Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].[CH3:7][N-:8][CH3:9].[CH3:10][N-]C.[Ti+4:13].C[C:15]1[CH2:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].[CH3:7][N-:8][CH3:9].[CH3:10][Ti+3:13][CH:18]1[CH:17]=[CH:16][CH:15]=[CH:19]1
Reactant: CC1=CC=CC1
Reactant: [Ti+4]
Agent: C[N-]C
Solvent: Cc1ccccc1
Product: C[Ti+3]C1C=CC=C1

Procedure:
A 250 mL Schlenk flask is charged with titanium tetrakis(dimethylamide), 3.73 g (16.64 mmole), and toluene, 100 mL. Methylcyclopentadiene, 5.33 g (66.54 mmole), is added to the magnetically stirred solution. The mixture is refluxed 1.5 hours. Solvent and volatiles are removed under vacuum leaving a brown residue. The residue is transferred to a microdistillation apparatus and a forerun of titanium tetrakis(dimethylamide) is distilled from the mixture (at 35°-40° C. and 0.025 mm Hg) followed by a red low melting solid (at 104°-108° C. and 0.025 mm Hg) which is determined to be methylcyclopentadienyltitanium tris(dimethylamide) by proton NMR.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[O:22])=[CH:20][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(N(C(C)C)C(C)C)C.Cl[C:40]([O:42][CH3:43])=[O:41]>C(Cl)Cl>[CH3:43][O:42][C:40]([NH:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[O:22])=[CH:20][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)=[NH:3])=[O:41]
Reactant: COC(=O)Cl
Reactant: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C(=N)N)cc1)n2C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C(=N)NC(=O)OC)cc1)n2C
Reaction time: 0.5 h

Procedure:
0.26 g of 2-(4-amidino-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-1-methyl-benzimidazole-hydrochloride are suspended in 50 ml of methylene chloride and, whilst cooling with ice, 0.5 ml of N-ethyl-diisopropylamine and 0,067 ml of methyl chloroformate are added. The mixture is stirred at ambient temperature, after half an hour a further 0.5 ml of N-ethyl-diisopropylamine and 0.03 ml of methyl chloroformate are added and, after another half hour, a further 0.1 ml of N-ethyl-diisopropylamine and 0.03 ml of methyl chloroformate. The mixture is stirred for a further half hour, evaporated down in vacuo and purified by column chromatography (silica gel; eluant:ethyl acetate/ethanol=100:2.5 to 100:12.5). Yield: 0.12 g (40% of theory), Rf value: 0.41 (silica gel; ethyl acetate/ethanol=8:2)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)C.[H][H]>[Ni].ClC1C=CC=CC=1Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: Clc1ccccc1Cl
Solvent: CCO
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.8 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), ethanol (300 ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (50 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml ethanol. The cis to trans ratio is 82 to 85/18 to 15. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>98%, trans<2%, dehalogenation product<0.1%, yield 0.80 to 0.82%].
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](Cl)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[C:20]([NH:23][CH:24]1[CH2:28][CH:27]([CH3:29])[NH:26][CH2:25]1)(=[O:22])[CH3:21]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:26]4[CH:27]([CH3:29])[CH2:28][CH:24]([NH:23][C:20](=[O:22])[CH3:21])[CH2:25]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC(=O)NC1CNC(C)C1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Product: CC(=O)NC1CC(C)N(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1

Procedure:
The condensation of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with 3-acetamido-5-methylpyrrolidine in a similar manner as described in example 1 give the titled product. Yield (68%), m.p 270–72° C., C20H22FN3O4, m/z 388 (M+1).
Reaction SMILES: [C:1](=[O:15])(OC(Cl)C(Cl)(Cl)Cl)[O:2][CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[F-].[K+].[F:18]C([O-])=O>C(#N)C1C=CC=CC=1>[F:18][C:1]([O:2][CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:15]
Reactant: O=C([O-])F
Reactant: CC(C)(C)COC(=O)OC(Cl)C(Cl)(Cl)Cl
Agent: [F-]
Agent: [K+]
Solvent: N#Cc1ccccc1
Product: CC(C)(C)COC(=O)F
Temperature: 65 °C
Yield: 76 %

