Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([I:17])[CH:13]=2)[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[BH4-].[Na+].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>ClCCl.CCO.O>[CH2:1]([C@@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([I:17])[CH:13]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC[C@@H]1CCc2cc(I)ccc2C1=O
Agent: CC[SiH](CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCC[C@@H]1CCc2cc(I)ccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a stirred solution of (R)-2-hexyl-6-iodo-3,4-dihydronaphthalen-1(2H)-one (I-8C, 21.6 g, 60.6 mmol) in dichloromethane (10 mL) and 100% EtOH (100 mL) was added sodium borohydride (4.59 g, 121 mmol) portionwise. The mixture was stirred at room temperature for 2 h before being quenched by adding acetone slowly (cooled with water bath). The mixture was concentrated under reduced pressure. The residue was mixed with saturated aqueous ammonium chloride solution (100 mL) and water (50 mL) and extracted with ethyl acetate (100 mL, 2×50 mL). The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil. The oil was dissolved in triethylsilane (70 mL, 438 mmol). TFA (100 mL, 1298 mmol) was added with vigorous stirring. The mixture was stirred at room temperature under nitrogen for 2.5 h. After water (150 mL) was added, the mixture was extracted with hexanes (100 mL, 2×50 mL). The combined extracts were washed with water (50 mL) and then saturated aqueous sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, and concentrated to give a yellow liquid. Flash chromatography purification (330 g silica gel column, gradient elution from 0 to 12% EtOAc in hexanes) afforded (R)-2-hexyl-6-iodo-1,2,3,4-tetrahydronaphthalene (18.4 g, 53.8 mmol) as a colorless liquid. 1H NMR (400 MHz, chloroform-d) δ 7.41 (s, 1H), 7.38 (dd, J=7.9, 1.8 Hz, 1H), 6.79 (d, J=8.1 Hz, 1H), 2.82-2.71 (m, 3H), 2.31 (dd, J=16.5, 10.6 Hz, 1H), 1.93-1.85 (m, 1H), 1.72-1.60 (m, 1H), 1.41-1.24 (m, 11H), 0.92-0.85 (m, 3H). Chiral SFC separation (CHIRALPAK® AS-H 25×3.0 cm, 5 μm, CO2/MeOH=95/5, 180 mL/min, 230 nm) gave (R)-2-hexyl-6-iodo-1,2,3,4-tetrahydronaphthalene (11.8 g, PK2) and its (S)-isomer (1.4 g, PK1) as liquids.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:15]1[CH2:21][S:18](=[O:20])(=[O:19])[O:17][CH2:16]1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH2:16][CH2:15][CH2:21][S:18]([OH:20])(=[O:19])=[O:17])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCO1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-chlorophenyl)-4-piperidinol (2.5 g, 11.8 mmol) in acetone (25 mL) was added 1,3-propane sultone (1.56 g, 13.0 mmol). The mixture was stirred at reflux for 2 h. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×20 mL) and dried in vacuo. This allowed the isolation of compound H, 2.83 g (72%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]#[CH:11].C[Mg+].[Br-].[CH2:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH:23]=[O:24])[CH2:19][CH2:18]1)[CH3:16].Cl>O1CCCC1>[CH2:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH:23]([OH:24])[C:11]#[C:10][C:3]2[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=2[F:1])[CH2:19][CH2:18]1)[CH3:16]
Reactant: C#Cc1ccc(F)c(F)c1F
Reactant: CC[C@H]1CC[C@H](C=O)CC1
Agent: C[Mg+]
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: CC[C@H]1CC[C@H](C(O)C#Cc2ccc(F)c(F)c2F)CC1
Reaction time: 1 h

Procedure:
Into the tetrahydrofuran (THF) (100 ml) solution containing 2,3,4-trifluorophenylacetylene (20 g), the THF solution (93 ml) of 1.5 M bromide methyl magnesium was added dropwise at 0° C., and stirred for 1 hour. Into this, the THF (50 ml) solution of trans-4-ethylcyclohexane carboaldehyde (18 g) was added dropwise, and stirred for 1 hour. The reaction solution was poured into 5% hydrochloric acid, extracted with ethyl acetate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain 1-(trans-4-ethylcyclohexyl)-3-(2,3,4-trifluorophenyl)-2-propyne-1-ol (38 g).
