Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@@H:32]([CH2:36][CH3:37])[C@H:33]([OH:35])[CH3:34]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@@H:32]([CH2:36][CH3:37])[C@H:33]([OH:35])[CH3:34])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH3:12]
Reactant: CC[C@H](N)[C@@H](C)O
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CS(C)=O
Product: CC[C@H](Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1)[C@@H](C)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (2.5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.2 mL, 10.96 eq, 1.14 mmol) followed by (2R,3S)-3-amino-pentan-2-ol (60 mg, 5.5 eq, 0.58 mmol). The reaction mixture was placed in a preheated oil bath at 160° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and water (50 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 25 mg (65%). (80% de 3S,2R: 20% de 3S,2S). 1H-NMR (d-CDCl3, 250 MHz): δ 0.90 & 1.05 (2×t, 3H, J=6.48 & 7.42 Hz, —NHCH(CH2CH3)CH(CH3)OH), 1.16 & 1.24 (2×d, 3H, J=6.31 & 6.16 Hz, —NHCH(CH2CH3)CH(CH3)OH) 1.57 (d, 6H, J=6.79 Hz, —CH(CH3)2), 1.77-2.09 (m, 2H, —NHCH(CH2CH3)CH(CH3)OH), 3.91-4.04 (m, 2H, —NHCH(CH2CH3)CH(CH3)OH), 4.58-4.69 (m, 1H, —CH(CH3)2), 4.83 (m, 3H, —HNCH2-Pyr & OH), 6.11-6.23 (m, 1H, —NHCH(CH2CH3)CH(CH3)OH), 7.24-7.32 (m, 3H, 2×Pyr-H+—N═CH—N—), 7.53-7.57 (m, 1H, Pyr-H), 7.74 (d, 1H, J=7.58 Hz, Pyr-H), 8.67 (m, 1H, HNCH2-Pyr). FABMS m/z (relative intensity): 370 ([M+H]+, 100), 324 (40), 289 (15), 243 (10), 233 (13), 199 (10). Accurate Mass (M+H): Actual: 370.2355, Measured: 370.2347.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH3:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH:35]=O)=[C:29]([CH3:37])[CH:28]=1>C1COCC1.CCOC(C)=O>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][N:23]2[CH2:24][CH2:25][CH:20]([CH3:19])[CH2:21][CH2:22]2)=[C:29]([CH3:37])[CH:28]=1
Reactant: Cc1cc(Br)ccc1CCC=O
Reactant: CC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ccc1CCCN1CCC(C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.70 g (3.30 mmol) of sodium triacetoxyborohydride and 0.16 mL of glacial acetic acid were added to a solution of 0.32 mL (2.70 mmol) of 4-methylpiperidine and 0.60 g (2.64 mmol) of 3-(4-bromo-2-methylphenyl)propionaldehyde in 10 mL of THF and the mixture was stirred for 2 hours at RT. The reaction mixture was diluted with EtOAc, and the organic phase was washed with semisaturated aqueous sodium bicarbonate solution washed, dried over magnesium sulfate, and evaporated down in vacuo. Yield: 0.65 (78% of theoretical); C16H24BrO (M=310.273); calc.: molpeak (M+H)+: 310/312 (Br); found: molpeak (M+H)+: 310/312 (Br); Rf value: 0.28 (silica gel, PE/EtOAc 3:2).
