Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]([CH:13]1[CH2:17][CH2:16][O:15][CH2:14]1)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:9][C:4]1[C:3]2[NH:10][C:11]([CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)=[N:1][C:2]=2[CH:7]=[C:6]([OH:8])[CH:5]=1
Reactant: Nc1cc(O)cc(Cl)c1NC(=O)C1CCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Oc1cc(Cl)c2[nH]c(C3CCOC3)nc2c1
Reaction time: 2 h

Procedure:
0.10 g (0.39 mmol) N-(2-amino-6-chloro-4-hydroxyphenyl)tetrahydrofuran-3-carboxamide were placed in 20 mL methanol, a spatula tip of p-toluenesulphonic acid monohydrate was added and the mixture was boiled for 2 h. The reaction mixture was evaporated down i.vac. and purified by chromatography. The fractions containing product were combined and evaporated down i.vac.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].CN(C=O)C.[CH2:27]([N:29]1[C:35](=[O:36])[C:34]([CH3:38])([CH3:37])[C:33](=[O:39])[N:32]([CH3:40])[C:31]2[CH:41]=[C:42]([OH:45])[CH:43]=[CH:44][C:30]1=2)[CH3:28]>C(OCC)(=O)C.O>[O:21]=[C:12]1[C:13]2[C:14](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:16])[N:11]1[CH2:10][CH2:9][CH2:8][O:45][C:42]1[CH:43]=[CH:44][C:30]2[N:29]([CH2:27][CH3:28])[C:35](=[O:36])[C:34]([CH3:37])([CH3:38])[C:33](=[O:39])[N:32]([CH3:40])[C:31]=2[CH:41]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(O)ccc21
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN3C(=O)c4ccccc4C3=O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
Potassium carbonate (2.99 g, 21.6 mmol) and N-(3-bromopropyl)phthalimide (2.32 g, 8.65 mmol) were added to a DMF solution (50 ml) of 1-ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.89 g, 7.2 mmol), and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with water and a saturated sodium chloride aqueous solution, in this order. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→3:7). The purified product was concentrated to dryness under reduced pressure to thereby obtain 2.70 g (yield: 83%) of 7-(3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]([NH:14][S@](C(C)(C)C)=O)([CH3:13])[C:9]([OH:12])([CH3:11])[CH3:10])[CH:7]=1.Cl>O1CCCC1>[NH2:14][C@@:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:21])([CH3:13])[C:9]([CH3:10])([OH:12])[CH3:11]
Reactant: CC(C)(C)[S@](=O)N[C@](C)(c1cc(Br)ccc1F)C(C)(C)O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(O)[C@](C)(N)c1cc(Br)ccc1F
Reaction time: 1.5 h

Procedure:
A solution of (S)-2-methyl-propane-2-sulfinic acid [(R)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1,2-dimethyl-propyl]-amide (4.2 g, 11.04 mmol) in tetrahydrofuran (200 ml) was cooled to 0° C. Hydrochloric acid (4 M in dioxane, 11 ml) was added dropwise. The ice bath was removed and stirring continued for 1.5 hours at room temperature. For the workup, the reaction mixture was poured onto a sodium carbonate solution (2 M), extracted twice with ethyl acetate, dried over sodium sulfate, and evaporated at reduced pressure, finally dried under high vacuum. The (R)-3-amino-3-(5-bromo-2-fluoro-phenyl)-2-methyl-butan-2-ol was obtained as light yellow oil (2.94 g, 96.4% of theory). Mass (calculated) C11H15BrFNO [276.147]; (found) [M+H]+=276, [M+2-H]+=278.
Reaction SMILES: [CH3:1][N:2]([CH2:16][C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:5]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.Cl>O>[CH3:1][N:2]([CH2:16][C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[C:6]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:5]=1
Reactant: CN(Cc1ccco1)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: O
Product: CN1CCN(c2ccc(C(=O)N(C)Cc3ccco3)cc2S(N)(=O)=O)CC1
Reaction time: 72 h