Reaction SMILES: [Na].C1(S(N)(=O)=O)C=CC=CC=1.[CH:12]1([NH:17][C:18]([NH:20]C2CCCC2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]1.N>>[CH:12]1([NH:17][C:18](=[O:19])[NH2:20])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(NC1CCCC1)NC1CCCC1
Agent: N
Agent: NS(=O)(=O)c1ccccc1
Agent: [Na]
Product: NC(=O)NC1CCCC1
Temperature: 220 °C

Procedure:
2 g of sodium salt of 4-(β-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonamide and 2.2 g of N,N'-dicyclopentyl-urea (m.p. 248° - 249°C, prepared from cyclopentyl-isocyanate and cyclopentyl-amine) were well mixed in a mortar. The mixture was heated to 220°C for 10 minutes in an Erlenmeyer flask on a pre-heated oil bath. After cooling, the sintered reaction cake was treated with 0.5 %-ammonia. After filtration, the filtrate was acidified and a precipitate was obtained which was separated by suction-filtration and dissolved once more in 0.5 %-ammonia. After filtration, the filtrate was acidified. The precipitate of crude N-[4-(β-<2-methoxy-5-chlorobenzamide>-ethyl)-benzenesulfonyl]-N'-cyclopentyl-urea that had separated was isolated by suction-filtration and dried. By treatment with methanol an at first smeary and then crystalline substance was obtained, which after suction-filtration, was once more recrystallized from methanol. The melting point of N-[4-(β-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl]-N'-cyclopentyl-urea obtained was 182° - 184°C.
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.C(=O)([O-])[O-].[NH4+].[NH4+].[Br:26][C:27]1[CH:28]=[C:29]([CH2:33][C:34]([OH:36])=O)[CH:30]=[CH:31][CH:32]=1.Cl.CN(C)CCCN=C=NCC>>[Br:26][C:27]1[CH:28]=[C:29]([CH2:33][C:34]([NH2:2])=[O:36])[CH:30]=[CH:31][CH:32]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1-Hydroxybenzotriazole (HOBT, 13.82 g, 102.3 mmol), N-ethyldiisopropyl amine (Hunig's base, 13.22 g, 102.3 mmol) and ammonium carbonate (27.0 g, 279.0 mmol) were added to a solution of (3-bromophenyl)acetic acid (20.0 g, 93.0 mmol) in freshly dried and distilled tetrahydrofuran (80 mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for about 5 minutes and then cooled to 0° C. and stirred at the same temperature for about 1 hour. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCLHCl, 19.61 g, 102.3 mmol) was added at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at room temperature for about 12 hours. The solvent was evaporated under vacuum and water was added. A white solid was obtained which was filtered, washed with water and dried. Yield: 12.69 g.