Reaction SMILES: [CH3:1][Mg]Cl.[CH:4]([S:7]([N:10]1[C:14]2[CH:15]=[C:16]([C:19](=[O:28])[C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[F:27])[CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[NH2:29])(=[O:9])=[O:8])([CH3:6])[CH3:5]>O1CCCC1>[NH2:29][C:11]1[N:10]([S:7]([CH:4]([CH3:6])[CH3:5])(=[O:8])=[O:9])[C:14]2[CH:15]=[C:16]([C:19]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[F:27])([CH3:1])[OH:28])[CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: C[Mg]Cl
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=O)c3cc(F)ccc3F)cc21
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(C)(O)c3cc(F)ccc3F)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
Methyl magnesium chloride (929 mL, 2.79 mol, 3M in tetrahydrofuran) was added slowly over 30 minutes to a solution of 1-isopropylsulfonyl-2-amino-6-(2,5-difluorobenzoyl)benzimidazole (352.7 g, 0.929 mol) in tetrahydrofuran while maintaining the temperature between -20° C. and -30° C. When the addition was complete, the reaction mixture was warmed slowly to room temperature over 2 hours. Additional 3M methyl magnesium chloride (186 mL, followed by 46.5 mL) was added until less than 1% ketone starting material remained by HPLC analysis. The reaction was quenched by the sequential addition of ethyl acetate (4.2 L) and 1N hydrochloric acid (4.2 L) and the mixture stirred for 1 hour. The phases were separated and the aqueous phase extracted with ethyl acetate (2.0 L). The combined organic fractions were washed with brine (4.0 L) and dried over magnesium sulfate. After filtration, removal of the solvent by rotary evaporation afforded 373 g of the title compound as a beige foam (93% purity, 94% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[S:21][C:20]([NH2:22])=[N:19][N:18]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:33][C@H:34]([CH3:37])[CH2:35][OH:36])(=[O:32])=[O:31]>>[NH2:22][C:20]1[S:21][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:24]3[C:25]([S:30]([NH:33][C@H:34]([CH3:37])[CH2:35][OH:36])(=[O:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:7][C:2]=2[F:1])=[N:18][N:19]=1
Reactant: C[C@H](CO)NS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3nnc(N)s3)c(F)c2)OC1(C)C
Product: C[C@H](CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2nnc(N)s2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,4-thiadiazol-2-amine and (R)-2-bromo-N-(1-hydroxypropan-2-yl)benzene-sulfonamide. MS (ESI): mass calcd. for C17H17FN4O3S2, 408.07; m/z found, 409.1 [M+H]+. 1H NMR (300 MHz, CD3OD) δ 8.15-8.12 (m, 2H), 7.68 (m, 1H), 7.61 (m, 1H), 7.44-7.38 (m, 3H), 3.42-3.38 (m, 1H), 3.30-3.25 (m, 1H), 3.22-3.18 (m, 1H), 1.02 (d, J=6.6, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](OCC)=[O:8])=[C:5]([CH3:12])[N:4]=[CH:3]1.[OH-].[Na+].S(=O)(O)[O-].[Na+].C=O>O>[CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[C:5]([CH3:12])[N:4]=[CH:3]1
Reactant: CCOC(=O)c1c(C)ncn1C
Agent: C=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1ncn(C)c1CO
Yield: 36.5 %

Procedure:
To a suspension of 1.68 g (0.01 mol) of 1,4-dimethyl-5-carbethoxyimidazole in 10 ml of water was added 0.8 g (0.02 mol) of sodium hydroxide. The mixture was heated to reflux for 30 min. Thereafter, 3.54 g (0.03 mol) of formaldehyde sodium bisulfite was added and heated to reflux for 4 hours. The water in the reaction mixture was removed, and the residue was extracted with isopropyl alcohol and filtered. The isopropyl alcohol extract was concentrated, and the residual solid recrystallized from ethyl acetate and filtered to afford 0.46 g of 1,4-dimethyl-5-hydroxymethylimidazole as a white powdered solid, m.p. 125°-127° C.
Reaction SMILES: [OH-].[K+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH2:12](Cl)/[CH:13]=[CH:14]/[CH2:15]Cl>[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC.S1(CCCC1)(=O)=O>[C:3]([C:4]1[CH2:15][CH:14]([CH:13]=[CH2:12])[O:6][C:5]=1[CH3:7])([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(C)=O
Reactant: ClC/C=C/CCl
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: C=CC1CC(C(=O)OCC)=C(C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