Procedure:
In this experiment, neopentyl 1,2,2,2-tetrachloroethyl carbonate is used as the starting material. A mixture of 3.3 g (0.011 mole) of neopentyl 1,2,2,2-tetrachloroethyl carbonate, 1 g (0.017 mole) of anhydrous KF, 5 g (0.001 mole) of polyethyleneglycol monomethylether (average molecular weight 5000 Aldrich) and 10 cc of benzonitrile is heated under stirring at 65° C. (oil bath). The reaction is stopped at the end of 34 hours. By infrared and NMR analysis it is determined that the fluoroformate is obtained in a 76% yield.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl[CH2:18][C:19]1[N:20]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:21]([C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)([CH3:26])[CH3:25])=[CH:22][N:23]=1>C1COCC1>[Cl:34][C:29]1[CH:28]=[C:27]([C:24]([C:21]2[N:20]([C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[C:19]([CH2:18][O:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)=[N:23][CH:22]=2)([CH3:26])[CH3:25])[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(CCl)n1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (202 mg, 1 mmol) in anhyd THF (3 mL) was added NaH (60% in mineral oil, 53 mg, 1.32 mmol). The mixture stirred at room temperature for 30 min, then a solution of 2-(chloromethyl)-5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (262 mg, 0.66 mmol) in THF (2 mL) was added. After stirring at ambient temperature overnight, the reaction was quenched by addition of MeOH and concentrated in vacuo. The residue was partitioned in water and EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (silica, 0-90% EtOAc/Hex) to give tert-butyl 4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methoxy)piperidine-1-carboxylate as a white solid (215 mg, 60%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25](Br)=[CH:24][N:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:36]([C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)#[CH:37]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:37]#[C:36][C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)=[CH:24][N:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Br)cn3)c2CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C#Cc4ccc(F)cc4)cn3)c2CC1
Temperature: 65 °C
Yield: 94.2 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-6-(5-bromopyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.0 g, 2.07 mmol), tetrakistriphenylphosphine palladium(0) (120 mg, 0.104 mmol), cuprous iodide-(20 mg, 0.105 mmol), triethylamine (2.60 mL) and 1-ethynyl-4-fluorobenzene (500 mg, 4.16 mmol) in DMF (8 mL). Degas the mixture, purge with nitrogen, and heat at 65° C. for 3 days. Dilute the mixture with water, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (50:1) to give 3-tert-butoxycarbonyl-7-chloro-6-[5-(4-fluorophenylethynyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a tan foam (1.02 g, 95%). MS (APCI+) m/z: 523 (M+H)+, 423 (M+H−Boc)+. Use a method similar to the General Procedure 14 to give the title compound as a tan powder. MS (APCI+) m/z: 423 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)=[N:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[N:6][CH:7]=1.[CH2:27]([Mg])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(OC)(C)C.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)[S@@](=O)N=C(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: [Mg]Cc1ccccc1
Solvent: COC(C)(C)C
Solvent: CCOCC
Product: CC(C)(C)[S@@](=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reaction time: 0.08 h
Yield: 72 %

