Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][CH:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:19][CH2:18]3)[CH2:10][CH2:9]1)(C)(C)C.[ClH:33]>O1CCOCC1.C(OCC)C>[ClH:33].[C:26]1([CH3:31])[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:20]1[CH2:19][CH2:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([O:14][C@H:11]3[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]3)[CH:16]=2)[O:21]1
Reactant: Cc1ccccc1C1CCc2cc(O[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)ccc2O1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1ccccc1C1CCc2cc(O[C@H]3CC[C@H](N)CC3)ccc2O1
Temperature: 0 °C

Procedure:
6 g (13.7 mmol) of [trans-4-(2-o-tolyl-chroman-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester were dissolved in 50 ml of 1,4-dioxane and 25 ml of 2N hydrogen chloride in diethyl ether. The diethyl ether was removed by evaporation and the remaining solution was refluxed until no starting material could be detected by RP-HPLC. The resulting suspension was cooled to 0° C. and the crystals were collected by filtration, washed once with cold methyl tert-butyl ether and dried in vacuum at 25° C. to yield 3.6 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].C(N(CC)CC)C.[C:18](Cl)(=[O:22])[CH:19]([CH3:21])[CH3:20]>C1COCC1>[Br:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([F:9])=[C:6]([NH:7][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:8]=1
Reactant: Nc1cc(Br)c(F)cc1F
Reactant: CC(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1cc(Br)c(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
Into a solution of 2.6 g (12.6 mmol) of 5-bromo-2,4-difluoroaniline and 2.1 mL (15.1 mmol) of triethylamine in 50 mL THF at 0° C. was slowly added 1.6 mL (15.1 mmol) of isobutyryl chloride. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in EtOAc and washed with H2O, saturated aqueous Na2CO3 and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give 3.3 g (11.8 mmol, 94%) of N-(5-bromo-2,4-difluorophenyl)-2-methylpropanamide: ESMS m/e: 278.1 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C@H:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[C:3]([OH:5])=[O:4])=[CH:8][CH:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of (S)-2-amino-3-(4-benzyloxy-phenyl)-propionic acid (2.7 g, 0.010 mol), 4-fluoro-benzene-sulfonyl chloride (2.0 g, 0.010 mol), and sodium carbonate (2.2 g, 0.020 mol) in a mixture of tetra-hydrofuran (20 mL) and water (20 mL) was stirred at room temperature for 3 days. The reaction mixture was partitioned between ethyl acetate and 1 M hydrochloric acid. The organic layer was washed with saturated sodium chloride solution, dried (MgSO4), and rotary-evaporated under reduced pressure to give an oil. The oil was chromatographed on silica gel (445 g, 230-400 mesh) eluting with dichloromethane-methanol (20:1), and the fractions containing product were rotary-evaporated to give a solid. The solid was recrystallized from toluene to give the title compound as a light yellow solid; yield 0.22 g (5%), mp=138-139° C.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:33])[C:4]([C:6]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:9]2[N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:17][N:16]=3)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][CH2:42][F:43]>C(#N)C.CN(C=O)C>[CH3:2][N:3]([CH3:33])[C:4]([C:6]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:9]2[N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:22][CH2:23][N:24]([CH2:41][CH2:42][F:43])[CH2:25][CH2:26]4)=[CH:17][N:16]=3)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5]
Reactant: FCCBr
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CCF)CC4)cn3)nc2n1C1CCCC1
Temperature: 80 °C
Yield: 55 %

