Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](Cl)[CH2:6][CH2:5]2.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:25]2[CH:29]=[CH:28][CH:27]=[N:26]2)[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=1)[CH2:6][CH2:5]2
Reactant: COC(=O)CC(c1ccc(O)cc1)n1cccn1
Reactant: ClC1CCc2cc(Br)ccc21
Product: COC(=O)CC(c1ccc(OC2CCc3cc(Br)ccc32)cc1)n1cccn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A mixture of 47.3 (0.16 mmol) and methyl 3-(4-hydroxyphenyl)-3-(1H-pyrazol-1-yl)propanoate 47.4 (obtained by the procedure of Example 58 set forth in US 2006/0004012 which is hereby incorporated by reference) (0.11 mmol) was stirred at 40° C. for 1 hour. After work up and chromatography, 47.5 was obtained in 30% yield. MS ESI (pos.) M/E: 441, 443 (M+H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.S(=O)(=O)(O)O.[C:24](=O)([O-])O.[Na+]>CO>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH3:24])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
To a solution of [3,5-bis(trifluoromethyl)phenyl]acetic acid (10 g) in methanol (50 mL) was added concentrated sulfuric acid (0.5 mL), and the mixture was stirred at 80° C. for 14 hr. The reaction mixture was cooled, basified with saturated aqueous sodium hydrogen carbonate solution, and concentrated under reduced pressure. The residue was diluted with ethyl acetate, and washed with saturated brine. The aqueous layer was extracted again with ethyl acetate, and the combined extract was dried, and concentrated to give methyl [3,5-bis(trifluoromethyl)phenyl]acetate (10.8 g, 100%) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11](=[O:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O>C(O)(=O)C>[Br:20][C:10]1[C:11](=[O:13])[NH:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc(-c2ccccc2)nc(-c2ccccc2)[nH]1
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccccc2)nc(-c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 60 h
Yield: 48.3 %

Procedure:
To a suspension of 13.37 g (56 mmol) of 2,6-diphenyl-4(3H)-pyrimidinone and 200 mL glacial acetic acid was added 15.1 g (84.8 mmol) of N-bromosuccinimide and the mixture was left to stir at room temperature for 60 h. The reaction was poured onto 100 g crushed ice and vacuum filtered, washing well with water, then air dried to yield 8.85 g (48%) 5-bromo-2,6-diphenyl-4(3H)-pyrimidinone, as a white solid. 1H-NMR (d6DMSO)δ7.55 (6H, m); 7.75 (2H, m); 8.15 (2H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][CH:10]=[C:9](/[CH:12]=[CH:13]\[C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]2[CH:7]=[C:6](/[CH:18]=[CH:19]/[C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>O1CCCC1.C(O)C.O>[CH3:1][C:2]1([CH3:30])[CH2:11][CH:10]=[C:9](/[CH:12]=[CH:13]\[C:14]([CH3:15])([CH3:16])[CH3:17])[C:8]2[CH:7]=[C:6](/[CH:18]=[CH:19]/[C:20]3[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc(/C=C/c2ccc3c(c2)C(/C=C\C(C)(C)C)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)/C=C\C1=CCC(C)(C)c2ccc(/C=C/c3ccc(C(=O)O)cc3)cc21
Reaction time: 30 h
Yield: 84.8 %

Procedure:
A solution of methyl 4-[(E)-(5,6-dihydro-5,5-dimethyl-8-((Z)-3,3-dimethyl-1-buten-1-yl)-2-naphthalenyl)ethenyl]benzoate (3.0 g, 7.49 mmol) in tetrahydrofuran (60 mL) and ethanol (30 mL) was treated with 4N sodium hydroxide (9.36 mL, 37.6 mmol) and stirred for 30 hours. The reaction mixture was diluted with water and acidified to pH 2 with concentrated hydrochloric acid. The acid precipitated and was extracted into ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude residue was dissolved in dichloromethane (75 mL) and ethanol (50 mL), filtered through a sintered glass and the filtrate was concentrated. The title material precipitated and was collected and dried to give a white solid (2.455 g, 85%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[F:15][C:16]([F:30])([F:29])[C:17]1[C:18]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][C:45]=1[F:46].Cl>>[Cl:39][C:40]1[CH:41]=[C:42]([C:2]2[CH:7]=[C:6]([N:26]3[CH2:25][CH2:24][N:23]([C:18]4[C:17]([C:16]([F:15])([F:29])[F:30])=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:28][CH2:27]3)[N:5]=[C:4]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:3]=2)[CH:43]=[CH:44][C:45]=1[F:46]
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Fc1ccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(N3CCOCC3)n2)cc1Cl
Temperature: 90 °C

