiH](CC)CC)C>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][NH2:18])=[N:15][CH:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNCc2ncc3n2CCN(Cc2ccccc2)C3)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ncc2n1CCN(Cc1ccccc1)C2
Temperature: 55 °C

Procedure:
A flask was charged with 1-(7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-N-(2,4-dimethoxybenzyl)methanamine (1.0 g, 2.6 mmol, prepared using H from 7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carbaldehyde [WO 03/076427, Preparation 138] with 2,4-dimethoxybenzylamine), DCM (20 mL) and TFA (10 mL). To the mixture was added triethylsilane (0.50 mL, 3.1 mmol) and the mixture was heated to about 55° C. for about 6 h. The solvents were removed under reduced pressure to give (7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)methanamine 2,2,2-trifluoroacetate (1.6 g) as a crude material that was used directly without further purification: LC/MS (Table 2, Method h) Rt=1.65 min; MS m/z: 243 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18]([C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1(C)C=CC=CC=1>[OH:25][C:18]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:26]2[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28](=[O:29])[N:10]1[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=C(Cl)c1ccccc1C(=O)c1ccccc1
Reactant: NCCc1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(O)(c2ccccc2)N1CCc1ccc(O)cc1

Procedure:
At room temperature, 1.46 g (10.63 mmol) of 2-(4-hydroxy-phenyl)ethylamine and 1.08 g (10.63 mmol) of triethylamine in 30 ml of absolute toluene were admixed dropwise with a solution of 2.0 g (8.17 mmol) of 2-benzoylbenzoyl chloride in 20 ml of absolute toluene. The reaction mixture was heated under reflux for 3 h and cooled, and the turbid solution was admixed with 20 ml of water. The organic phase was separated off, washed three times with 1 M aqueous hydrochloric acid and evaporated to dryness using a rotary evaporator. The solid residue was purified by column chromatography on silica gel 60. Elution was carried out using a toluene/ethyl acetate gradient (0 to 20% ethyl acetate). The product-containing fractions were evaporated to dryness using a rotary evaporator. The residue was suspended in diethyl ether and filtered off with suction. Yield: 0.21 g. M.p.: 188° C.
Reaction SMILES: B#B.[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:7][CH2:6][C:5]1=O.Cl.N>O1CCCC1>[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:7][CH2:6][CH2:5]1
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Agent: B#B
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: CN1CCN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: -10 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of 30 ml of 1.07 M diborane in tetrahydrofuran was added with stirring 1.43 g of 1-methyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one at -15° to -10° C. After further stirring at -10° C for 2 hours, the reaction mixture was poured into 100 ml of ice-water and 20 ml of concentrated hydrochloric acid was added thereto. The mixture was reflexed for one hour. After having been cooled, the resultant red solution was neutralized with 28%-aqueous ammonia, and then extracted with ether. The ether extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. There were obtained 1.35 g of 1-methyl-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepine, which were recrystallized from n-hexane to give prisms melting at 99.5° to 101,0° C.
Reaction SMILES: C([O:8][CH2:9][C:10]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH2:13][OH:14])[CH2:11][OH:12])C1C=CC=CC=1.N.[Na].[Cl-].[NH4+]>C(OCC)C>[CH:15]1([C:10]([CH2:9][OH:8])([CH2:11][OH:12])[CH2:13][OH:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: OCC(CO)(COCc1ccccc1)C1CCCCC1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OCC(CO)(CO)C1CCCCC1

Procedure:
2-Benzyloxymethyl-2-cyclohexyl-propan-1,3-diol (5.5 g.) in dry diethyl ether (50 ml.) was added to liquid ammonia (200 ml) at -70°. Sodium (2.5 g.) was added to the stirred solution. Stirring was maintained at -70°, for 1 hour. The mixture was allowed to warm up to 0° and solid ammonium chloride (15 g.) was added cautiously. The ammonia was removed from the reaction mixture under a current of nitrogen. Methanol (25 ml.) was added to the stirred mixture to destroy residual sodium. Dichloromethane (400 ml) was added and the mixture was filtered. The filtrates were evaporated in vacuo. 2-Cyclohexyl-2-hydroxymethyl-propan-1,3-diol was obtained as a colourless solid (3.2 g.).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:19]#[N:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:19]#[N:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(C2(C#N)CCOCC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#CC1(c2ccc(O)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.3 %

