Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:11])=[CH:6][CH:5]=1.[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][CH2:28][C@@H:27]1[CH2:31]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][CH2:28][C@@H:27]1[CH2:31][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[O:11])[C:7]2[CH:8]=[CH:9][C:4]([I:3])=[CH:5][CH:6]=2)=[CH:13][CH:14]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: O=C(c1ccc(O)cc1)c1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(C(=O)c2ccc(I)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
To a 25 mL vial which contained a suspension of NaH (60% in mineral oil, 60 mg, 1.5 mmol) in DMF (10 mL) was added the product from step 1 (324 mg, 1 mmol) at 0° C. The mixture was allowed to warm to rt and stir at rt for 30 min then cooled to 0° C. To this reaction mixture was added (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg, 1.1 mmol) at 0° C. The resulting mixture was allowed warm to rt and stir at rt for 30 min and then was heated to 95° C. and stirred at 95° C. for 16 h. After cooling to rt, the mixture was poured onto 100 mL ice-water solution and this solution was allowed to stir at 0° C. for 30 min. The solid which formed was filtered out, dried through air to afford the title product (280 mg, 60%); 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.82-2.11 (m, 4H), 3.30-3.48 (m, 2H), 3.85-4.05 (m, 1H), 4.07-4.30 (m, 2H), 6.96-7.25 (m, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.83 (d, J=8.4 Hz, 2H):
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:20][CH2:21][NH2:22])[C:5](=[O:19])[C:6]1[C:14]([I:15])=[C:13]([NH2:16])[C:12]([I:17])=[C:8]([C:9]([OH:11])=[O:10])[C:7]=1[I:18].[Br:23][CH2:24][C:25](Br)=[O:26]>CC(N(C)C)=O>[Br:23][CH2:24][C:25]([NH:1][CH2:2][CH2:3][N:4]([CH2:20][CH2:21][NH:22][C:25](=[O:26])[CH2:24][Br:23])[C:5](=[O:19])[C:6]1[C:14]([I:15])=[C:13]([NH:16][C:25](=[O:26])[CH2:24][Br:23])[C:12]([I:17])=[C:8]([C:9]([OH:11])=[O:10])[C:7]=1[I:18])=[O:26]
Reactant: NCCN(CCN)C(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: O=C(Br)CBr
Solvent: CC(=O)N(C)C
Product: O=C(CBr)NCCN(CCNC(=O)CBr)C(=O)c1c(I)c(NC(=O)CBr)c(I)c(C(=O)O)c1I
Temperature: 40 °C
Reaction time: 20 h

Procedure:
50 g (77.8 mmol) of N,N-bis-(2-aminoethyl)-5-amino-2,4,6-triiodoisophthalic acid amide (title compound 6a) is dissolved in 500 ml of dimethylacetamide, and 70.6 g (350 mmol) of bromoacetyl bromide (Aldrich) is added in drops over 15 minutes at 0° C. Then, it is stirred for 20 hours at 40° C. The reaction mixture is poured into 4000 ml of ice water, the accumulating solid is filtered off, dissolved in 800 ml of ethyl acetate and extracted three times with 250 ml each of water. The organic phase is dried on sodium sulfate, and the solvent is evaporated to the dry state. The crude product is recrystallized from methyl-tert-butyl ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=O)[C:5](=[CH:8][C:9]=1[F:10])[CH:6]=O.[C:13]1(=[O:20])[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[C:9]([F:10])=[CH:8][C:5]2[C:4](=[CH:11][C:18]3[C:13](=[O:20])[C:14]4[C:15]([C:16](=[O:19])[C:17]=3[CH:6]=2)=[CH:11][C:4]2[C:5](=[CH:8][C:9]([F:10])=[C:2]([F:1])[CH:3]=2)[CH:6]=4)[CH:3]=1
Reactant: O=Cc1cc(F)c(F)cc1C=O
Reactant: O=C1CCC(=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1c2cc3cc(F)c(F)cc3cc2C(=O)c2cc3cc(F)c(F)cc3cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