Procedure:
To a rubber-septum-capped vial containing 4,6-dichloro-2-morpholinopyrimidine (0.2 M in dioxane, 0.25 mL) and 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine (0.2 M in dioxane, 0.28 mL) (Oakwood Products, Inc., West Columbia, S.C.) add aqueous K3PO4 (0.5 M, 0.125 mL). Heat the mixture at 90° C. for 24 hours. After cooling, add 3-chloro-4-fluorophenylboronic acid (0.2 M in dioxane, 0.35 mL) and K3PO4 (0.5 M in water, 0.10 mL) and flush the vial with argon. Add Pd(PPh3)4 (0.01 M in toluene, 0.125 mL). Heat the mixture at 80° C. overnight, add EtOAc(0.5 mL), separate the organic phase and load onto a 6-mL cartridge containing 1 g of SCX (a sulfonic acid-pregnated silica gel strong cation exchanger). Wash the SCX cartridge with 5 mL of MeOH and elute the product with 10% Et3N in EtOAc (5 mL). Concentrate the eluent to give the pure product which can be converted to the HCl salt: LCMS (m/e); 523, 1H NMR (CDCl3); d 3.4 (br s, 4 H), 3.8 (br s, 4 H), 4.0 (br s, 8 H), 6.4 (br s, 1H), 7.1 (br s, 1H), 7.2 (br s, 1H), 7.9 (m, 3 H), 8.5 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH:25]([F:29])[C:26]([OH:28])=O)[N:9]=2)[CH:7]=1.[CH:32]1([NH2:35])[CH2:34][CH2:33]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH:25]([F:29])[C:26]([NH:35][CH:32]3[CH2:34][CH2:33]3)=[O:28])[N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1nn(C(F)C(=O)O)cc1NC(=O)c1cnn2cccnc12
Reactant: NC1CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(C(F)C(=O)NC2CC2)cc1NC(=O)c1cnn2cccnc12
Reaction time: 1 h
Yield: 21.4 %