Procedure:
To a solution of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide hydrochloride (150 mg, 0.318 mmol) and potassium carbonate (132 mg, 0.955 mmol) in acetonitrile (3 mL) and DMF (2 mL) is added 1-bromo-2-fluoroethane (0.035 mL, 0.478 mmol) and the reaction mixture is heated to 80° C. for 24 h in a sealed reaction vial. Upon cooling, the reaction mixture is partitioned between dichloromethane and water. The organic layer is separated and the aqueous layer extracted further with dichloromethane. The combined organics are ished with brine, dried (MgSO4), filtered and concentrated. The crude product is purified using silica gel chromatography (0 to 10% methanol/dichloromethane) to give 7-cyclopentyl-2-{5-[4-(2-fluoro-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (84 mg, 55%) as an off white solid.
Reaction SMILES: [OH-].[Na+].[NH2:3][C@H:4]([C:8]([OH:10])=[O:9])[CH:5]([CH3:7])[CH3:6].C([O-])([O-])=O.[Na+].[Na+].Cl[C:18]([O:20][CH3:21])=[O:19]>O.C(O)C>[CH3:21][O:20][C:18]([NH:3][C@@H:4]([CH:5]([CH3:7])[CH3:6])[C:8]([OH:10])=[O:9])=[O:19]
Reactant: COC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 0 °C
Reaction time: 15 h
Yield: 65.1 %

Procedure:
1N NaOH in water (1250 mL) was added into to L-Valine (150 g, 1280 mmol) in a 3 L round bottom flask equipped with a magnetic stir bar. To this solution was added Na2CO3 (67.8 g, 640 mmol) and the reaction mixture was cooled to 0° C. in an ice-water bath. Methyl chloroformate (107 mL, 1390 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred for 15 hours. The reaction mixture was washed with ethyl acetate (3×400 mL). The aqueous layer was cooled over an ice-water bath and acidified by concentrated HCl (aq) to pH=2. The reaction mixture was extracted with CH2Cl2 (3×1000 mL). The combined organic layers were dried over Na2SO4 and the solvent was concentrated to afford the crude product. The crude product was heated at reflux with 150 mL ethanol and 150 mL water for 2 hours. Then the mixture was cooled to room temperature and the crystalline solids were filtered to give (S)-2-(methoxycarbonylamino)-3-methyl-butanoic acid (146 g, 65% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(Cl)(=O)C([Cl:30])=O>C(Cl)Cl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:30])=[O:8])=[CH:5][C:4]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCCCCCOc1cc(C(=O)O)ccc1OC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1cc(C(=O)Cl)ccc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.6 %

Procedure:
To a mixture of 50 g of product from Example 42 in 500 ml of methylene chloride and 15 drops of dimethylformamide is added, dropwise, 26.12 g of oxalyl chloride. The reaction is stirred at room temperature for 18 hours and concentrated in vacuo. The residue is recrystallized from diethyl ether to give 52.3 g of the desired product as white crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20](O)=[O:21])=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.C1(C)C=CC=CC=1.O=S(Cl)[Cl:37]>CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([Cl:37])=[O:21])=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(C(=O)O)c2)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(C(=O)Cl)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
A mixture of 3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-benzoic acid (16.44 g, 44.39 mmol), toluene (180 mL), SOCl2 (19.4 mL, 265.8 mmol), and anhydrous DMF (1 mL) was heated to reflux overnight, cooled to room temperature, and evaporated to dryness. The residue was co-evaporated twice with toluene followed by high vacuum at 70° C. for 4 h to give 3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-benzoyl chloride as a solid (17 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:26][CH:25]=2)[CH:8]=[N:7][CH:6]=1
Reactant: COC(=O)c1cncc(Br)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 80 °C
Yield: 54.5 %

Procedure:
81 mg (0.07 mmol)Pd(PPh3)4 was added under argon at room temperature to a solution of 1.0 g (4.63 mmol) methyl-5-bromo-pyridine-3-carboxylate in 23 ml N,N-dimethylformamide and the mixture was heated to 80° C. Then 2.26 g (6.94 mmol) cesium carbonate and 1.05 g (5.09 mmol) of 4-(trifluoromethoxy)phenyl boronic acid were added and the mixture was stirred at 80° C. over night. The reaction mixture was cooled to room temperature, filtered, and the filtrate evaporated. The residue was taken up with ethyl acetate, washed twice with water, dried over sodium sulphate and evaporated. Chromatography on silica (eluent: ethyl acetate/n-heptane 1:3) gave 0.75 g (49%) of 5-(4-Trifluoromethoxy-phenyl)-nicotinic acid methyl ester
Reaction SMILES: [Br-].[Br-].C[N+]([CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][N+](C)(C)C)(C)C.Cl[P:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[C:35]1([P:34]([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]=2[CH2:28][P:34]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: C[N+](C)(C)Cc1ccc2ccccc2c1-c1c(C[N+](C)(C)C)ccc2ccccc12
Agent: [Br-]
Solvent: CN(C)C=O
Product: c1ccc(P(Cc2ccc3ccccc3c2-c2c(CP(c3ccccc3)c3ccccc3)ccc3ccccc23)c2ccccc2)cc1
Yield: 78.4 %