To a solution of 4,5-difluorophthalaldehyde (Compound 22)(0.48 g, 2.8 mmol, 2 molar equivalents) and 1,4-cyclohexanedione (0.16 g, 1.4 mmol, 1 molar equivalent) in ethanol (40 ml) was added a solution of 5% aqueous NaOH (0.6 ml) at room temperature. The reaction mixture was stirred for 30 minutes at room temperature and then warmed to 60° C. After 1 hour at 60° C., the reaction mixture was cooled to room temperature. The resulting precipitate was filtered, washed with water (15 ml), ethanol (30 ml) and diethyl ether (30 ml) to give the title compound as a yellow powder (0.35 g, 64%) used as obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:21]4[C:16](=[CH:17][C:18]([C:22](O)=[O:23])=[CH:19][CH:20]=4)[CH:15]=[C:14]3[C:25](=[O:36])[NH:26][CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[CH:8]=2)=[CH:4][CH:3]=1.CCN(CC)CC>C1COCC1.ClC(OCC)=O>[CH:33]([N:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:25]([C:14]2[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:21]3[C:16]([CH:15]=2)=[CH:17][C:18]([CH2:22][OH:23])=[CH:19][CH:20]=3)=[O:36])[CH2:28][CH2:29]1)([CH3:35])[CH3:34]
Reactant: CC(C)N1CCC(NC(=O)c2cc3cc(C(=O)O)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)N1CCC(NC(=O)c2cc3cc(CO)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: -7 °C
Reaction time: 2 h

Procedure:
To a solution of 100 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-indole-5-carboxylic acid and 50 μl NEt3 in 4 ml THF, 17 μl ethyl chloroformate were added at −7° C. After stirring for 2 h at −7° C. the reaction mixture was filtered, the filtrate was treated with 24 mg NaBH4 and warmed to room temperature. After 2 h additional 24 mg NaBH4 were added and the reaction mixture stirred for 16 h. Then, 110 μl MeOH in 4 ml THF were added within 2 h and the reaction mixture was stirred for additional 4 h at room temperature. After removal of the solvents under reduced pressure the residue was purified by chromatography on silica gel eluting with DCM/MeOH 8:2. The fractions containing the product were collected and evaporated under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:19][CH3:20])=[N:7][N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)[C:9]=1[CH2:10][CH3:11])=[O:4].[CH:21]#[C:22][CH2:23][CH2:24][CH2:25][CH3:26]>N1CCCCC1.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:19][CH3:20])=[N:7][N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:13]=2)[C:9]=1[CH2:10][CH3:11])=[O:4]
Reactant: C#CCCCC
Reactant: CCc1nn(-c2cccc(Br)c2)c(CC)c1C(=O)OC
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CCCCC#Cc1cccc(-n2nc(CC)c(C(=O)OC)c2CC)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution of 4.20 g (10.0 mmol) of 1-(3-bromo-phenyl)-3,5-diethyl-1H-pyrazole-4-carboxylic acid methyl ester (intermediate 1C) in 35 ml of piperidine was treated with 0.19 g (1.0 mmol) of copper(I)iodide and 1.16 g (1.0 mmol) of tetrakis-(triphenylphosphine)-palladium. The reaction mixture was warmed up to 60° C. and after 15 min, a solution of 0.82 g=1.00 ml (10.0 mmol) of hex-1-yne in 15 ml of piperidine was added drop by drop during 1 hour. After 30 min, the oil bath temperature was steadily increased to 80° C. The reaction mixture was then stirred at 80° C. for 4 hours, and subsequently cooled down to RT. The solvent was evaporated and the residue poured into crashed ice, acidified with HCl (37%) to pH 1-2 and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (n-heptane:EtOAc 1:0-9:1) to afford the title compound as light yellow oil. MS: 339.0 (MH+).