Procedure:
To 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)-2-fluoroacetic acid (39.1 mg, 0.088 mmol) and cyclopropylamine (10 mg, 0.18 mmol) in 1.0 mL DMF was added (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (91 mg, 0.18 mmol) and the mixture stirred for 1 h. The crude mixture was purified by reverse phase HPLC and lyophilized to give 9.1 mg (21%) of N-(3-(5-chloro-2-methoxyphenyl)-1-(2-(cyclopropylamino)-1-fluoro-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a colorless solid. LCMS (ESI) m+H=484.1. 1H NMR (400 MHz, DMSO) δ 9.77 (s, 1H), 9.34 (dd, J=7.0, 1.4 Hz, 1H), 8.83 (d, J=4.4 Hz, 1H), 8.76 (dd, J=4.2, 1.5 Hz, 1H), 8.68 (s, 1H), 8.55 (s, 1H), 7.58 (dd, J=8.9, 2.7 Hz, 1H), 7.37 (t, J=5.7 Hz, 2H), 7.29 (dd, J=7.0, 4.2 Hz, 1H), 6.80 (d, J=50.7 Hz, 1H), 3.85 (s, 3H), 2.82 (dd, J=7.3, 3.3 Hz, 1H), 0.70 (t, J=7.0 Hz, 2H), 0.64-0.57 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[CH3:19][CH:20]1[CH2:25][NH:24][CH2:23][CH2:22][NH:21]1.C(C(CCCC)C([O-])=O)C.[Na+:36]>C(OC(=O)C)C.C(Cl)(Cl)Cl>[Na+:36].[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:24]3[CH2:23][CH2:22][NH:21][CH:20]([CH3:19])[CH2:25]3)[CH:11]=2)[C:6](=[O:17])[C:7]([C:14]([O-:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CC1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCn1cc(C(=O)[O-])c(=O)c2cc(F)c(N3CCNC(C)C3)cc21
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
A mixture of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid [J. Med. Chem., 23, 1358 (1980)] (0.52 g, 2 mmol) and 2-methylpiperazine (0.8 g, 8 mmol) was heated at 175° for 5 hours. The residue was dissolved in ethylacetate (10 mL) and chloroform (10 mL), and a solution of sodium-2-ethyl- hexanoate (0.33 g, 2 mmol) in ethyl acetate (20 mL) was added. The mixture was stirred for 30 minutes and the precipitate was collected. The crude product was purified by preparative liquid chromatography (C-18 reverse phase, gradient 0-40% acetonitrile in water) to give a pale yellow lyophilized solid (0.5 g, 75% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH2:22]O)=[CH:9]\[C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1.CO.[BH4-].[Na+]>C(OCC)(=O)C>[CH:24]1([NH:27][CH2:22]/[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH2:26][CH2:25]1
Reactant: COC(=O)C=Cc1ccc(/C=C(/CO)c2ccc(F)cc2)cc1
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccc(/C=C(/CNC2CC2)c2ccc(F)cc2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of methyl 3-(1E)(4-(2-(4-fluorophenyl)-3-hydroxyprop-1-en-1-yl)phenyl)acrylate (0.44 g, 1.4 mmol) and cyclopropylamine (0.14 g, 2.4 mmol) was stirred with MeOH (40 mL) for 3 hours. To the reaction mixture, sodium borohydride (0.09 g, 2.3 mmol) was added and stirred for 30 minutes. Subsequently the reaction mixture was diluted with ethyl acetate (300 mL) and washed successively with water (2×100 ml) and brine (1×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to afford the pure title compound as a pale yellow sticky compound (0.4 g, 80% yield).
Reaction SMILES: Br[CH2:2][CH2:3][Cl:4].[CH3:5][C:6]1[C:15]([C:16]2[S:17][C:18]([C:27]3[N:31]=[CH:30][N:29]([CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][O:33]4)[N:28]=3)=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:20]=2)=[C:9]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][N:8]2[N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:4][CH2:3][CH2:2][O:14][C:11]1[CH:12]=[CH:13][N:8]2[N:7]=[C:6]([CH3:5])[C:15]([C:16]3[S:17][C:18]([C:27]4[N:31]=[CH:30][N:29]([CH:32]5[CH2:37][CH2:36][CH2:35][CH2:34][O:33]5)[N:28]=4)=[C:19]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:20]=3)=[C:9]2[CH:10]=1
Reactant: ClCCBr
Reactant: Cc1nn2ccc(O)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1nn2ccc(OCCCl)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Yield: 93.6 %

Procedure:
The title compound has been prepared according to the similar manner described in 85-B (ii) from 1-bromo-2-chloroethane (163 μL, 1.96 mmol), 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyrazolo[1,5-a]pyridin-5-ol (300 mg, 0.654 mmol) obtained in Example 31-B-(i) and cesium carbonate (639 mg, 1.96 mmol). The crude product has been roughly purified by simple filtration through silica gel pad (5 g) and then washed with diethyl ether (20 mL) to give title compound (319 mg, 93%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.C([Li])CCC.CN(C)[CH:18]=[O:19]>CCOCC>[CH3:1][O:2][CH:3]([O:9][CH3:10])[C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH:18]=[O:19]
Reactant: COC(OC)c1ccsc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: COC(OC)c1ccsc1C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2a (423 g., 2.68 moles) in anhydrous ether (1 L) was added dropwise in 1 hour a freshly prepared solution of n-butyllithium (27 moles) in ether keeping a gentle reflux under dry N2. Reflux being continued for 0.5 hour, a solution of DMF (dimethylformamide) (432 g., 6 moles) in anhydrous ether (0.8 L) was added dropwise to the mixture over a period of 0.75 hour with vigorous stirring. After the complete addition the mixture was stirred overnight, poured onto crushed ice (1 Kg.) with stirring and allowed to rise to room temperature. The organic layer was separated and the water layer was saturated with NaCl and extracted thoroughly with ether (2×200 ml.). The ether extracts were combined, dried over MgSO4 and concentrated. The residue was distilled under reduced pressure and the pale yellow oil was collected at 100°-125° C., 0.7 mmHg. Yield, 277 g. (56%).
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[C:5]([CH3:18])=[C:6]([CH:11]=[CH:12][C:13]=1[S:14]([CH3:17])(=[O:16])=[O:15])[C:7]([O:9][CH3:10])=[O:8].C=C.[CH2:21](N(CC)CC)[CH3:22].Cl>[Cl].C(Cl)(Cl)Cl.CCOCC.O>[O:1]1[CH2:22][CH2:21][C:3]([C:4]2[C:5]([CH3:18])=[C:6]([CH:11]=[CH:12][C:13]=2[S:14]([CH3:17])(=[O:15])=[O:16])[C:7]([O:9][CH3:10])=[O:8])=[N:2]1
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1C
Agent: C=C
Agent: Cl
Agent: [Cl]
Solvent: O
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOCC2)c1C
Reaction time: 0.58 h