Procedure:
103 Grams of 4-chloro-3-sulfamoylbenzoic acid-N-methyl-2-furylmethylamide (0.3 mole) were heated under reflux with 0.3 l of N-methylpiperazine for 5 hours. After the reaction solution had been poured into 2 l of water, the pH value of the mixture was adjusted to 8.0 with 5N HCl. After standing at room temperature for 3 days, the separated yellow resin had crystallized. The reaction product was suction-filtered, washed thoroughly with water and was recrystallized from a mixture of methanol and water.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].C1OCCOCCOCCOCCOC1.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[N:3]([S:41]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:43])=[O:42])[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]c1Cl
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1Cl
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
To a solution (40 mL) of ethyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate (1.0 g) in tetrahydrofuran was added sodium hydride (60% in oil, 488 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (2.65 g) was added dropwise and the mixture was stirred for 30 min. Benzenesulfonyl chloride (1.84 g) was added, and the mixture was further stirred for 24 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=85:15), and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 1.27 g, 81%).
Reaction SMILES: [C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=O)[CH:10]=2)[NH2:2].Cl.[NH2:25][OH:26].C(=O)(O)[O-].[Na+]>CO>[C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[N:25][OH:26])[CH:10]=2)[NH2:2]
Reactant: NO
Reactant: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: NC(=O)OCC1c2c(O)cc(C=NO)cc2N2CC3NC3C1(O)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of 4-formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (100 mg) in methanol (5 ml) were added hydroxylamine hydrochloride (90 mg) and sodium bicarbonate (106 mg). The mixture was stirred for 1 hour at ambient temperature and evaporated in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform, methanol and water (6:4:1, v/v) to afford 6,9-dihydroxy-4-hydroxyiminomethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (105 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[C:22]([NH2:29])[CH:21]=2)([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:29][C:22]1[CH:21]=[C:20]([C:11]([C:4]2[CH:5]=[CH:6][C:7]([NH2:8])=[C:2]([NH2:1])[CH:3]=2)([C:12]([F:13])([F:14])[F:15])[C:16]([F:17])([F:18])[F:19])[CH:25]=[CH:24][C:23]=1[NH2:26]
Reactant: Nc1cc(C(c2ccc([N+](=O)[O-])c(N)c2)(C(F)(F)F)C(F)(F)F)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(C(c2ccc(N)c(N)c2)(C(F)(F)F)C(F)(F)F)cc1N
Reaction time: 0.25 h