Procedure:
Boron tribromide (1M in DCM, 262 ml) was added to a solution of 4-(4-methoxyphenyl)-tetrahydro-2H-pyran-4-carbonitrile (14.7 g, 67.9 mmol) in DCM (294 ml) at 0° C. under N2 keeping the temperature below 5° C. The reaction was allowed to warm to room temperature and stirred for 48 hours. The mixture was cooled to −10-0° C. with dry ice acetone and quenched with saturated aqueous sodium bicarbonate (294 ml). The mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was separated and the aqueous extracted with DCM (3×250 ml). The combined organic extracts were dried over MgSO4, filtered, washed with DCM and concentrated in vacuo to give the title compound (10.8 g, 78%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Li]CCCC>CN(C=O)C.CO>[C:13]1([S:19]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([CH3:3])=[CH:5]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reaction time: 0.25 h
Yield: 85 %

Procedure:
50% sodium hydride (1.1 g) was added to a solution of 3-methylindole (4 g) dissolved in anhydrous DMF (50 ml), keeping the temperature under 30° C. Stir for 15 minutes, then drip carefully the phenylsulphonyl chloride (4.7 ml) dissolved in anhydrous DMF (20 ml) and leave under stirring for 2 hours at 25° C. Then add methanol (5 ml) to decompose the possible present traces of BuLi; remove the solvent under reduced pressure, add water (20 ml) and extract exhaustively with methylenchloride. The organic phase is made anhydrous on sodium sulfate and the solvent is removed under reduced pressure. The residue (9.5 g) is ground in methylenchloride/hexane 1:1 to obtain N-(phenylsulphonyl)-3-methylindole (2 g) (m.p. 116-120° C.). The mother liquors are chromatographied to recover more product, eluting with methylenchloride/hexane 1:1. N-(phenylsulphonyl)-3-methylindole (7 g) is recovered from the intermediate fractions, removing the solvent under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([CH:18]([CH3:20])[CH3:19])[O:15][C:14](=[O:16])[CH:13]=[C:12]([OH:17])[CH2:11]2)=[CH:4][CH:3]=1.[CH:21]([C:24]1[C:25]([S:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:26][C:27]2[S:31][CH:30]=[N:29][C:28]=2[CH:32]=1)([CH3:23])[CH3:22].CCN(CC)CC>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2([CH:18]([CH3:20])[CH3:19])[O:15][C:14](=[O:16])[C:13]([S:33][C:25]3[C:24]([CH:21]([CH3:23])[CH3:22])=[CH:32][C:28]4[N:29]=[CH:30][S:31][C:27]=4[CH:26]=3)=[C:12]([OH:17])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: CC(C)C1(CCc2ccc(F)cc2)CC(O)=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc3scnc3cc2C(C)C)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)c1cc2ncsc2cc1SC1=C(O)CC(CCc2ccc(F)cc2)(C(C)C)OC1=O

Procedure:
The title compound was prepared according to General Method 16b using 6-[(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydropyran-2-one (Example E-27; 0.5 g, 1.8 mmol), toluene-4-thiosulfonic acid S-(5-isopropyl-benzothiazol-6-yl)ester (Example BB-4; 0.65 g, 1.8 mmol), NEt3 (0.22 g, 2.16 mmol), and acetonitrile (10 mL). The crude compound was purified by flash silica gel chromatography (25% EtOAc in hexanes to 100% EtOAc to 5% MeOH in EtOAc as eluents), mp 104-105° C. MS (APCI): 486.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17](Br)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2.[N:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26][CH:25]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([C:28]3[CH:29]=[N:24][CH:25]=[N:26][CH:27]=3)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2
Reactant: OB(O)c1cncnc1
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(-c2cncnc2)c1
Yield: 32.8 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromo-4-fluorophenyl)propan-2-yl]carbamate (150 mg, 0.389 mmol), pyrimidine-5-boronic acid (75.9 mg, 0.613 mmol) and tris(dibenzylideneacetone)dipalladium(0) gave the title compound as a white solid (49 mg, 31%). 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.92 (s, 2H), 7.55-7.41 (m, 2H), 7.19 (dd, J=8.7, 9.9 Hz, 1H), 5.37 (s, 1H), 4.72-4.49 (m, 1H), 3.34-2.04 (m, 6H), 2.04-0.98 (m, 5H), 1.66 (t, J=10.9 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3) δ 159.9, 157.9, 157.4, 156.6, 154.7, 130.2, 127.85, 127.77, 126.9, 122.0, 121.8, 116.7, 116.5, 116.2, 71.6, 55.9, 54.9, 47.6, 46.7, 30.3, 29.6, 25.6, 24.8, 19.8 ppm. Purity: 93% UPLCMS (210 nm); retention time 0.63 min; (M+1) 384.9
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([C:17](OCC)=[O:18])=[CH:4][N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+].O>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:15][CH2:16]3)[NH:11][N:10]=2)[C:5]([CH2:17][OH:18])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.1 %

