Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](CCCC)(CCCC)(CCCC)CCCC.[F-].[F:19][C:20]([F:51])([F:50])[C:21]1[CH:22]=[C:23]([NH:27][C:28]([C:30]2[C:34]3[CH:35]=[CH:36][C:37]([O:39][Si](C(C)C)(C(C)C)C(C)C)=[CH:38][C:33]=3[O:32][N:31]=2)=[O:29])[CH:24]=[CH:25][CH:26]=1>C1COCC1>[F:51][C:20]([F:19])([F:50])[C:21]1[CH:22]=[C:23]([NH:27][C:28]([C:30]2[C:34]3[CH:35]=[CH:36][C:37]([OH:39])=[CH:38][C:33]=3[O:32][N:31]=2)=[O:29])[CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)[Si](Oc1ccc2c(C(=O)Nc3cccc(C(F)(F)F)c3)noc2c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1noc2cc(O)ccc12
Reaction time: 0.92 h

Procedure:
5.5 ml of a 1 M solution of Bu4NF in THF are added to a solution of 1.045 g (2.18 mMol) 6-triisopropylsilanyloxy-benzo[d]isoxazole-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide dissolved in 25 ml THF. After 55 min, the solution is concentrated in vacuo, the residue redissolved in water and EtOAc, the aq. layer separated off and extracted twice with EtOAc. The organic layers are washed twice with water and brine, dried (Na2SO4) and concentrated. Trituration in hexane gives the title compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][C:2]21[CH2:11][CH2:10][CH:9]1[CH:7]([O:8]1)[CH2:6]2.[CH3:12][NH:13][CH3:14].[OH-].[Na+]>>[CH3:12][N:13]([CH3:14])[C@H:7]1[C@H:9]([OH:8])[CH2:10][CH2:11][C:2]2([O:3][CH2:4][CH2:5][O:1]2)[CH2:6]1
Reactant: CNC
Reactant: C1COC2(CCC3OC3C2)O1
Agent: [Na+]
Agent: [OH-]
Product: CN(C)[C@@H]1CC2(CC[C@H]1O)OCCO2

Procedure:
A mixture of 25.0 g (0.16 mol) of spiro[7-oxabicyclo[4.1.0]-heptane-3,2'-[1,3]-dioxolane] from Example 1, Part D, and 87.0 ml (0.05 mol) of of 40% aqueous dimethylamine was heated in an oil bath at 90° for four hours. The reaction mixture was cooled to 0° and treated with NaOH pellets until two phases separated. Methylene chloride (CH2Cl2) was added, the phases were separated, the aqueous phase was extracted twice with CH2Cl2, the combined organic phases were dried (MgSO4) and the solvent removed in vacuo leaving 31.0 g of a yellow liquid. The crude yellow liquid product thus obtained was distilled at reduced pressure through a short path to give 28.0 g (88%) of the subtitled amino-alcohol: bp 83°-87° (0.2 mm); IR (nujol) 3460 (OH) cm-1, 2780 (N--C--H), 1134, 1090, 1050, 1040, 925 (C-O); mass spec. m/e 201 (M+). nmr (CDCl3); 54.7 (S, 1H, OH), 3.95 (S, 4H, O(CH2CH2O), 3.1-3.5 (m, 1H, CH-OH), δ2.3-2.7 (m, 1H, CH--N), 2.25 (S, 6H, N(CH3)2)2, 1-2 (m, 6H, ring CH2). The IR and nmr spectra were in agreement with the structure assignment.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:9].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.CO>[Br:9][C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[C:1]([CH3:8])[CH:2]=1
Reactant: [Br-]
Reactant: Cc1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(Br)ccc1O
Reaction time: 1 h
Yield: 178.1 %

Procedure:
To a solution of o-cresol (6.0 g) in dichloromethane (120 ml) and methanol (80 ml) was added little by little the solid of tetrabutylammonium tribromide (27.0 g), and the mixture was stirred for 1 hour and concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ether (4 times). The organic layer was washed with saturated brine (twice) and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give solid, which was dried in vacuo to give colorless solid of 4-bromo-2-methylphenol (9.3 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[C:11]([Si:15]([CH3:18])([CH3:17])Cl)([CH3:14])([CH3:13])[CH3:12]>>[CH3:17][Si:15]([CH3:18])([C:11]([CH3:14])([CH3:13])[CH3:12])[O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:10]
Reactant: OCCCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)OCCCCCCO
Yield: 52.6 %