Procedure:
The procedure of Example 7 is repeated, but using an electrolyte comprising 5.58 g (0.010 mol) of 2,2'-bis[(trimethylammonio)methyl]-1,1'-binaphthyl dibromide, 6.62 g (0.030 mol) of chlorodiphenylphosphine and 50 ml of dimethyl formamide (max. 0.1% of water) in the electrolysis. The amount of charge is 0.96 Ah. Workup gives 5.1 g of 2,2'-bis[(diphenylphosphino)methyl]-1,1'-binaphthyl ("naphos"). This corresponds to a yield of 78% based on 2,2'-bis[(trimethylammonio)methyl]-1,1'-binaphthyl dibromide used.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[NH:9][C:10](=O)[C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[CH:13]=1.[OH-].[Na+].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:10]1[C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[CH:13]=[C:8]([CH3:7])[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cn2ccnc2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: Cc1cn2ccnc2c(Cl)n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
Pyridine (0.4 mL, 4.9 mmol) was added to a solution of 6-methyl-7H-imidazo[1,2-a]pyrazin-8-one (0.97 g, 6.5 mmol) in POCl3 (19 mL) and the reaction is stirred at 120° C. under N2 atmosphere for 4 h 30 min. The reaction is cooled to 60° C. and poured into 60 g of ice and stirred for 1 h. The solution is neutralized with NaOH (10%), extracted with CHCl3/IPA 9/1, dried with MgSO4 anh., filtered and concentrated. The crude product is purified by column chromatography using a gradient of (DCM/MeOH:99/1 to 95/5) to give 8-chloro-6-methyl-imidazo[1,2-a]pyrazine as a pale yellow solid (0.383 g, 35%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[C@H:15]2[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C@@H:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:26]([F:29])([F:28])[F:27])[C:8]=2[C:7]1=[O:30].I[CH3:32]>C1COCC1.COC(C)(C)C>[CH3:32][O:3][CH2:4][CH2:5][N:6]1[C@H:15]2[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C@@H:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:26]([F:27])([F:29])[F:28])[C:8]=2[C:7]1=[O:30]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3C(=O)N(CCO)[C@H]2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COCCN1C(=O)c2c(cccc2C(F)(F)F)[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21
Reaction time: 0.33 h
Yield: 37 %