Procedure:
To the solution of ethyl 2-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-5-carboxylate (3.0 g, 8.5 mmol, 1 eq) in THF (300 ml) at −78° C., LiAlH4 (3.0 g) was added slowly. After stirring at RT for 1 h, Na2SO4.H2O was added and stirred at 23° C. for 0.5 h. The mixture was filtered and extracted with EtOAc (3×50 ml). The combined organic phases were washed (brine), dried (Na2SO4), filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (PE/EtOAc=1:1 as eluant) to give (2-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-5-yl)methanol (450 mg, 17.03%) as white solid. LC-MS (m/z)=311.15 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](OS(C2C=CC(C)=CC=2)(=O)=O)[C@@H:10]([N:24]=[N+:25]=[N-:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-:27].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:27])[C@@H:10]([N:24]=[N+:25]=[N-:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2N=[N+]=[N-])cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](F)[C@@H](N=[N+]=[N-])C1

Procedure:
38.2 A solution of 440 mg (3S,4S)-3-azido-4-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester in 8.6 ml 1M tetrabutylammonium fluoride solution in THF was stirred overnight at r.t. The reaction mixture was concentrated. The crude product was isolated by column chromatography (silica gel, gradient: cyclohexane->cyclohexane/EtOAc 1:1) to give 150 mg (3S,4R)-3-azido-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester as colorless liquid. MS 230 ([M])
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=2[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(O[C:26](OC2N=CC=CC=2)=[S:27])N=CC=1>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([N:18]=[C:26]=[S:27])[CH:13]=[CH:14][C:15]=2[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N)c2c1N(C(=O)OC(C)(C)C)CC2
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(N=C=S)c2c1N(C(=O)OC(C)(C)C)CC2
Reaction time: 1 h
Yield: 93.6 %

Procedure:
1-t-Butoxycarbonyl-4-amino-2,3-dihydro-7-methylindole (1.625 g, 6.55 mmol) is dissolved in methylene chloride (15 mL). To this solution is added 4-dimethylaminopyridine (0.160 g, 1.31 mmol) and di-2-pyridyl thionocarbonate (1.52 g, 6.55 mmol). The volume of solvent is brought to 30 mL, and the solution is allowed to stir for one hour. The solution is diluted to 150 mL with chloroform and washed first with four 75-mL portions of aqueous citric acid solution followed by three 100-mL portions of aqueous potassium carbonate. The organic layer is dried over anhydrous potassium carbonate, filtered and the solvent is removed by rotary evaporation to yield an orange, oily solid. The crude product is purified by silica gel flash column chromatography using 4% ethyl acetate/hexanes to afford 1.78 g of N-t-butoxycarbonyl-2,3-dihydro-4-isothiocyanato-7-methylindole as a white solid (94% yield).
Reaction SMILES: C(OC([NH:8][NH:9][C:10]([C:12]1[CH:16]=[CH:15][O:14][N:13]=1)=[O:11])=O)(C)(C)C.Cl.O1CCOCC1>>[O:14]1[CH:15]=[CH:16][C:12]([C:10]([NH:9][NH2:8])=[O:11])=[N:13]1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccon1
Agent: Cl
Solvent: C1COCCO1
Product: NNC(=O)c1ccon1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Solid t-butyl-2-(3-isoxazolylcarbonyl)hydrazinecarboxylate (I88) (510 mg, 1.639 mmol) was treated with a solution of hydrochloric acid (4 M) in dioxane (8.19 ml, 32.8 mmol) and stirred under argon at RT for 6 hr. The solvent was evaporated in vacuo and the residue dissolved in methanol (˜10 ml), added to a 10 g SCX column and eluted with Dichloromethane (˜50 ml), methanol (˜50 ml) and a solution of ammonia (2 M) in methanol (˜100 ml). The basic fractions were combined and evaporated in vacuo to afford the free base as yellow dendriform crystals in 211.0 mg.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][C:22]([F:31])([F:30])[CH:23]([F:29])[O:24][C:25]([F:28])([F:27])[F:26])[C:3]=1[Cl:32].N(OC(C)(C)C)=O>O1CCCC1>[Cl:32][C:3]1[C:4]([O:21][C:22]([F:31])([F:30])[CH:23]([F:29])[O:24][C:25]([F:26])([F:27])[F:28])=[N:5][N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[CH:2]=1
Reactant: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)c(Cl)c2N)cc1SCC(F)(F)F
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: Cc1cc(F)c(-n2cc(Cl)c(OC(F)(F)C(F)OC(F)(F)F)n2)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.9 g of 5-amino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole was dissolved in 30 mL of acetonitrile, and 0.27 g of N-chlorosuccinimide was added under cooling with ice. After stirring for 10 minutes under cooling with ice, the solvent was distilled off under reduced pressure, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 5-amino-4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole. Then, the obtained pyrazole derivative was dissolved in 30 mL of tetrahydrofuran, and 0.3 mL of t-butyl nitrite was added under cooling with ice. After stirring at room temperature for 12 hours, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:hexane=1:10) to obtain 0.75 of 4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)\[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[C:21](#[N:23])[CH3:22]>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([O:3][C:4]([C:5]1[C:21]([CH3:22])=[N:23][N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:20])[CH3:2]
Reactant: CCOC(=O)/C=C(\Nc1ccccc1)c1ccccc1
Reactant: CC#N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: CCOC(=O)c1c(C)nn(-c2ccccc2)c1-c1ccccc1
Yield: 88 %