Procedure:
Using the procedure of Step A of Preparation 16, 8.12 g of sodium hydride at 50% in oil, 20 g of 1,6-hexane diol and 25.5 g of terbutyl dimethyl chloro silane were reacted to obtain after chromatography, 20.7 g of the expected product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:11]=1[C:12](Cl)=[O:13]>CN(C)C1C=CN=CC=1.ClC(Cl)Cl>[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:11]=1[C:12]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:13]
Reactant: Cc1ccccc1N
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
To a stirred solution of 42.8 parts of 2-methylbenzenamine in 375 parts of trichloromethane are added dropwise 41.8 parts of 2,6-dichlorobenzoyl chloride at reflux temperature. Then there are added 1.2 parts of N,N-dimethyl-4-pyridinamine and stirring is continued for 3 hours at reflux. The reaction mixture is allowed to cool to room temperature overnight and diluted with 375 parts of trichloromethane. The organic phase is washed successively with 100 parts of water, 100 parts of a hydrochloric acid solution 3 N and again 100 parts of water, dried, filtered and evaporated. The residue is crystallized from 200 parts of 2-propanol, yielding 40.6 parts (72.5%) 2,6-dichloro-N-(2-methylphenyl)benzamide; mp. 182.5° C.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]1[CH:26]=[CH:25][C:18]([CH2:19]OS(C)(=O)=O)=[CH:17][C:16]=1[N+:27]([O-:29])=[O:28]>CCOC(C)=O>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([CH2:19][C:18]2[CH:25]=[CH:26][C:15]([F:14])=[C:16]([N+:27]([O-:29])=[O:28])[CH:17]=2)[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CS(=O)(=O)OCc1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1.0 eq of methanesulfonic acid 4-fluoro-3-nitro-benzyl ester (2B) in DMF (about 0.6 M 2B in DMF) was added about 1.05 eq of TEA and about 1.0 eq of t-butyl piperazine-1-carboxylate. The mixture was stirred for 30 min at room temperature, diluted with EtOAc, washed with NH4Cl solution, dried (Na2SO4) and evaporated. Purification by flash chromatography over silica with 50% EtOAc/hexanes as the eluant afforded 4-(4-fluoro-3-nitro-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (2C).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10](O)[CH2:11][CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:14][C:15]1[C:16]([OH:24])=[C:17]([CH3:23])[C:18]([CH3:22])=[C:19]([CH:21]=1)[OH:20]>ClCCCl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:21]2[C:19](=[O:20])[C:18]([CH3:22])=[C:17]([CH3:23])[C:16](=[O:24])[C:15]=2[CH3:14])[CH2:11][CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCC(O)c1ccc(C(C)C)cc1
Reactant: Cc1cc(O)c(C)c(C)c1O
Solvent: ClCCCl
Product: CCC(C1=C(C)C(=O)C(C)=C(C)C1=O)c1ccc(C(C)C)cc1
Reaction time: 3 h
Yield: 62.1 %

Procedure:
Boron trifluoride/ethyl ether complex (1.30 g, 9.33 mmol) was dropwise added to a suspension of 1-(4-isopropylphenyl)propan-1-ol (5.00 g, 28.0 mmol) and trimethylhydroquinone (4.30 g, 28.0 mmol) in 1,2-dichloroethane (100 mL) at 60° C. in a nitrogen atmosphere, and the mixture was stirred for 3 hours at the same temperature. After cooling, the reaction mixture was washed with an aqueous solution of iron(III) chloride and water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=30/1) to obtain the title compound (5.40 g, yield 62%).
Reaction SMILES: [CH:1]1([C:4](=[O:16])[CH:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([O:8]C)=O)[CH2:3][CH2:2]1.[CH2:17]=[N:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1(C)C(C)=CC=CC=1>[CH:1]1([C:4]2[O:16][CH2:17][N:18]([C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6](=[O:8])[C:5]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)C(C(=O)C1CC1)c1ccccc1
Reactant: C=NC(C)(C)C(=O)OCC
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(C)(C)N1COC(C2CC2)=C(c2ccccc2)C1=O