Procedure:
To a suspension of sodium hydride (8 mg of 60% dispersion in mineral oil, hexane-washed, 0.20 mmol) in 2 mL of THF was added (3aR,9bS)-tert-butyl 4-(2-hydroxyethyl)-5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 20, Part A (40 mg, 0.10 mmol) in 2 mL THF. The reaction was stirred for 20 min, at which time gas evolution had ceased. Then there was added iodomethane (0.125 mL of a 2M solution in tert-butyl methyl ether, 0.25 mmol) and the reaction was allowed to stir at ambient temperature for 18 h. TLC analysis showed that starting material remained. Additional sodium hydride (8 mg of 60% dispersion in mineral oil, 0.20 mmol) and iodomethane (0.125 mL of a 2M solution in tert-butyl methyl ether, 0.25 mmol) were added and the reaction was allowed to stir at 40° C. for 2 h. The reaction was quenched with 10 mL of 1N HCl and extracted with EtOAc. The organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (230-400 mesh silica gel, elution with 4:1 hexane/EtOAc) to afford 15 mg (37%) of the title compound. 1H NMR (CDCl3): δ 7.79 (d, 1H, J=7.7 Hz), 7.57-7.52 (m, 2H), 7.25-7.22 (m, 1H), 4.15-4.10 (m, 1H), 4.08-3.98 (m, 2H), 3.82-3.77 (m, 1H), 3.61-3.54 (m, 2H), 3.50-3.27 (overlapping m, 4H), 3.31 and 3.28 (singlets, 3H), 1.50 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24]OS(C)(=O)=O)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[N-:35]=[N+:36]=[N-:37].[Na+]>CCOC(C)=O>[N:35]([CH2:24][CH2:23][O:22][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCOS(C)(=O)=O)c2cccc(F)c2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN=[N+]=[N-])c2cccc(F)c2)C1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
(R)-tert-Butyl 3-((R)-(3-fluorophenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (13.8 g, 32 mmol) was dissolved into anhydrous DMF (150 mL), solid NaN3 (6.1 g, 96 mmol, 3 eq) was added and the reaction mixture was heated to 80° for overnight. The reaction mixture was cooled to rt and then was added with EtOAc (500 mL), the organic phase was washed with water (3×100 mL) and brine (2×80 mL), dried over Na2SO4 and concentrated in vacuo to give crude (R)-tert-butyl 3-((R)-(2-azidoethoxy)(3-fluorophenyl)methyl)piperidine-1-carboxylate (12 g), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:19])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12)[NH2:5].C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28].C(=O)(O)[O-].[Na+].C[O-].[Na+]>ClCCl>[F:19][C:7]1[CH:6]=[C:4]([NH:5][C:27](=[O:29])[CH3:28])[CH:3]=[C:2]([F:1])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12
Reactant: CC(=O)Cl
Reactant: Nc1cc(F)c(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cc(F)c(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
1.60 g (6.14 mmol) of 3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline are suspended in 45 ml of dichloromethane and cooled to 0° C. 2.57 ml (18.4 mmol) of triethylamine and 0.87 ml (12.3 mmol) of acetyl chloride are added dropwise, and stirring at 0° C. is continued for 2.5 hours. A further 0.86 ml (6.14 mmol) of triethylamine and 0.44 ml (6.14 mmol) of acetyl chloride are added, and the mixture is allowed to react for another hour. Saturated sodium bicarbonate solution is then added, and the mixture is stirred at RT for 10 min. The mixture is extracted twice with dichloromethane. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure. The crude product is taken up in 45 ml of ethanol. 1.14 ml (6.14 mmol) of 5.4M sodium methoxide solution are added, and the mixture is stirred at RT for 30 min. The mixture is concentrated and the product is purified by chromatography on silica gel (mobile phase: dichloromethane/methanol (7N ammonia) 100:1 to 100:5).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:11])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12.[CH:12]1([CH2:17][CH2:18][C:19](Cl)=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[C:3]([NH:11][C:19](=[O:20])[CH2:18][CH2:17][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12
Reactant: Nc1nn2cccnc2c1Br
Reactant: O=C(Cl)CCC1CCCC1
Product: O=C(CCC1CCCC1)Nc1nn2cccnc2c1Br

Procedure:
The product from Example 110A and 3-cyclopentylpropionyl chloride were processed using the method analogous to that described in Example 1D to provide the title compound. MS (APCI) m/z 337/339 (M+H)+.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12.[Br-].[CH2:20]([Zn+])[CH2:21][CH3:22]>O1CCOCC1>[CH2:20]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12)[CH2:21][CH3:22]
Reactant: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Reactant: CCC[Zn+]
Agent: [Br-]
Solvent: C1COCCO1
Product: CCCc1cccc2c1CCN1C(=O)CNC(=O)C=C21
Temperature: 120 °C