Procedure:
According to AVV A, (Z-3-phenyl-3-phenylamino acrylic acid ethylester (267.3 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into acetonitrile (3.0 ml, 57.1 mmol, 57.1 equiv.) for 21 hours at 110° C. The blue-green raw product (389.3 mg) was purified by means of column chromatography (silica gel (50 g), pentane/EtOAc 98:2→0:100). The product was obtained in the form of a white solid (269.3 mg, 0.88 mmol, 88%).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>O1CCOCC1.O>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)CCc1cn(Cc2ccc(C(=O)OC(C)(C)C)cc2OC)c2cc(C(=O)NCC3CCCC3)ccc12
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CCc1cn(Cc2ccc(C(=O)O)cc2OC)c2cc(C(=O)NCC3CCCC3)ccc12
Reaction time: 24 h
Yield: 32.1 %

Procedure:
A solution of t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-methoxycarbonylethyl)indol-1-ylmethyl]-3-methoxybenzoate (1.04 g) in dioxane (6 ml) was treated with triethylamine (0.65 ml) and trimethylsilyl trifluoromethanesulphonate (0.8 ml). The solution was stirred for 24 hours and then was diluted with water to give a viscous oil. The liquids were decanted and the oil was triturated successively with water and hexane. The resultant solid was recrystallized from ethyl acetate/hexane to give 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-methoxycarbonylethyl)indol-1-ylmethyl]-3-methoxybenzoic acid (0.3 g, 32%) as an ivory powder; mp 181-182°.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:12][CH:11]=1.N1C=CN=C1>CN(C)C=O>[Si:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)OCc2ccccc2)cc1
Reaction time: 4 h
Yield: 62.5 %

Procedure:
t-Butyldimethylsilyl chloride (3.07 g, 20.4 mmol) was added in one portion to a stirred solution of benzyl (4-hydroxyphenyl)acetate (4.70 g, 19.4 mmol) and imidazole (1.39 g, 20.4 mmol) in dimethylformamide (25 mL) at room temperature under nitrogen. After stirring for 4 h the volatiles were evaporated and the residue partitioned between water (100 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous phase washed with ethyl acetate (2×100 mL). The organic extracts were combined, dried (magnesium sulfate) and the solvent evaporated. The residue was chromatographed on silica gel (10% diethyl ether: cyclohexane) to give the title compound as a colourless oil (4.32 g, 62%). LC/MS: 4.13 min; z/e 374, calcd (M+18) 374. 1H NMR (400 MHz: CDCl3): 7.15 (5H), 6.95 (2H), 6.60 (2H), 4.95 (2H) 3.40 (2H), 0.8 (9H), 0.00 (6H).