Procedure:
A mixture of methyl 3-cyclopropyl-3-oxo-2-phenylpropanoate (6.54 g) and ethyl 2-(N-methyleneamino)-2-methylpropanoate was heated under reflux in xylene in the presence of 5A molecular sieve (33 g) for 7 hours. The mixture was evaporated and purified by chromatography on silica gel, eluting with hexane/ethyl acetate (7:3) to give ethyl 2-(6-cyclopropyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (7.56 g), as an oil, NMR (CDCl3)δ 0.7-0.78(m,2H), 0.95-1.01(m,2H), 1.22(t,3H), 1.54(s,6H), 1.52-1.61(m,1H), 4.14(q,2H), 5.17(s,2H), 7.21-7.42(m,5H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[NH:19][C:20](=[O:24])[C:21]([CH3:23])=[O:22])=[CH:8][CH:7]=[CH:6][N:5]2[C:25]=1[CH2:26][C:27]#[CH:28].C(O)(=O)C.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>C(O)C>[C:20]([NH:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=1[CH2:11][O:10][C:9]1[C:4]2[N:5]([C:25]([CH2:26][C:27]#[CH:28])=[C:2]([CH3:1])[N:3]=2)[CH:6]=[CH:7][CH:8]=1)(=[O:24])[CH:21]([CH3:23])[OH:22]
Reactant: C#CCc1c(C)nc2c(OCc3c(C)cccc3NC(=O)C(C)=O)cccn12
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: C#CCc1c(C)nc2c(OCc3c(C)cccc3NC(=O)C(C)O)cccn12
Yield: 47.8 %

Procedure:
To a solution of 2-methyl-3-(2-propynyl)-8-(2-pyruvamido-6-methylbenzyloxy)imidazo[1,2-a]pyridine (287 mg) in the mixture of acetic acid (0.13 ml) and ethanol (3 ml), sodium cyanoborohydride (72 mg) was added portionwise for 2.5 hours at 5° C. The mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (10 g) and eluted with a mixture of chloroform and methanol (100.1) to give 8-(2-lactamido-6-methylbenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (138 mg).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:22]([C:25]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:26]=1[NH2:27])([CH3:24])[CH3:23].[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](O)=[O:44]>CN(C=O)C>[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([NH:27][C:26]1[C:25]([CH:22]([CH3:24])[CH3:23])=[CH:31][CH:30]=[CH:29][C:28]=1[CH:32]([CH3:34])[CH3:33])=[O:44]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(O)CCCCCCCBr
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCCCCCCBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.7 %

Procedure:
WSC (1.05 g 5.5 mmols) and HOBt (743 mg, 5.5 mmols) were added to a DMF (15 ml) solution of 2,6-diisopropylaniline (886 mg, 5 mmols) and 8-bromooctanoic acid (1.67 g, 7.5 mmols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ether. The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer:hexane/acetone=5/1), and the resulting crystals were recrystallized from other-hexane to obtain 720 mg (yield: 38%) of 8-bromo-N-(2,6-diisopropylphenyl) octanamide as colorless needle-like crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]([NH:8][C:9]1[C:10]([C:15]([O:17]C)=O)=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:7])[CH3:2].C([O-])C.[Na+:23]>CCO>[CH2:1]([O:3][C:4]([C:5]1[C:6]([O-:7])=[N:8][C:9]2[C:10]([C:15]=1[O-:17])=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:19])[CH3:2].[Na+:23].[Na+:23]
Reactant: CCOC(=O)CC(=O)Nc1cccnc1C(=O)OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c([O-])nc2cccnc2c1[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 3-(3-ethoxy-3-oxopropanamido)picolinate (3.7 g, 14.67 mmol) in EtOH (50 mL) was added sodium ethanolate (6.56 mL, 17.60 mmol). The reaction was stirred at rt for 1 h. After this time the reaction was concentrated in vacuo and dried under vacuum overnight to give sodium 3-(ethoxycarbonyl)-1,5-naphthyridine-2,4-bis(olate): 1H NMR (400 MHz, DMSO-d6) δ ppm 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (1H, dd, J=4.5, 1.6 Hz), 7.46 (1H, dd, J=8.2, 1.6 Hz), 7.29 (1H, dd, J=8.2, 4.3 Hz), 4.08 (2H, q, J=7.0 Hz), 1.13-1.24 (3H, m).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[C:12](=[O:18])[NH:13][CH:14]=[C:15]([I:17])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:21]>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[C:12]([O:18][CH3:21])=[N:13][CH:14]=[C:15]([I:17])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(I)c[nH]c1=O)OCc1ccccc1
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1ncc(I)cc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.2 %