Procedure:
96.7 g (0.23 mol) of 2,2-bis-(3-amino-4-nitrophenyl) hexafluoropropane are dissolved in 1,000 ml of ethyl acetate and reduced with hydrogen (100 bar) at 25° C. in an autoclave after the addition of 3 g of a palladium/charcoal catalyst (5% Pd). After filtering off the catalyst, the ethyl acetate is separated off on the rotary evaporator. The residue is taken up using 1 1 of water and adjusted to a pH of 1 using 1:1 hydrochloric acid. The mixture is then heated to 70°-80° C., 20 g of activated charcoal are added, the mixture is stirred at 70°-80° C. for 15 minutes and the activated charcoal is filtered off. The colorless filtrate is saturated with nitrogen and is adjusted at 10°-20° C. to a pH of 7 using 1:1 ammonia solution under inert gas. The precipitate is separated off, washed well with water and dried to constant weight under reduced pressure. Yield 74 g (0.20 mol); gas chromatographic purity above 99.9%; white solid; m.p. 218°-220° C.
Reaction SMILES: C(=S)(OC1C=CC=CC=1)O[CH:3]([C:8]1[CH:9]=[N:10][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)[C:4]([F:7])([F:6])[F:5].[SnH](CC1C=CC=CC=1)(CC1C=CC=CC=1)[CH2:29]C1C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[CH2:13]([N:11]1[CH:12]=[C:8]([CH2:3][C:4]([F:5])([F:6])[F:7])[C:9]([CH3:29])=[N:10]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(C[SnH](Cc2ccccc2)Cc2ccccc2)cc1
Reactant: FC(F)(F)C(OC(=S)Oc1ccccc1)c1cnn(Cc2ccccc2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: Cc1nn(Cc2ccccc2)cc1CC(F)(F)F
Temperature: 80 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of O-(1-(1-benzyl-1H-pyrazol-4-yl)-2,2,2-trifluoroethyl) O-phenyl carbonothioate (compound 314.4, 1.34 g, 3.30 mmol) in toluene (20 mL) was added Bn3SnH (3.84 mL, 13.2 mmol), AIBN (320 mg, 1.95 mmol). The reaction mixture was stirred for 1 h at 80° C. under nitrogen, then concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:20) as the eluent to furnish 650 mg (78%) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][C:23]=2[F:27])=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:28]1[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29]1>CCCCCCC.CCO.CO>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][C:23]=3[F:27])[C:2]([N:28]3[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O[C@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2[nH]ncc2F)c1
Solvent: CCCCCCC
Solvent: CO
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](O)C2)c(-c2[nH]ncc2F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 5 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(4-fluoro-1H-pyrazol-5-yl)nicotinamide (Stage 25.1) and (S)-3-pyrrolidinol to afford a white solid. HPLC (Condition 5) tR=5.69 min, HPLC Chiral (CHIRALCEL® OD-H, 250×4.6 mm, eluent:n-heptane/EtOH/MeOH (85:10:5), 1 mL/min, UV 210 nm) tR=12.62 min, UPLC-MS (Condition 6) tR=0.97 min, m/z=468.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.71-1.81 (m, 1H) 1.81-1.92 (m, 1H) 3.02 (d, J=11.34 Hz, 1H) 3.24-3.37 (m, 2H) 3.40-3.49 (m, 1H) 4.23 (br. s, 1H) 4.89 (br. s, 1H) 7.32 (d, J=9.4 Hz, 2H) 7.76-7.98 (m, J=9.00 Hz, 3H) 8.03 (d, J=2.35 Hz, 1H) 8.79 (d, J=2.35 Hz, 1H) 10.20 (br. s, 1H) 12.99 (br. s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([CH3:23])[CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35]>C1COCC1>[CH3:23][C:4]1[CH:3]=[C:2]([NH:1][C:34](=[O:35])[O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:22]=[CH:21][C:5]=1[O:6][C:7]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=2)=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2C)n1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)Oc3ccccc3)cc2C)n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To 4-(2-(4-amino-2-methylphenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (200 mg, 0.65 mmol) in THF (4 mL) was added diisopropylethylamine (0.097 mL, 0.72 mmol) and phenyl chloroformate (102 mg, 0.65 mmol). The mixture was stirred for 3.5 hours at RT and used without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:8][NH:7][C:6](=[O:9])[N:5]2[CH:10]=1.[C:11]([NH:15][C:16]1[C:25]([CH3:26])=[N:24][C:23]2[C:18](=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:20]=[CH:21][CH:22]=2)[N:17]=1)([CH3:14])([CH3:13])[CH3:12].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.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]>[C:11]([NH:15][C:16]1[C:25]([CH3:26])=[N:24][C:23]2[C:18]([N:17]=1)=[C:19]([C:2]1[CH:3]=[C:4]3[CH2:8][NH:7][C:6](=[O:9])[N:5]3[CH:10]=1)[CH:20]=[CH:21][CH:22]=2)([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1nc2cccc(B3OC(C)(C)C(C)(C)O3)c2nc1NC(C)(C)C
Reactant: O=C1NCc2cc(Br)cn21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3cc4n(c3)C(=O)NC4)c2nc1NC(C)(C)C
Temperature: 70 °C
Reaction time: 1.17 h
Yield: 55.9 %

Procedure:
A mixture of 6-bromo-1H-pyrrolo[1,2-c]imidazol-3(2H)-one (20.5 mg, 0.102 mmol), N-(tert-butyl)-3-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-2-amine (Example 174b; 43.5 mg, 0.102 mmol), K3PO4 (64.9 mg, 0.306 mmol), Pd2dba3 (Aldrich; 4.67 mg, 5.10 μmol), and XPhos (Strem Chemicals, Inc. MA; 4.86 mg, 10.20 μmol) in a mixture of dioxane (1.0 mL) and water (0.25 mL) was stirred under argon at 70° C. for 70 min. The reaction mixture was subsequently concentrated onto silica gel and chromatographically purified (silica gel, 0-100% EtOAc/hexanes) to provide 6-(3-(tert-butylamino)-2-methyl-quinoxalin-5-yl)-1H-pyrrolo[1,2-c]imidazol-3(2H)-one (19.0 mg, 0.057 mmol, 56% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.94 (1H, s), 7.79 (1H, br. s.), 7.70 (1H, d, J=7.4 Hz), 7.37 (1H, t, J=7.8 Hz), 6.56 (1H, d, J=1.2 Hz), 5.41 (1H, br. s.), 4.71 (1H, br. s.), 4.50 (2H, s), 2.57 (3H, s), 1.59 (9H, s). m/z (ESI, +ve) 336.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[C:13]([F:15])[N:12]=[C:11]([F:16])[CH:10]=2)[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([C:23](=O)[CH3:24])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[C:13]([F:15])[N:12]=[C:11]([F:16])[CH:10]=2)[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([CH:23]([NH2:32])[CH3:24])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c(C)c(-c2cc(F)nc(F)c2)c1-c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Cc1c(Cl)cc(C(C)N)c(-c2ccccc2)c1-c1cc(F)nc(F)c1
Temperature: 65 °C