Reaction SMILES: [H][H].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1>CO.[Rh]>[OH:3][CH:4]1[CH2:5][CH2:6][CH:7]([CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:15]([O:17][CH3:18])=[O:16])[CH2:8][CH2:9]1
Reactant: [H][H]
Reactant: COC(=O)C(C(=O)OC)c1ccc(O)cc1
Agent: [Rh]
Solvent: CO
Product: COC(=O)C(C(=O)OC)C1CCC(O)CC1

Procedure:
At 60° C. and a hydrogen pressure of 150 bar, 67.3 g of dimethyl (4-hydroxyphenyl)malonate in 500 ml of methanol were hydrogenated in the presence of 5 g of rhodium/carbon catalyst (5%). The catalyst was filtered off and the mixture was concentrated. This to give the title product as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([NH2:26])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[CH:24][CH:23]=[N:22]1.CCN(C(C)C)C(C)C.O>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([NH:26][C:17]2[CH:18]=[CH:19][C:20]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[C:15]([F:14])[CH:16]=2)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1ccc(-n2cccn2)c(F)c1
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(Cl)nc1Nc1ccc(-n2cccn2)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.9 %

Procedure:
To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (280 mg, 1.27 mmol) and 3-fluoro-4-(1H-pyrazol-1-yl)benzenamine (230 mg, 1.30 mmol) in CH3CN (8 mL) at room temperature, DIEA (0.442 mL, 2.54 mmol) was added. The mixture was stirred at room temperature for 48 h. Water (15 mL) was added to induce precipitation. The precipitate was collected, dried on vacuum to give ethyl 2-chloro-4-(3-fluoro-4-(1H-pyrazol-1-yl)phenylamino)pyrimidine-5-carboxylate as a solid (275 mg). MS 362.3 and 364.3 (M+H, Cl pattern)
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.[CH2:12]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:26])[C:23]([O-:25])=[O:24])=[CH:18][CH:17]=1)[CH:13]([CH3:15])[CH3:14].[Na+]>CN(C)C=O>[CH2:12]([C:16]1[CH:17]=[CH:18][C:19]([CH:22]([CH3:26])[C:23]([O:25][CH:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[O:3]2)=[O:24])=[CH:20][CH:21]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)Cc1ccc(C(C)C(=O)[O-])cc1
Reactant: O=C1OC(Br)c2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(C(C)C(=O)OC2OC(=O)c3ccccc32)cc1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
To a solution of 10.65 g of 3-bromophthalide in 100 ml of dimethylformamide, 11.5 g of sodium 2-(4-isobutylphenyl)propionate is added under stirring at room temperature. The reaction mixture is stirred 24 hours at room temperature, and it is then poured into 500 ml of ice water. After extraction with chloroform, the organic phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally it is dried on anhydrous sodium sulfate and evaporated to dryness. The residue, crystallized from petroleum ether, yields 12.3 g of phthalidyl 2-(4-isobutylphenyl)propionate, having the same physico-chemical characteristics of the compounds of Example 1.
Reaction SMILES: C(N(CC)CC)C.C([SiH](CC)CC)C.[CH2:15]([O:20][C:21]([N:23]1[C:27](=[O:28])[CH2:26][CH2:25][CH:24]1[C:29]([O:31]CC1C=CC=CC=1)=[O:30])=[O:22])[CH2:16][CH2:17][CH:18]=[CH2:19]>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:15]([O:20][C:21]([N:23]1[C:27](=[O:28])[CH2:26][CH2:25][CH:24]1[C:29]([OH:31])=[O:30])=[O:22])[CH2:16][CH2:17][CH:18]=[CH2:19]
Reactant: C=CCCCOC(=O)N1C(=O)CCC1C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCCOC(=O)N1C(=O)CCC1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
Under nitrogen, to a stirring solution of 240 mg of palladium acetate (1.1 mmol) in 20 mL of de-gassed dichloromethane, was added 460 uL of triethylamine (3.3 mmol), and 5.33 mL of triethylsilane (33 mmol). After stirring at rt for 15 min, 7.3 g of intermediate 17-2 in 25 mL of de-gassed dichloromethane was added in. The resulting solution was stirred at rt overnight. The reaction mixture was passed through a celite pad, and the filtrate was concentrated and purified by flash column chromatography using DCM/MeOH (v/v 9/1) as eluent, giving colorless oil 4.55 g (85%). LC-MS: m/z=240.1 (ES−).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH:10]2[C:15]3([CH2:21][C:20](=[O:22])[NH:19][CH2:18][CH2:17][S:16]3(=[O:24])=[O:23])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31]Cl>CS(C)=O.C(OCC)(=O)C>[C:3]1([CH2:9][CH:10]2[C:15]3([CH2:21][C:20](=[O:22])[N:19]([CH2:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)[CH2:18][CH2:17][S:16]3(=[O:23])=[O:24])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1ccccn1
Reactant: O=C1CC2(CCCCC2Cc2ccccc2)S(=O)(=O)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C1CC2(CCCCC2Cc2ccccc2)S(=O)(=O)CCN1Cc1ccccn1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A stirred suspension of sodium hydride (20 mg) in dimethylsulfoxide (2 ml) was heated at 60° C. under nitrogen atmosphere. After one hour, 1-phenylmethyl-11-oxo-7-thia-10-azaspiro[5.6]dodecane 7,7-dioxide (0.20 g) and 2-pyridylmethyl chloride (0.2 ml) were added to the solution and the mixture was allowed to stand at room temperature for one hour. The mixture was diluted with ethyl acetate (20 ml) and washed with a saturated aqueous solution (20 ml) of sodium bicarbonate, water (20 ml) and brine (20 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified with silica gel (6 g) column chromatography (ethyl acetate) to give 1-phenylmethyl-10-(2-pyridylmethyl)-11-oxo-7-thia-10-azaspiro[5.6]dodecane 7,7-dioxide (0.21 g).