4-Carbethoxy-5-methyl-2-vinyl-2,3-dihydrofuran was prepared using a phase transfer procedure similar to that of Example I. For the reaction, three grams tricaprylylmethylammonium chloride, 62 grams potassium hydroxide, and 100 mls sulfolane were charged to a reactor and a mixture of 65 grams ethyl acetoacetate and 95 grams 1,4-dichlorobutene-2 slowly added over a period of one hour while maintaining the temperature below 30° C. The mixture was then stirred for two hours at ambient temperature and then heated to 150° C. until the reaction was essentially complete. The reaction mixture was poured into ice-water, extracted with ether, and the ether evaporated using a rotary evaporator. The resulting product, which consisted of essentially a 1:1 mixture of 4-carbethoxy-5-methyl-2-vinyl-2,3-dihydrofuran and ethyl-1-acetyl-2-vinylcyclopropane-1-carboxylate, was distilled. Sixty grams of the 4-carbethoxy-5-methyl-2-vinyl-2,3-dihydrofuran obtained from the distillation was combined with 100 mls ethyl acetate and 0.4 grams supported hydrogenation catalyst (5% Pd on carbon) and hydrogenated in the usual manner. The catalyst was removed at the conclusion of the hydrogenation by filtration and ethyl acetate stripped under reduced pressure to obtain crude 4-carbethoxy-2-ethyl-5-methyl-2,3-dihydrofuran. Distillation of the crude product yielded essentially pure 4-carbethoxy-2-ethyl-5-methyl-2,3-dihydrofuran with chemical and physical properties and fragrance characteristics the same as described for the product of Example IX.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[CH:20]=[N:19][C:11]2[NH:12][C:13](=O)[C@H:14]([CH3:17])[NH:15][CH2:16][C:10]=2[CH:9]=1>C1COCC1>[Br:7][C:8]1[CH:20]=[N:19][C:11]2[NH:12][CH2:13][C@H:14]([CH3:17])[NH:15][CH2:16][C:10]=2[CH:9]=1
Reactant: C[C@@H]1NCc2cc(Br)cnc2NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1CNc2ncc(Br)cc2CN1
Temperature: 25 °C

Procedure:
To a solution of LAH (2.5 mL, 2.52 mmol) was added a solution of (S)-7-bromo-3-methyl-4,5-dihydro-1H-pyrido[2,3-e][1,4]diazepin-2(3H)-one (375 mg, 1.26 mmol) in THF (10 mL) at 0° C. The reaction was warmed to room temperature and stirred over night. Once the reaction was complete, it was cooled to 0° C. and carefully quenched with water (10 mL), and extracted with ethyl acetate (4×15 mL), dried over sodium sulfate and concentrated. Preparative HPLC was used to purify the title compound as a white solid (166 mg, 55%): 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=2.4 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 4.36 (2s, 2H), 4.21 (d, J=14.3 Hz, 1H), 6.33-3.61 (m, 2H), 3.26-3.13 (m, 1H), 1.36 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[C:13]1([NH:19]N)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:8]2[NH:19][C:13]3[C:18]([CH:9]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:7]=1
Reactant: COc1ccc(Br)cc1C(C)=O
Reactant: NNc1ccccc1
Solvent: O
Product: COc1ccc(Br)cc1-c1cc2ccccc2[nH]1
Temperature: 110 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
The mixture of 1-(5-bromo-2-methoxyphenyl)ethanone (10 g, 43.6 mmol), phenylhydrazine (7.07 g, 65.5 mmol) was stirred in PPA (50 mL) at 110° C. for 2 hours. The reaction mixture was added to water and basified to pH=7, then extracted with ethyl acetate and washed with brine, dried over Na2SO4. After concentrated, the resulting residue was purified using column chromatography to provide the product of 2-(5-bromo-2-methoxyphenyl)-1H-indole (10 g, yield: 71%). 1H-NMR (CDCl3, 400 MHz) δ 9.57 (s, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.34˜7.42 (m, 2H), 7.09˜7.21 (m, 2H), 6.90 (d, J=8.8 Hz, 1H), 4.00 (s, 3H). MS (M+H)+: 302/304.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1>[Pd].C(O)(=O)C>[OH:8][C:7]1[C:9]([O:10][CH3:11])=[CH:12][C:2]([CH3:1])=[CH:3][C:4]=1[O:5][CH3:6]
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc(C)cc(OC)c1O

Procedure:
According to Liebigs Annalen der Chemie 1976, Issue 7/8, page 1445, in a similar manner syringaldehyde (4-hydroxy-3,5-dimethoxybenzaldehyde) is hydrogenated in the presence of 10% palladium on activated carbon, also in glacial acetic acid, to give 4-hydroxy-3,5-dimethoxytoluene.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][C:10](Cl)=[O:11].[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][C:18]([C:24]#[N:25])=[C:17]2[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Br:33])[CH:28]=1>O1CCCC1>[Br:33][C:29]1[CH:28]=[C:27]([NH:26][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:10](=[O:11])[CH2:9][Cl:8])[CH:15]=3)[N:20]=[CH:19][C:18]=2[C:24]#[N:25])[CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)CCl
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cnc2ccc(NC(=O)CCl)cc2c1Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
Triethylamine (0.359 g, 3.55 mmol) and chloroacetyl chloride (0.402 g, 3.55 mmol) were added to an ice cold solution of 1.00 g (2.96 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 12 mL of tetrahydrofuran under N2. After stirring overnight at 25° C., volatile material was removed and the residue was slurried in water and collected. Recrystallization from methanol gave 0.540 g of tan solid: mass spectrum (electrospray, m/e): M+H 415,417.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH3:9])=[CH:6][CH:5]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][C:13]=3[CH:14]=2)[N:3]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[N:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:13]=3[CH:14]=2)[CH:5]=[CH:6][C:7]=1[NH:8][CH3:9]