Reaction SMILES: COC1C=CC(C[N:8]([C@H:19]2[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C@H:20]2[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)C(OCC2C=CC=CC=2)=O)=CC=1>CO.CC(O)=O.[Pd]>[NH2:8][C@H:19]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C@H:20]1[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1
Reactant: COc1ccc(CN(C(=O)OCc2ccccc2)[C@H]2CC[C@H](CN3CCCC3)[C@H]2c2ccc(F)cc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: N[C@H]1CC[C@H](CN2CCCC2)[C@H]1c1ccc(F)cc1
Yield: 77.6 %

Procedure:
A solution of 477 mg of product from Step D in 5 mL of methanol and 0.117 mL of HOAc was hydrogenated over 70 mg of 10% Pd/C at 40 psi for 18 h. The mixture was filtered and evaporated to afford 188 mg of oil. The residue was purified by flash chromatography eluting with 2 to 10% methanol in methylene chloride to obtain 108 mg of title compound. Mass spec (NH3 /CI): 263 (M+1).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]([CH:27](O)[C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)=[C:25]([CH:40]([CH3:42])[CH3:41])[CH:24]=[C:23]3[C:18]=2[C:19](=[O:45])[CH2:20][C:21]([CH3:44])([CH3:43])[O:22]3)=[CH:13][CH:12]=1.O>ClCCl>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]([CH:27]([F:7])[C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]([F:36])([F:38])[F:37])=[CH:32][CH:33]=3)=[C:25]([CH:40]([CH3:41])[CH3:42])[CH:24]=[C:23]3[C:18]=2[C:19](=[O:45])[CH2:20][C:21]([CH3:43])([CH3:44])[O:22]3)=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(OC(F)(F)F)cc1)C(=O)CC(C)(C)O2
Solvent: ClCCl
Solvent: O
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(OC(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reaction time: 2.5 h

Procedure:
At −78° C., a solution of 45 μl (340 μmol) of diethylaminosulfur trifluoride in 1 ml of dichloromethane is slowly added dropwise to a solution of 157 mg (310 μmol) of rac-5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethoxy)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 24A) in 4 ml of dichloromethane, and the mixture is stirred at this temperature for 2.5 h. The mixture is then allowed to thaw slowly to −15° C. and stirred for a further 1.5 h. Water is then added, and the mixture is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. Column chromatography of the residue on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 10:1→15:1) gives the target compound.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[C:8]([C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:18]=2)=[C:7]([C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21])[N:6]([CH3:25])[N:5]=1.O>O1CCCC1>[Br:3][C:4]1[C:8]([C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:18]=2)=[C:7]([CH:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])[N:6]([CH3:25])[N:5]=1
Reactant: COC(=O)C(=O)c1c(-c2ccc3c(c2)CCCO3)c(Br)nn1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(O)c1c(-c2ccc3c(c2)CCCO3)c(Br)nn1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
Under a nitrogen atmosphere, sodium borohydride (36 mg, 0.95 mmol) was added portionwise to a solution of methyl 2-[3-bromo-4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-1H-pyrazol-5-yl]-2-oxoacetate (11g) (300 mg, 0.79 mmol) in anhydrous tetrahydrofuran (8 mL) at 0° C. After 30 minutes stirring at 0° C., water was added (5 mL) and the mixture was concentrated in vacuo. The crude was dissolved in ethyl acetate (10 mL) then successively washed with water (10 mL), and brine (10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (dichloromethane/ethyl acetate 80/20) to provide methyl 2-[3-bromo-4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-1H-pyrazol-5-yl]-2-hydroxyacetate (11h) (204 mg, 0.54 mmol, 68%).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].S(=O)(=O)(O)O>[O-2].[O-2].[O-2].[Fe+2].[Fe+2].O>[OH2:2].[OH:2][C:1]1[C:3]([OH:4])=[CH:5][C:6]2[C:7]3[C:6](=[CH:5][C:3]([OH:4])=[C:1]([OH:2])[CH:8]=3)[C:6]3[C:7](=[CH:8][C:1]([OH:2])=[C:3]([OH:2])[CH:5]=3)[C:7]=2[CH:8]=1
Reactant: Oc1ccccc1O
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: Oc1cc2c3cc(O)c(O)cc3c3cc(O)c(O)cc3c2cc1O
Temperature: 30 °C
Yield: 68.1 %

Procedure:
Catechol (22.0 g, 0.2 moles) and diiron trioxide (ferric oxide) (31.9 g, 0.2 moles) were added into water (44 mL), and 98% sulfuric acid (176 g, 1.76 moles) was added dropwise to the solution while temperature of the solution is maintained at 30° C. or lower, to adjust the concentration in percent by weight of sulfuric acid in the reaction system at 80%. The solution was reacted at 30° C. for 6 hours with stirring. After completion of the reaction, water (200 mL) was added dropwise to the reaction solution while temperature of the solution was maintained at 30° C. or lower, and the reaction solution was stirred at the same temperature for another 30 minutes. The resultant precipitate was collected by filtration, and the obtained crude crystal was washed with water. The crude crystal was further dispersed in water (400 mL), and the dispersion liquid was stirred for 30 minutes, and then filtered to collect crystal. After the collected crystal was dispersed in acetone (400 mL), the dispersion liquid was stirred for 30 minutes. After that, the dispersion liquid was filtered to filter off insoluble matter, and activated charcoal (10.81 g) was added to the filtrate, which was then stirred for 30 minutes. After stirring, the filtrate was concentrated under reduced pressure to distill off an excess amount of acetone. Subsequently, water (160 mL) was poured into the concentrated filtrate (solution of about 160 mL). This solution was slowly heated up from 56° C. under normal pressure to concentrate the solution. Crystal precipitated when temperature of the concentrated solution became 70 to 80° C. Concentration was further continued, and stopped when temperature of the concentrated solution became 90° C. The crystal thus precipitated was collected by filtration, and then dried, to give type B′ crystal of 2,3,6,7,10,11-hexahydroxytriphenylene monohydrate (9.32 g, theoretical yield from catechol: 40.8%) in dark yellow powder form. Also, water content of the obtained the type B′ crystal was measured using a Karl-Fischer measuring instrument (Moisture Meter KF-200, manufactured by Mitsubishi Chem. Corp.), and found to be 5.5%. On the other hand, since molecular weight of 2,3,6,7,10,11-hexahydroxytriphenylene monohydrate was 342.30 (C18H12O6.H2O) and that of water was 18.02, and also theoretical water content of 2,3,6,7,10,11-hexahydroxytriphenylene monohydrate was 5.26%, the obtained type B′ crystal was confirmed to be monohydrate of 2,3,6,7,10,11-hexahydroxytriphenylene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C@H:17]([CH2:18]O)[CH2:16][O:15][C:14]3=[O:20])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(S(F)(F)F)CC)C.C(Cl)[Cl:31]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C@H:17]([CH2:18][Cl:31])[CH2:16][O:15][C:14]3=[O:20])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC[C@@H](CO)N1c1nc(-c2ccc(Br)cc2)cs1
Reactant: ClCCl
Agent: CCN(CC)S(F)(F)F
Product: O=C1OC[C@@H](CCl)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
(4R)-3-[4-(4-Bromophenyl)-1,3-thiazol-2-yl]-4-(hydroxymethyl)-1,3-oxazolidin-2-one (80 mg, 0.23 mmol), prepared in Example 71, was dissolved in 5 mL methylene chloride and cooled to −78° C. A solution of (diethylamino)sulfur trifluoride (0.034 mL, 0.25 mmol) in 5 mL of methylene chloride was added dropwise. The mixture was stirred at −78° C. for 1 h then warmed to 25° C. The reaction was quenched by pouring over ice and was then diluted with water and methylene chloride. The layers were separated and the aqueous layer was extracted with methylene chloride. The organics were combined and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (gradient 10% acetone/hexane to 20% acetone/hexane) afforded the title compound (12 mg, 14%) as a white solid. HRMS: calcd for C13H10BrClN2O2S+H+, 372.94076; found (ESI, [M+H]+), 372.9406. Analytical HPLC: retention time 10.6 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[CH2:9])[C:5]([CH3:13])=[C:4]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1)[NH2:26].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:11]([O:10][C:8]([C:6]1[C:5]([CH3:13])=[C:4]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[N:3]=[C:2]([NH:26][C:25]2[CH:27]=[CH:28][C:29]([N:30]3[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]3)=[C:23]([O:22][CH3:21])[CH:24]=2)[N:7]=1)=[CH2:9])[CH3:12]
Reactant: C=C(OCC)c1nc(Cl)nc(COCC(F)(F)F)c1C
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C=C(OCC)c1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(COCC(F)(F)F)c1C
Temperature: 120 °C
Yield: 47.4 %

Procedure:
2-Chloro-4-(1-ethoxyvinyl)-5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (70 mg, 0.23 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (46 mg, 0.23 mmol), palladium(II) acetate (8 mg, 0.03 mmol), 2-(dicyclohexylphosphino)biphenyl (12 mg, 0.03 mmol) and cesium carbonate (147 mg, 0.45 mmol) were mixed in dioxane (4 mL). The vial was capped, evacuated and flushed with nitrogen. The reaction mixture was heated by microwave irradiation at 120° C. for 1.5 h. The mixture was filtered through a pad of silica and the silica was washed by 5% of MeOH in DCM. The solvents were evaporated and the residue was purified by preparative HPLC to give the title compound 52 mg (48%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[C:12]([Cl:27])=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]4)=[CH:9][N:8]([CH3:28])[C:4]=2[N:5]=[CH:6][N:7]=1.[ClH:29]>>[ClH:27].[ClH:29].[Cl:27][C:12]1[C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH3:28])[CH:9]=2)=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][NH:16]2