Procedure:
6.00 g of crude methyl 3-hydroxyiminomethyl-4-methylsulfonyl-2-methylbenzoate was dissolved in 100 ml of chloroform Chlorine was blown into the resulting solution, with stirring, for 35 minutes at -3~3° C. The solution was further stirred for 30 minutes at 0° C. Nitrogen gas was blown into the reaction solution to remove excessive chlorine. Further chloroform was distilled out under reduced pressure to give viscous oil. The obtained oil was dissolved in 90 ml of ether, and ethylene was blown in, with stirring, for 5 minutes at -10° C. Then 7 ml of triethylamine and 7 ml of ether were added dropwise at -10° C. Further ethylene was blown in for 20 minutes. The resulting reaction mixture was transferred to a 200 ml, stainless-steel autoclave, which was cooled beforehand, and stirred for 3.5 hours at 60~70° C. The reaction solution was cooled down, poured into water, acidified with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, then with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure. The obtained crude product was purified by column chromatography on silica gel with n-hexane/ethyl acetate=2/1 to give 3.20 g of the title compound as white crystals. m.p. 104~106.5° C.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.[CH3:27][C:28](C)([O-])[CH3:29].[K+].C(Br)C=C>O1CCCC1>[CH2:29]([N:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:9]/[C:8]/1=[N:10]\[C:11](=[O:21])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[CH:28]=[CH2:27]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a solution of Example 244A (410 mg, 1.3 mmol) in 5 mL of tetrahydrofuran:N,N-dimethylformamide (4/1) at 0° C. was added potassium tert-butoxide (230 mg, 1.9 mmol). The reaction mixture was stirred for 1 hour then allyl bromide (0.16 mL, 1.9 mmol) was added. The mixture was warmed to 65° C. and stirred overnight. The mixture was cooled to ambient temperature, concentrated, diluted with CH2Cl2 and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by chromatography (20-50% ethyl acetate/hexane gradient) afforded the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 1.34 (s, 9H), 3.90 (s, 3H), 4.78-4.85 (m, 3H), 522-5.36 (m, 2H), 5.90-6.09 (m, J=17.0, 10.17 Hz, 1H), 6.62 (s, 1H), 6.90 (d, J=9.2 Hz, 1H), 7.32 (dd, J=8.8, 3.1 Hz, 1H), 8.00 (d, J=2.7 Hz, 1H); MS (DCI/NH3) m/z 365 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[O:18][CH3:17])[CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCC1
Reactant: COc1ccccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)C1=Cc2cc(Br)ccc2N(Cc2ccccc2OC)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.7 %

Procedure:
To a solution of methyl 7-bromo-2,3-dihydro-1-benzazepine-4-carboxylate (1.5 g) and 2-methoxybenzaldehyde (3.62 g) in 1,2-dichloroethane (50 ml) was added sodium triacetoxyborohydride (2.82 g), and the mixture was stirred under nitrogen atmosphere at room temperature for 1 day. Then, water was added to the mixture, and the mixture was extracted-with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=5:1) to give methyl 7-bromo-1-(2-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (1.62 g) as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@@H:13]([C:17]([OH:19])=O)[C@H:14]([CH3:16])[OH:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[C:38]([O:42][NH2:43])([CH3:41])([CH3:40])[CH3:39].Cl.CN(CCCN=C=NCC)C>C(Cl)Cl.O>[C:38]([O:42][NH:43][C:17](=[O:19])[C@H:13]([NH:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:10])=[O:11])[C@H:14]([OH:15])[CH3:16])([CH3:41])([CH3:40])[CH3:39]
Reactant: COc1ccc(S(=O)(=O)N[C@@H](C(=O)O)[C@H](C)O)cc1
Reactant: CC(C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(S(=O)(=O)N[C@@H](C(=O)NOC(C)(C)C)[C@@H](C)O)cc1
Reaction time: 8 h