Procedure:
A mixture of 1-[4-chloro-6-(2,6-difluoropyridin-4-yl)-5-methylbiphenyl-2-yl]ethanone (60 mg, 0.2 mmol), ammonium acetate (130 mg, 1.7 mmol) and sodium cyanoborohydride (21 mg, 0.34 mmol) in methanol (0.6 mL) and acetonitrile (0.6 mL) was heated at 65° C. overnight in a sealed tube. The mixture was then cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (60 mg, 100%). LCMS calculated for C20H15ClF2N (M−NH2)+: m/z=342.1. found: 342.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:15](=O)[CH2:14][CH:13]([CH2:17][CH3:18])[CH:12]([C:19]#[N:20])[C:11]2=O)=[CH:4][CH:3]=1.B.O1CCCC1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C@@H:13]([CH2:17][CH3:18])[C@H:12]([CH2:19][NH2:20])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: CCC1CC(=O)N(CCc2ccc(F)cc2)C(=O)C1C#N
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CC[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CN
Temperature: 25 °C
Reaction time: 65 h
Yield: 37.1 %

Procedure:
1-[2-(4-Fluorophenyl)ethyl]-4-ethyl-2,6-dioxopiperidine-3-carbonitrile (1.0 g, 3.47 mmol) was treated with 1.0 M borane in tetrahydrofuran (69.4 mL, 69.4 mmol) and stirred at room temperature for 65 hours. The solution was cooled on an ice bath and treated very slowly with 2.0 N hydrochloric acid. The mixture was concentrated under vacuum to remove the tetrahydrofuran, and the aqueous residue was heated at reflux for 60 minutes. The mixture was cooled to room temperature and treated with 50% aqueous sodium hydroxide to adjust the pH to about 11. The mixture was extracted with ethyl acetate, and the organic extracts were dried over sodium sulfate and concentrated. The residue was purified by flash chromatography, eluting with 5% methanol in dichloromethane containing 0.5% aqueous ammonia, to provide an oil (340 mg, 37%). 1H NMR (300 MHz, CDCl3) δ7.16 (m, 2H), 6.97 (t, J=9 Hz, 2H), 3.13 (m, 1H), 3.00 (m, 1H), 2.92 (dd, J=13, 3 Hz, 1H), 2.83 (m, 2H), 2.58 (m, 2H), 1.99 (td, J=12, 3 Hz, 1H), 1.9-1.0 (m, 8H), 0.90 (t, J=7 Hz, 3H). Mass spec (ES+) m/z 265.4 (M+H+, 100%).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH2:7]([N:11]1[C:20](=[O:21])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:22])[CH2:8][CH:9]=[CH2:10].BrC1C=CC(S(O[C@@H:34]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:36]([C:46]([O:48][CH3:49])=[O:47])[CH2:35]2)(=O)=O)=CC=1.CCOC(C)=O>CN1C(=O)CCC1.O>[CH2:7]([N:11]1[C:20]([O:21][C@H:34]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:36]([C:46]([O:48][CH3:49])=[O:47])[CH2:35]2)=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:22])[CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCN1C(=O)Cc2ccccc2C1=O
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCCn1c(O[C@@H]2C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C2)cc2ccccc2c1=O
Temperature: 40 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
Cs2CO3 (1.1 g, 3.39 mmol) was added to a solution of 2-but-3-en-1-ylisoquinoline-1,3(2H,4H)-dione (0.49 g, 2.26 mmol) and 1-t-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (1.05 g, 2.26 mmol) in NMP (10 mL), and the reaction mixture was stirred for 16 hours at 40° C. An additional portion of 1-t-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (1.0 g, 2.16 mmol) was added, and the reaction mixture was stirred at 40° C. for 16 hours. The reaction mixture was cooled and poured onto a mixture of EtOAc and H2O, and the layers were separated. The organic layer was washed with H2O (2×), 1N HCl (1×) and brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (gradient elution, 10-40% EtOAc/Hexane) to afford the title compound (0.83 g, 83%) as an oil. LCMS (ES+) m/z 443.0 (M+H)+.
Reaction SMILES: [C:1](=[O:34])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C@H:3]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:15][C:6]2[C:7]3[CH:8]=[N:9][NH:10][C:11]=3[C:12]([Cl:14])=[CH:13][C:5]=2[CH2:4]1.CN(C=O)C.C(N(CC)CC)C.[NH:47]1[CH2:52][CH2:51][CH:50]([N:53]2[C:61]3[C:56](=[N:57][CH:58]=[CH:59][CH:60]=3)[NH:55][C:54]2=[O:62])[CH2:49][CH2:48]1>>[O:62]=[C:54]1[NH:55][C:56]2=[N:57][CH:58]=[CH:59][CH:60]=[C:61]2[N:53]1[CH:50]1[CH2:51][CH2:52][N:47]([C:1]([O:2][C@H:3]2[C:17](=[O:18])[N:16]([CH2:19][C:20]([F:23])([F:21])[F:22])[CH2:15][C:6]3[C:7]4[CH:8]=[N:9][NH:10][C:11]=4[C:12]([Cl:14])=[CH:13][C:5]=3[CH2:4]2)=[O:34])[CH2:48][CH2:49]1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reaction time: 12 h
Yield: 80 %