Reactant: CNc1ccc(-c2cc3cc(OC)ccc3o2)nc1F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNc1ccc(-c2cc3cc(O)ccc3o2)nc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.7 %

Procedure:
To a stirred solution of [2-fluoro-6-(5-methoxy-benzofuran-2-yl)-pyridin-3-yl]-methyl-amine (31 mg, 0.114 mmol) in dichloromethane (3 mL) at 0° C. under nitrogen atmosphere, BBr3 (1M solution in CH2Cl2, 0.568 mL, 0.568 mmol) was added dropwise. The reaction mixture was stirred for 1.5 hours at room temperature. The mixture was then cooled to 0° C., saturated sodium bicarbonate solution was added (5 mL) and the resulting mixture was extracted with dichloromethane (50 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification of the crude product by flash chromatography using 30% ethyl acetate in hexane afforded the title compound 2-(6-fluoro-5-methylamino-pyridin-2-yl)-benzofuran-5-ol (22 mg) as an off-white solid. 1H NMR (400 MHz, METHANOL-d4) δ: 7.62 (d, J=7.90 Hz, 1H), 7.28 (d, J=8.78 Hz, 1H), 7.08 (dd, J=10.54, 8.20 Hz, 1H), 6.97 (s, 1H), 6.92 (d, J=2.34 Hz, 1H), 6.74 (dd, J=8.78, 2.34 Hz, 1H), 2.87 (s, 3H). ESMS: m/z 259.47 [M+1]+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([O:21][CH3:22])[C:15]=2[F:23])=[N:11][C:10]=1[C:24]([O:26]C)=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>CCOC(C)=O.[Cl-].[Na+].O.O.CO>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([O:21][CH3:22])[C:15]=2[F:23])=[N:11][C:10]=1[C:24]([OH:26])=[O:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1nc(-c2c(F)ccc(OC)c2F)sc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(F)c(-c2nc(C(=O)O)c(NC(=O)OC(C)(C)C)s2)c1F
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
To a mixture of methyl 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxylate (48.5 mg, 0.121 mmol) and lithium hydroxide, monohydrate (37 mg, 0.89 mmol) was added MeOH (1.5 mL), followed by water (1.5 mL). The reaction mixture was stirred at 60° C. for 3.5 h. The reaction mixture was allowed to cool to room temperature and 4.0 M hydrogen chloride in water (0.25 mL, 0.99 mmol) was added to adjust the pH to 1-2. The mixture was diluted with EtOAc (50 mL) and brine (50 mL). The aqueous layer was further extracted with EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the sub-title compound as a white solid which was used directly in the next step without further purification (52.2 mg). LCMS calc. for C16H17F2N2O5S (M+H)+: m/z=387.1. Found: 387.1.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][S:39]([C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)(=[O:41])=[O:40].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:45]2[CH:46]=[CH:47][C:42]([S:39]([CH3:38])(=[O:41])=[O:40])=[CH:43][CH:44]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 41 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (500 mg, 0.93 mmol), 4-methylsulfonyl phenylboronic acid (560 mg, 2.78 mmol), and dichlorobis(triphenylphosphine)palladium (II) (65.3 mg, 0.09 mmol) in dioxane (4 mL) was added an aqueous sodium carbonate solution (2 M, 1.40 mL, 2.8 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 25% ethyl acetate/hexanes) to afford 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-fluoro-1H-pyrrolo[2,3-b]pyridine (200 mg, 41%) as a light yellow solid: LC/MS m/e calcd for C27H25FN2O4S2 [M+H]+ 525.64, observed 525.1.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[Si:7]([O:24][C@H:25]([CH3:41])[C@H:26]([NH:36][CH2:37][C@@H:38]([OH:40])[CH3:39])[C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:7]([O:24][C@H:25]([CH3:41])[C@H:26]([N:36]1[CH2:37][C@H:38]([CH3:39])[O:40][C:2](=[O:3])[C:1]1=[O:5])[C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=1)([C:20]([CH3:22])([CH3:23])[CH3:21])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@H](O)CN[C@H](c1cc(F)c(F)c(F)c1)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CN([C@H](c2cc(F)c(F)c(F)c2)[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(=O)C(=O)O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (45 μl) was added dropwise to a solution of (S)-1-[(1R,2R)-2-tert-butyldiphenylsilanyloxy-1-(3,4,5-trifluorophenyl)propylamino]propan-2-ol (171 mg), TEA (0.17 ml), and 4-(N,N-dimethylamino)pyridine (8 mg) in methylene chloride (2 ml) under ice-cooling in a nitrogen atmosphere, and the reaction solution was stirred at the same temperature for two hours. Ice water was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was sequentially washed with water, 1 N hydrochloric acid, water, a saturated sodium bicarbonate solution, and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (heptane:ethyl acetate=9:1 to 3:1) to obtain 96 mg of the title compound.