Procedure:
90-1. To a degassed solution of 9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (1.0 g, 2.82 mmol) and propylzinc(II)-bromide (14.1 mL, 7.05 mmol, 0.5M in THF) in dioxane (28 mL) was added PEPPSI-iPr (0.29 g, 0.424 mmol) under argon and the mixture was heated in a pressure vessel at 120° C. for 2.5 h. The reaction mixture was allowed to warm to rt and the solvent was removed under reduced pressure. The residue was suspended in DCM/MeOH (9:1, v/v), filtrated through a pad of celite and the filtrate was evaporated under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: from 1% MeOH in DCM to 10% MeOH in DCM in 35 min) to yield the product as an oil. The title compound was crystallized from diethyl ether to afford yellow crystals (370 mg). UPLC-MS: MS 271.2 (M+H+); UPLC rt 0.86 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)([CH2:14][CH3:15])[C:9](=[O:13])[CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:33][CH2:34]Br>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)([C:9]2[O:13][CH2:33][CH2:34][C:10]=2[C:11]#[N:12])[CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: CCC(C(=O)CC#N)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C1=C(C#N)CCO1)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 0.5 h

Procedure:
To a solution of N-(1-(3-(4-chlorophenyl)-1-cyano-2-oxopentan-3-yl)-1H-indol-4-yl)methanesulfonamide (50 mg, 0.116 mmol, enantiomer A), as described in Example 28 step A, in DMF (2 mL) was added NaH (9 mg, 0348 mmol, 60% in oil) at 0° C. After stirring for 30 min, 1,2-dibromoethane (22 mg, 0.116 mmol) was added to the mixture at 0° C. The resulting mixture was stirred at 0° C. for another 1 h, and then quenched with water (15 mL), extracted with ethyl acetate. The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography eluting with PE/EA (5/1 to 3/1, v/v) to give the title compound as a colorless amorphous solid. LC/MS m/z=456.1 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24]>O>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: CCCCCCCCO
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCC(=O)S(=O)(=O)c1ccccn1
Reaction time: 3 h
Yield: 99 %

Procedure:
To 3.0 mL of anhydrous triethylamine (23.04 mmol, 30 equiv.) at 0° C. was added 1-octanol (0.10 g 0.77 mmol, 1 equiv.) followed by the addition of 2-pyridylsulfonyl chloride in one portion. The mixture was kept at 0° C. for 3 hours followed by the addition of water (5 mL). The resulting mixture was extracted with diethyl ether (3×50 mL), then the organic extracts were combined and washed with aqueous NaHCO3 solution (50 mL), dried (MgSO4), and concentrated under reduced pressure. Column chromatography (2% EtOAc/Hex) afforded 15 (99%): 1H NMR (CDCl3, 400 MHz) δ 8.68 (d, J=7.0 Hz, 1H, ArH), 7.94 (p, J=8.8 Hz, 2H, ArH), 7.54 (t, J=6.4 Hz, 1H, ArH), 4.26 (t, J=6.7 Hz, 2H, CH2OSO2R), 1.61 (p, J=7.9 Hz, 2H), 1.13 (m, 10H), 0.76 (t, J=7.0 Hz, 3H); MALDI-FTMS 294.1130 (C13H21NO3S+Na+ requires 294.1134).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:11]=1>>[CH:31]1([C:27]2[CH:28]=[C:29]([CH3:30])[C:24]([N:21]3[CH2:22][CH2:23][N:18]([C:16]([C:13]4[CH:14]=[CH:15][C:10]([N:7]5[C@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]5=[O:8])=[CH:11][C:12]=4[S:34]([CH3:37])(=[O:36])=[O:35])=[O:17])[CH2:19][CH2:20]3)=[N:25][CH:26]=2)[CH2:32][CH2:33]1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2S(C)(=O)=O)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)CC[C@H]3CO)cc2S(C)(=O)=O)CC1
Yield: 56.8 %

Procedure:
Using (S)-5-hydroxymethylpyrrolidin-2-one (127 mg) and (4-bromo-2-methanesulfonylphenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (478 mg) described in Preparation Example 126 and by the reaction and treatment in the same manner as in Example 1, the title compound (291 mg) was obtained.