Reaction SMILES: C(OC([N:8]([CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:30][CH3:31])=[C:23]([C:28]#[N:29])[CH:24]=2)[CH2:19]1)[CH2:9][CH2:10][NH:11][CH2:12][C:13](OCC)=[O:14])=O)(C)(C)C.Cl.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:31][O:30][C:22]1[C:23]([C:28]#[N:29])=[CH:24][C:25]2[CH2:26][CH2:27][CH:18]([N:8]3[CH2:9][CH2:10][NH:11][CH2:12][C:13]3=[O:14])[CH2:19][C:20]=2[CH:21]=1
Reactant: CCOC(=O)CNCCN(C(=O)OC(C)(C)C)C1CCc2cc(C#N)c(OC)cc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1C#N)CCC(N1CCNCC1=O)C2
Temperature: 25 °C

Procedure:
To a solution of Ethyl N-{2-[(tert-butoxycarbonyl)(6-cyano-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino]ethyl}glycinate (100 mg, 0.232 mmol) in dioxane was added HCl (1.16 ml, 4.6 mmol). The mixture was allowed to stir at RT until there was no SM left. The volatiles were removed, and the residue was dissolved in EtOH (15 ml). To this solution was added Hunig's Base (0.20 ml, 1.16 mmol). The solution was sealed in a microwave tube and heated to 155° C. for 5 hours. The product was then purified by MPLC. LC-MS (IE, m/z): 286 [M+1]+.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Br:29])=[CH:20][N:21]=[C:22]([O:27]C)[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.[ClH:30].CO>>[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Br:29])=[CH:20][N:21]=[C:22]([OH:27])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:15])=[O:16])[CH2:10]1.[ClH:30]
Reactant: COc1ncc(Br)c2c(S(=O)(=O)N3CCC(NC(=O)OC(C)(C)C)C3)cccc12
Agent: Cl
Solvent: CO
Product: NC1CCN(S(=O)(=O)c2cccc3c(O)ncc(Br)c23)C1
Temperature: 50 °C
Reaction time: 50 h

Procedure:
Intermediate 4 (25 mg) obtained in Example 6, Step B is added with 10% hydrogen chloride/methanol (10 ml), and the mixture is stirred at 50° C. for 50 hours. The solvent is evaporated under reduced pressure to obtain the title compound as hydrochloride (13 mg (predictive yield)).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[N+]([O-])(O)=O.[O:13]([CH2:17][CH2:18][NH2:19])[N+:14]([O-:16])=[O:15].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(OC(C)C)(C)C>>[O:13]([CH2:17][CH2:18][NH:19][C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[N+:14]([O-:16])=[O:15]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(O)c1ccco1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: O=C(NCCO[N+](=O)[O-])c1ccco1
Yield: 59.1 %

Procedure:
Following a similar treatment to that in Example 2, using 0.34 g of 2-furancarboxylic acid and 0.50 g of nitroxyethylamine nitrate and using diphenylphosphoryl azide instead of ethyl cyanophosphate, 0.35 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].C(OC([N:36]1[C:40]([C:41]#[N:42])=[CH:39][CH:38]=[C:37]1B(O)O)=O)(C)(C)C>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:37]3[NH:36][C:40]([C:41]#[N:42])=[CH:39][CH:38]=3)[C:3]([N:22]3[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Reactant: CC(C)(C)OC(=O)n1c(C#N)ccc1B(O)O