Procedure:
(R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl 4-nitrophenyl carbonate (115 mg, 0.23 mmol) in DMF (10.00 mL, 129 mmol) was added triethylamine (0.128 mL, 0.920 mmol) followed by 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one, 1.00HCl (70.3 mg, 0.276 mmol). After 12 h, the solvent was removed and the product was purified by flash chromatography using 5% methanol in dichloromethane to give (R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (106 mg, 0.183 mmol, 80% yield). 1H NMR (500 MHz, CD3OD): in δ 8.29 (s, 1H), 8.03 (br, 1H), 7.96 (d, J=5.5 Hz, 1H), 7.71 (m, 1H), 7.27 (s, 1H), 7.13-7.12 (m, 1H), 6.10 (m, 1H), 5.44 (d, J=17 Hz, 1H), 4.88 (d, J=17 Hz, 1H), 4.72-4.60 (m, 2H), 4.50-4.39 (m, 1H), 4.38-4.22 (m, 1H), 4.21-4.02 (m, 1H), 3.40-3.40 (m, 1H), 3.39-3.27 (m, 2H), 3.23-2.97 (m, 2H), 2.71-2.23 (m, 2H), 1.95-1.74 (m, 2H); MS (ESI) 578 (M+H); Rf=2.15.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([C:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][N+:10]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[Cl-].[NH4+]>CO.O1CCCC1.[Zn]>[NH2:10][CH2:9][CH:8]([C:7]1[C:2]([F:1])=[C:3]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:4]=[CH:5][CH:6]=1)[C:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:19][CH:20]=2)[NH:15][CH:14]=1
Reactant: COCCOc1ccc2c(C(C[N+](=O)[O-])c3cccc(NC(=O)OCc4ccccc4)c3F)c[nH]c2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: COCCOc1ccc2c(C(CN)c3cccc(NC(=O)OCc4ccccc4)c3F)c[nH]c2c1
Reaction time: 3 h
Yield: 85.9 %

Procedure:
To a solution of benzyl 2-fluoro-3-(1-(6-(2-methoxyethoxy)-1H-indol-3-yl)-2-nitroethyl)phenylcarbamate (3.75 g, 7.39 mmol) and ammonium chloride (5.93 g, 111 mmol) in methanol (148 mL) and tetrahydrofuran (148 mL) under nitrogen was added zinc (7.25 g, 111 mmol). After 3 hr, the reaction was filtered through a pad of CELITE®, rinsed with EtOAc and MeOH. The filtrate was concentrated in vacuo. Water (40 mL) was added followed by saturated aq. NaHCO3 (to pH ˜11 by litmus paper) and extracted with EtOAc (4×50 mL). The organic layers were combined, washed with brine (40 mL), dried over MgSO4, and concentrated in vacuo to give the desired product (3.523 g, 6.35 mmol, 86% yield) as a light tan solid.