Procedure:
(5-Iodo-2-oxo-1,2-dihydro-pyridin-3-yl)-carbamic acid benzyl ester (3.68 g, 9.94 mmol) was dissolved in chloroform (50 mL) at room temperature under nitrogen in the dark (foil wrapped). Silver carbonate (3.70 g, 13.2 mmol) was added followed by iodomethane (6.2 mL, 99.4 mmol). The reaction mixture was allowed to stir at room temperature for 48 hours. The silver salts were removed by filtration through a pad of celite, washing with more chloroform and the filtrate concentrated in vacuo. The residue was purified by column chromatography to give the title compound as a white solid (3.14 g, 82% yield). MS (ES+) m/e=385. 1H NMR (CDCl3) δH 3.97 (3H, s), 5.23 (2H, s), 7.15 (1H, br s), 7.35-7.47 (5H, m), 8.00 (1H, s), 8.64 (1H, br s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[C:14]([F:16])([F:15])[F:17])[CH2:9][CH2:10]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Fc1ccc(N2CCNCC2)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCN(c2ccc(F)cc2C(F)(F)F)CC1
Yield: 69.2 %

Procedure:
Sulfonylation of 1-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine (386 mg, 1.55 mmol) with 4-chlorobenzene-1-sulfonyl chloride (328.2 mg, 1.555 mmol) was carried out according to the representative sulfonation procedure described in Example 1 using anhydrous dichloromethane (3 mL) as solvent and diisopropylethylamine (1.35 mL, 7.775 mmol) as base. 1-[(4-chlorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]piperazine was obtained in 69.2% yield (455 mg) as white solid.
Reaction SMILES: [Li]CCCC.Br[C:7]1[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=1.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([C:27]3[N:31]([CH3:32])[C:30]([CH3:33])=[N:29][CH:28]=3)[OH:26])[CH:23]=2)[N:18]=[C:17]([O:34][CH3:35])[C:16]=1[CH2:36][C:37]1[CH:38]=[N:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=1>C1COCC1>[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:27]3[N:31]([CH3:32])[C:30]([CH3:33])=[N:29][CH:28]=3)([C:7]3[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=3)[OH:26])[CH:23]=2)[N:18]=[C:17]([O:34][CH3:35])[C:16]=1[CH2:36][C:37]1[CH:38]=[N:39][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:41][CH:42]=1
Reactant: Cc1ncc(Br)n1C
Reactant: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cnc(C)n3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 1.3 mL, 3.25 mmol) was added dropwise by syringe to a solution of 5-bromo-1,2-dimethyl-1H-imidazole (614.1 mg, 3.509 mmol) in dry THF (12 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of (4-chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone (0.830 g, 1.75 mmol, Intermediate 45: step f) in dry THF (5 mL) was added dropwise. The reaction was stirred for 5 minutes, then was removed from the cold bath and allowed to warm to ambient temperature. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was partitioned between water and dichloromethane. The separated aqueous phase was further extracted with dichloromethane. The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (silica gel, 0-5% MeOH-DCM) followed by trituration with dichloromethane to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J=2.1 Hz, 1H), 8.22 (d, J=2.2 Hz, 1H), 7.79 (dd, J=8.0, 2.1 Hz, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.41 (dd, J=8.8, 2.1 Hz, 1H), 6.15 (s, 2H), 5.47 (s, 1H), 4.34 (s, 2H), 4.06 (s, 3H), 3.40 (s, 6H), 2.29 (s, 6H); MS m/e 571.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][OH:12].[H-].[Na+].O>O1CCCC1>[CH3:11][O:12][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: CO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a stirred solution of 10 g of 2-chloro-5-nitropyridine and 2 g of dry methanol in 40 ml of dry tetrahydrofuran, 2.8 g of sodium hydride (about 60%, in oil) is added under cooling in an ice-water bath. The mixture is stirred at room temperature for 1 hour, and 30 ml of water is added. The mixture is extracted with three 40-ml portions of ethyl acetate, and the combined extracts are dried over magnesium sulfate. The solvent is distilled off to give 8.0 g of crude 2-methoxy-5-nitropyridine.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[C:20]([F:27])=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>>[Cl:18][C:19]1[C:20]([F:27])=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: Fc1c(Cl)cccc1CBr
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cccc(Cl)c1F