Reaction SMILES: [ClH:1].[OH:2][S:3]([OH:6])(=[O:5])=[O:4].[CH3:7][C:8]([OH:10])=[O:9]>>[ClH:1].[OH:5][S:3]([OH:6])(=[O:4])=[O:2].[C:8]([OH:10])(=[O:9])[CH2:7][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CC(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Product: O=C(O)CCC(=O)O

Procedure:
Free base 8l was added to methanesulfonic acid at 0° C. and the resulting mixture was allowed to warm to room temperature and stir for 2 h. The reaction mixture was then poured into cold MeOH (between −10° C. and 0° C.) and the precipitated solid was filtered, washed with MeOH (100 mL) and dried in vacuo. The dried solid was then dissolved in water (˜200 mL) and lyophilized to provide the methanesulfonate monohydrate salt 8l. (1.020 g, 84%). 1H NMR (DMSO-D6): δ 1.75-1.85 (m, 2H), 2.35 (s, 3H), 2.78-2.84 (m, 2H), 2.96-3.12 (m, 4H), 3.36 (d, J=12.3 Hz, 2H), 3.61 (t, J=11.4 Hz, 2H), 3.94 (d, J=12.9 Hz, 2H), 4.03 (s, 2H), 7.49-7.55 (m, 1H), 7.76-7.84 (m, 3H), 7.99 (d, J=0.9 Hz, 1H), 8.15 (d, J=8.4 Hz, 1H), 8.25 (d, J=8.4 Hz, 1H), 9.59 (s, 1H), 12.42 (s, 1H); 13C NMR (DMSO-D6): δ 24.27, 33.86, 51.89, 54.51, 64.02, 119.70, 120.39, 123.53, 126.09, 126.45, 128.63, 133.66, 135.80, 138.71, 141.21, 144.57, 163.29; Anal. Calcd for C24H31N3O8S2: C, 52.06; H, 5.46; N, 7.59, Karl-Fisher, 3.36. Found: C, 51.85; H, 5.35, N, 7.30, Karl-Fisher, 4.32. Similarly, HCl, H2SO4, CH3COOH, and succinic acid salts of 8l were prepared by substituting methanesulfonic acid with HCl, H2SO4 and CH3COOH, respectively
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C.[Li]CCCC>C1(C)C=CC=CC=1.C1COCC1>[Cl:19][C:5]1[CH:4]=[CH:3][C:2]([B:24]([OH:25])[OH:23])=[CH:18][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1
Reactant: FC(F)(F)c1ccc(Oc2cc(Br)ccc2Cl)nc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OB(O)c1ccc(Cl)c(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: -40 °C
Reaction time: 1 h
Yield: 120.8 %

Procedure:
To a solution of 2-(5-bromo-2-chlorophenoxy)-5-(trifluoromethyl)pyridine (2.6 g, 7.3 mmol) and triisopropylborate (2.0 mL, 8.76 mmol) in toluene (15 mL) and THF (7 mL) under a N2 atmosphere was added n-BuLi (6.8 mL, 10.95 mmol) while maintaining the reaction at −70° C. The reaction was stirred for 1 h at −40° C. Gradually the temperature was increased to −20° C. and then 0° C. The reaction was quenched with 2N HCl and allowed to warm to RT. The reaction mixture was concentrated and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (2.8 g). 1H NMR (500 MHz, DMSO-d6): δ 8.56 (s, 1H), 8.29 (m, 3H), 7.94 (s, 1H), 7.81 (d, J=7.9 Hz, 1H), 7.36 (d, J=8.05 Hz, 2H); m/z (316.4, M− H−).