Procedure:
N-[4-methoxybenzenesulfonyl]-(D)-threonine (4.0 g, 13.84 mmol), 1-hydroxybenzotriazole (1.87 g, 13.84 mmol), 4-methylmorpholine (7.9 mL, 69.2 mmol), and O-t-butylhydroxylamine hydrochloride (5.22 g, 41.52 mmol) are dissolved in methylene chloride (100 mL). To this solution is added N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (3.45 g, 17.99 mmol), and the reaction is stirred overnight. The mixture is then diluted with water and extracted with methylene chloride. The combined organic extracts are washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude product is purified by silica gel chromatography (ethyl acetate) to give N-(t-butyloxy)-2(R)-[[4-methoxybenzenesulfonyl]-amino]-3(R)-hydroxybutanamide.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])=[O:18].O>CC(C)=O.C(OCC)(=O)C>[C:7]([CH:9]([CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])=[O:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8]
Reactant: O=C(CBr)c1ccccc1F
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(C#N)CC(=O)c1ccccc1F
Temperature: 45 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a solution of 2′-fluoroacetophenone (28.6 g) in ethyl acetate (400 mL) was added copper (II) bromide (92.6 g), and the mixture was heated under reflux for 4 hr. The reaction mixture was allowed to cool to room temperature and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give crude 2-bromo-1-(2-fluorophenyl)ethanone (yield 90.5 g) as an oil. Potassium carbonate (88 g) was added to ethyl cyanoacetate (168 g), and the mixture was stirred at 45° C. for 1 hr. A solution (360 mL) of crude 2-bromo-1-(2-fluorophenyl)ethanone (90.5 g) in acetone was added dropwise over 20 min. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hr. Water (300 mL) and ethyl acetate (300 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 10% aqueous sodium dihydrogen phosphate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=20:1→4:1) to give the title compound as an oil (yield 64.0 g, about 100%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:23]=[CH:22][C:21](=[O:24])[CH2:20][CH2:19]3)=[C:14]([F:25])[CH:13]=2)[CH2:7]1)=O)C.[CH3:26][NH2:27]>CO>[CH3:26][NH:27][C:4]([C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:23]=[CH:22][C:21](=[O:24])[CH2:20][CH2:19]3)=[C:14]([F:25])[CH:13]=2)[CH2:7]1)=[O:3]
Reactant: CCOC(=O)C1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
To a stirred solution of 3-[4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxylic acid ethyl ester (EXAMPLE 69, within Step 6, 120 mg, 0.34 mmol) in MeOH (1 mL) is added MeNH2 (2 mL, 4.0 mmol, 2.0 M solution in MeOH). The reaction mixture is stirred for 1 h at room temperature. Solvent is removed and the residue purified by column chromatography (10% MeOH/CH2Cl2) to give the title compound as a pale yellow solid (60 mg, 52%), 1H NMR (300 MHz, DMSO) δ 8.39 (m, 1H), 7.65-7.38 (m, 4H), 5.06 (dd, 1H), 4.98 (d, 1H), 4.27 (t, 1H), 4.02 (dd, 1H), 3.87 (t, 2H), 2.65 (d, 3H); MS for C16H16FN3O4 m/z 334.5 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>C(O)C>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[O:7][CH:15]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccc(F)cc1
Solvent: CCO
Product: Fc1ccc(-c2nc(CCl)co2)cc1
Yield: 28.3 %

Procedure:
4-Fluorobenzamide (10.0 g) and 1,3-dichloroacetone (9.5 g) were dissolved in ethanol (100 mL), and the mixture was refluxed for 8 hr. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 7:1) to give the title compound (4.3 g) as a white solid.