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3-chloro-2-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:16]=[CH:17][C:9]=2[C:8]=1[C:27]1[C:28]([CH3:37])=[C:29]2[C:34](=[CH:35][CH:36]=1)[O:33][CH2:32][CH2:31][CH2:30]2)[C:3]([O:5][CH3:6])=[O:4].C(O[C:42]([CH3:45])([CH3:44])[CH3:43])(=O)C.Cl(O)(=O)(=O)=O>>[C:42]([O:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[N:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH:16]=[CH:17][C:9]=2[C:8]=1[C:27]1[C:28]([CH3:37])=[C:29]2[C:34](=[CH:35][CH:36]=1)[O:33][CH2:32][CH2:31][CH2:30]2)[C:3]([O:5][CH3:6])=[O:4])([CH3:45])([CH3:44])[CH3:43]
Reactant: COC(=O)C(O)c1c(-c2ccc3c(c2C)CCCO3)c2ccn(Cc3ccc(OC)cc3)c2c(=O)n1C
Reactant: CC(=O)OC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2ccn(Cc3ccc(OC)cc3)c2c(=O)n1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60.7 %

Procedure:
An ice cold solution of methyl 2-hydroxy-2-(1-(4-methoxybenzyl)-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (325 mg, 0.647 mmol) in tert-butyl acetate (8735 μl, 64.7 mmol) was treated with perchloric acid (55.6 μl, 0.647 mmol), and stirred for 20 min. The reaction was then kept in the refrigerator without stirring for 2 days. The reaction was quenched with sat. NaHCO3 at 0° C., extracted with EtOAc 2×, washed with Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-100% EtOAc/Hexane) gave methyl 2-(tert-butoxy)-2-(1-(4-methoxybenzyl)-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (219.3 mg, 0.393 mmol, 60.7% yield, racemate) as white solid. The racemate was resolved using a Chiralpak IC column (30×250 mm) with isocratic conditions of 10% EtOH in hexane. The flow rate was 40 mL/min and the baseline was monitored at 280 nm using an Agilent 1100 series prep LC. The third isomer eluting from the column was isolated to afford (S)(M)-methyl 2-(tert-butoxy)-2-(1-(4-methoxybenzyl)-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (52.9 mg, 0.095 mmol, 14.6% yield) as clear oil: 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.29 (d, J=8.5 Hz, 2H), 6.99-6.91 (m, 2H), 6.85 (d, J=8.5 Hz, 2H), 6.69 (d, J=8.4 Hz, 1H), 5.86 (d, J=14.6 Hz, 1H), 5.71-5.61 (m, 2H), 5.09 (s, 1H), 4.20 (t, J=5.2 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.65 (s, 3H), 2.76-2.62 (m, 2H), 2.13-2.04 (m, 2H), 1.91 (s, 3H), 1.11 (s, 9H); LCMS (m/z) ES+=559 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:13][CH:14]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=4)[CH2:18][CH2:17][N:16]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:15]3)=[O:12])[CH:9]=2)[N:4]([C:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:3]=1.[N:53]1[CH:58]=[CH:57][C:56](B(O)O)=[CH:55][CH:54]=1>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>[F:26][C:22]1[CH:21]=[C:20]([CH:19]2[CH2:18][CH2:17][N:16]([C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])[CH2:15][CH:14]2[NH:13][C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:3]=[C:2]3[C:56]2[CH:57]=[CH:58][N:53]=[CH:54][CH:55]=2)=[O:12])[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(F)c2)C(NC(=O)c2ccc3c(c2)c(Br)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(F)c2)C(NC(=O)c2ccc3c(c2)c(-c2ccncc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 80 °C

Procedure:
tert-butyl 3-(3-bromo-1-trityl-1H-indazole-5-carboxamido)-4-(3-fluorophenyl)-piperidine-1-carboxylate (80 mg, 0.105 mmol) was added to a vial containing pyridin-4-ylboronic acid (13 mg, 0.105 mmol) and tetrakis(triphenylphosphine)palladium (13 mg, 0.0105 mmol). After purging the vial with nitrogen gas, dioxane (0.5 mL) and 2M sodium carbonate (0.5 mL) was added to the vial respectively. The reaction mixture was stirred and was heated to 80° C. for overnight. Upon completion, the mixture was concentrated under vacuo. Water (3 mL) was added and was extracted using dichloromethane (3×5 mL). The extracts were combined and dried using anhydrous sodium sulfate. The resulting suspension was filtered and concentrated. The crude product was progressed to the next step without purification.