Reactant: Cn1cc(-c2ccc3c(c2Cl)CCN3C(=O)OC(C)(C)C)c2c(N)ncnc21
Agent: Cl
Product: Cn1cc(-c2ccc3c(c2Cl)CCN3)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 199.9 %

Procedure:
A suspension of 1,1-dimethylethyl 5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-chloro-2,3-dihydro-1H-indole-1-carboxylate (0.716 g, 1.791 mmol) in HCl (4 M, dioxane) (30 mL, 120 mmol) was stirred at room temperature overnight. LCMS indicated good conversion. The reaction mixture was concentrated to afford 5-(4-chloro-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (667 mg, 1.790 mmol, 100% yield) as an off-white solid. LC-MS (ES) m/z=300 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d ppm 3.05 (t, J=8.59 Hz, 2H), 3.56-3.63 (m, 2H), 3.81-3.98 (m, 8H), 6.55-6.62 (m, 1H), 7.01 (d, J=7.58 Hz, 1H), 7.49 (s, 1H), 8.45 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([O:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[C:27]([CH:31]=1)[C:28](Cl)=[O:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C1C=CC=CC=1.C(OCC)C>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([O:32][CH2:33][C:34]([F:35])([F:37])[F:36])=[C:27]([CH:31]=1)[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:29])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cl)c1cc(OCc2ccccc2)ccc1OCC(F)(F)F
Reactant: NCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=C(NCc1ccccn1)c1cc(OCc2ccccc2)ccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3.2 g (0.0299 mole) of 2-aminomethylpyridine and 12.1 g (0.114 mole) of sodium carbonate in 100 ml of benzene is added dropwise a solution of 9.8 g (0.0285 mole) of 5-benzyloxy-2-(2,2,2-trifluoroethoxy)benzoyl chloride in 30 ml benzene. The mixture is stirred for about 16 hours at room temperature. Water and diethyl ether are added. The ether layer is separated, washed with water, then with saturated aqueous sodium chloride solution. The solution is dried over magnesium sulfate, and the magnesium sulfate is removed by filtration. The filtrate is evaporated to provide a white solid, 5-benzyloxy-N-(2-pyridylmethyl)-2-(2,2,2-trifluoroethoxy)benzamide. The infrared and nuclear magnetic resonance spectra of this product are consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13].N1C=CC=CC=1.[CH3:21][NH:22][S:23](Cl)(=[O:25])=[O:24].O>C(Cl)Cl>[OH:14][CH:11]([CH2:10][O:9][C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[CH2:12][O:13][S:23](=[O:25])(=[O:24])[NH:22][CH3:21]
Reactant: COc1ccccc1OCC(O)CO
Reactant: CNS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CNS(=O)(=O)OCC(O)COc1ccccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.7 %

Procedure:
A solution of 26.5 g (0.13 mole) of glycerol guaiacolate in 100 ml of methylene chloride and 10.8 ml (0.13 mole) of pyridine was added in a thin stream to a stirred solution of 17.1 g (0.13 mole) of N-methylsulfamoyl chloride (Preparation 24) in 70 ml of methylene chloride, and the reaction mixture was stirred at ambient temperature for 2 hr. The reaction mixture was treated with 150 ml of water, the layers were separated, and the organic layer was washed successively with a 200 ml portion of 2N hydrochloric acid solution, four 200 ml portions of water, dried (magnesium sulfate), and the solvent was evaporated under reduced pressure to yield a viscous oil. The oil was purified by preparative high pressure liquid chromatography. Fractions containing the desired product were combined and the solvents evaporated under reduced pressure to give 13.9 g (37%) of the title compound as a yellow gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([NH:16][C:17]2[C:18]([N:26]3[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32]C(=O)OC(C)(C)C)[CH2:27]3)=[C:19]3[CH2:25][CH2:24][CH2:23][C:20]3=[N:21][CH:22]=2)=[O:15])[N:13]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO.[NH4+].[OH-]>[NH2:32][C@H:28]1[CH2:29][CH2:30][CH2:31][N:26]([C:18]2[C:17]([NH:16][C:14]([C:12]3[N:13]=[C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[S:10][CH:11]=3)=[O:15])=[CH:22][N:21]=[C:20]3[CH2:23][CH2:24][CH2:25][C:19]=23)[CH2:27]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3c2CCC3)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3c2CCC3)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
tert-Butyl {(3S)-1-[3-({[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate (4 mg, 0.007 mmol) was dissolved in DCM (0.02 mL) and then TFA (0.03 mL, 0.4 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min. and then concentrated to give a residue, which was diluted with MeOH and neutralized with small amount of NH4OH. The mixture was filtered and purified by preparative LC-MS (XBridge™ preparative C18 30×10 mm, 5 m OBD™ column, at flow rate of 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to afford the title compound (1.9 mg, 58%). LCMS calc. for C23H24F2N5OS (M+H)+: m/z=456.2. Found: 456.1.