Product: N#Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2C[C@H](O)[C@@H](O)C2)[nH]1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 29 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)nicotinamide (Stage 46.1) and (1-(tert-butoxycarbonyl)-5-cyano-1H-pyrrol-2-yl)boronic acid (Stage 29.1) to afford a rose solid. UPLC-MS (Condition 3) tR=0.97 min, m/z=490.0 [M+H]+, m/z=487.9 [M−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.02 (d, J=11.86 Hz, 2H) 3.46 (dd, J=11.86, 3.55 Hz, 2H) 3.90 (br. s, 2H) 5.09 (d, J=2.93 Hz, 2H) 6.29 (dd, J=3.67, 2.45 Hz, 1H) 7.03 (dd, J=3.67, 2.32 Hz, 1H) 7.34 (d, J=9.17 Hz, 2H) 7.83-7.90 (m, 2H) 8.07 (d, J=2.32 Hz, 1H) 8.76 (d, J=2.32 Hz, 1H) 10.18 (s, 1H) 12.63-12.68 (m, 1H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[NH:19][N:18]=[C:17]([CH3:20])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.Cl.[CH3:35][O:36][C:37]1[CH:45]=[N:44][C:43]([N:46]2[CH:50]=[C:49]([CH3:51])[N:48]=[N:47]2)=[C:42]2[C:38]=1[C:39]([C:52](=[O:56])C(O)=O)=[CH:40][NH:41]2.C(N(CC)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[C:21]1([C:14](=[C:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:52]([C:39]3[C:38]4[C:42](=[C:43]([N:46]5[CH:50]=[C:49]([CH3:51])[N:48]=[N:47]5)[N:44]=[CH:45][C:37]=4[O:36][CH3:35])[NH:41][CH:40]=3)=[O:56])[CH2:9][CH2:10]2)[C:15]2[NH:19][N:18]=[C:17]([CH3:20])[CH:16]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cnc(-n2cc(C)nn2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: Cc1cc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2)[nH]n1
Agent: CCN(CC)C(C)C
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cnc(-n2cc(C)nn2)c2[nH]cc(C(=O)C(=O)N3CCC(=C(c4ccccc4)c4cc(C)n[nH]4)CC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
To a solution of 4-[1-phenyl-1-(3-methylpyrazol-5-yl)methylene]piperidine-1-carboxylic acid tert-butyl ester (0.0190 g, 0.0538 mmol) in CH2Cl2 (1 mL) was added TFA (0.4 mL) and the mixture was stirred at rt for 30 min. The solvent was then removed in vacuo and the material was dissolved in CHCl3 (2 mL). To this solution was added 4-methoxy-7-(4-methyl-1,2,3-triazol-1-yl)-6-azaindol-3-yl-oxoacetic acid hydrochloride salt (0.0187 g, 0.0621 mmol) and iPrNEt2 (0.050 mL, 0.287 mmol), followed by BOP-Cl (0.0221 g, 0.868 mmol). The mixture was allowed to stir at rt for 2 h and then the solvent was removed in vacuo. The resulting residue was diluted with H2O and extracted with EtOAc (×3). The combined organic layers were washed (H2O, brine), dried (Na2SO4) and concentrated, and the residue was purified by preparative HPLC (NH4OAc) to give the title compound (0.0128 g, 44%) as a colorless solid:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:33]([O-])=O)[C:18]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH2:33])[C:18]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@@H]1CCCN(Cc2ccccc2)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@@H]1CCCN(Cc2ccccc2)C1
Yield: 85.3 %

Procedure:
A mixture of (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-((R)-1-benzyl-piperidin-3-yl)amine (about 0.77 mmol), iron powder (129 mg, 2.31 mmol) and ammonium chloride (206 mg, 3.85 mmol) in ethanol/water (8 ml, 3:1) was heated to reflux for 4 hours. After cooling the mixture was filtered through CELITE®, thoroughly washing the filter cake with ethanol. The filtrate and washings were combined and concentrated under vacuum. The resulting residue was partitioned between ethyl acetate and water, and the organic layer dried with sodium sulfate and concentrated under vacuum. Purification by column chromatography on silica gel (gradient: 0 to 10% methanol in DCM) gave a residue, which was purified by column chromatography on silica gel (gradient: 0 to 5% methanol in ethyl acetate) affording 303 mg (84%) of 1-benzenesulfonyl-N*4*-((R)-1-benzyl-piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridine-4,5-diamine. LCMS (Method B, ESI): RT=2.48-2.68 min, m+H=462.6; 1H NMR (400 MHz, CDCl3) δ: 8.12-8.08 (m, 2H), 7.79 (s, 1H), 7.55-7.49 (m, 1H), 7.46-7.38 (m, 3H), 7.37-7.22 (m, 5H), 6.47 (s, 1H), 5.32-5.26 (br m, 1H), 4.00-3.87 (br m, 1H), 3.58-3.46 (br m, 2H), 2.94-2.28 (br m, 6H), 1.82-1.67 (br m, 2H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:34]=[CH:33][C:10]2[CH2:11][C@@H:12]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:13](=[O:27])[N:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:15][C:9]=2[CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[CH:34]=[CH:33][C:10]2[CH2:11][C@@H:12]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:13](=[O:27])[N:14]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=3)[CH2:15][C:9]=2[CH:8]=1
Reactant: COC(=O)C[C@@H]1Cc2ccc(OC)cc2CN(Cc2ccc(C(F)(F)F)cc2)C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)C[C@@H]1Cc2ccc(O)cc2CN(Cc2ccc(C(F)(F)F)cc2)C1=O
Temperature: -5 °C
Reaction time: 1.5 h
Yield: 92.2 %

Procedure:
A solution of boron tribromide in CH2Cl2 (1.0 M, 160 mL, 160 mmol) was added dropwise over 30 min to a solution of methyl (S)-8-methoxy-3-oxo-2-(4-trifluoromethylbenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (16.67 g, 39.6 mmol) in anhydrous CH2Cl2 (150 mL) at −20° C. under argon. After an additional 1.5 hr at −15 to −20° C., the reaction was recooled to −20° C. and quenched by careful dropwise addition of MeOH (160 mL). The reaction was stirred at −10 to 0° C. for 1 hr, then was concentrated on the rotavap. The residue was reconcentrated from MeOH (2×). Purification by flash chromatography on silica gel (50 to 100% ethyl acetate/hexanes) gave the title compound (14.87 g, 92%) as a white solid: [α]D −81.8° (c, 1.0, MeOH); TLC (silica, 50% EtOAc/hexane) Rf 0.54; MS (ES) m/e 408.2 (M+H)+; 1H NMR (400, CDCl3+2% DMSO-d6) δ 7.53 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H), 6.93 (d, J=8.4 Hz, 1H), 6.70 (dd, 1H), 6.41 (d, J=2.3 Hz, 1H), 5.16 (d, J=16.4 Hz, 1H), 5.01 (d, J=15.6 Hz, 1H), 4.39 (d, J=15.6 Hz, 1H), 3.84 (m, 1H), 3.73 (d, J=16.4 Hz, 1H), 3.71 (s, 3H), 3.01 (dd, 1H), 2.98 (m, 1H), 2.90 (dd, 1H), 2.47 (dd, 1H).