Procedure:
To a solution of (R)-N-((5-chloropyridin-2-yl)(3-fluoro-5-(trifluoromethyl)phenyl)methylene)-2-methylpropane-2-sulfinamide (1.09 g, 2.68 mmol) in anhydrous TBME (45 mL) at −78° C. under argon was added BF3Et2O (0.57 mL, 5.38 mmol). After 5 min, benzylmagnesium grignard (5.38 mL, 5.38 mmol, 1.0M in ether) was added dropwise with stirring. After 40 min, LCMS indicated that the reaction was complete and the cold solution was quenched with saturated NaCl (ca 20 mL), transferred to a separation funnel and the organic phase extracted with EtOAc (3×20 mL). The combined organic portions were dried, decanted, concentrated and purified by silica gel ISCO chromatography.2×120 g cartridge columns were used 0-60% EtOAc/hexanes over 20 min. A trace amount of minor diastereomer eluted first followed by the major diastereomer (R)-N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (0.97 g, 72% yield). Rf0.4 (Hexane:EtOAc 2:1) LCMS: 2.15 min [M+1] 499.1 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 4.15 min (4 min gradient, MeOH/H2O 0.2% PPA); Purity 99%; NMR: 400 MHz 1H (CDCl3) 8.65 ppm, d, 1H, J=2.6 Hz; 7.62 ppm, dd, 1H, J=2.6 and J=8.8 Hz; 7.36 ppm, 4H, m; 7.29 ppm, 1H, m; 7.24 ppm, 1H, m; 7.14 ppm, 2H, m; 6.99 ppm, 1H, d, J=10.1 Hz; 6.81 ppm, 1H, d, J=6.6 Hz; 4.09 ppm, 1H, d, J=13.2 Hz; 3.69 ppm, 1H, d, J=13.2 Hz; 1.18 ppm, 9H, s.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)=[CH:16][CH:15]=1)[CH2:6][CH2:5]2.C(=O)=O.C[Li].C([Li])CCC.CON(C)[C:41](=[O:43])[CH3:42]>O.C1COCC1>[C:41]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)=[CH:16][CH:15]=1)[CH2:6][CH2:5]2)(=[O:43])[CH3:42]
Reactant: CON(C)C(C)=O
Reactant: O=C(N[C@H]1CCc2cc(Br)ccc2C1)c1ccc(OC[C@@H]2CCCO2)cc1
Agent: O=C=O
Agent: [Li]C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Temperature: 25 °C

Procedure:
A mixture of N-((S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (1.0 g) and THF (10 ml) was cooled to −78° C. (dry ice bath), and a solution of methyllithium (2.0 ml; 1.6 M in diethyl ether) was added dropwise. One minute after the addition had ended, a solution of butyllithium (1.4 ml; 2.5 M in toluene) was added dropwise. One minute after the addition had ended, N-methoxy-N-methylacetamide (0.24 g) was added. After warming to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phases were dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (eluent: 1:1 heptane/ethyl acetate). The product was thus obtained with the molecular weight of 393.49 (C24H27NO4); MS (ESI): 394 (M+H+).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH2:9]([O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([C:27](O)=[O:28])[CH:21]=[CH:20]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl.C(N=C=NCCCN(C)C)C.O>C(Cl)Cl>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([C:27]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])=[O:28])[CH:21]=[CH:20]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCOc1ccc2cc(C(=O)O)ccc2c1
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCCCCOc1ccc2cc(C(=O)ON3C(=O)CCC3=O)ccc2c1
Reaction time: 3 h
Yield: 79.5 %

Procedure:
To a susupension of N-hydroxysuccinimide (0.56 g) and 6-heptyloxy -2-naphthoic acid (1.39 g) in methylene chloride (42 ml) was added 1-ethyl -3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.21 g) and stirred for 3 hours at room temparature. The reaction mixture was added to water (100 ml). The organic layer was separated and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give succinimido 6-heptyloxy -2-naphthoate (1.48 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][CH3:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]>CN(C)C(=O)C>[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[CH:7][CH:6]=1)(=[O:12])[CH2:10][CH3:11]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCC(=O)Nc1ccc(N)cc1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CCC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 0 °C
Yield: 97.5 %

Procedure:
To a solution of N-(4-aminophenyl)propanamide (2.00 g, 10.3 mmol) and pyridine (2.50 ml, 30.9 mmol) in N,N-dimethylacetamide (40 ml) was added 2,2,2-trichloroethyl chloroformate (2.13 ml, 15.5 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 2 hours. The reaction mixture was poured into ice-water, and 3.41 g (97.4%) of the desired product was collected by filtration as a solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][C:18]=2[F:25])=[CH:13][CH:12]=1.[OH-].[K+].O>CO>[Cl:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]([C:3]3[C:4]4[C:9](=[N:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[OH:22])=[CH:19][C:18]=2[F:25])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(OCc2ccc(Cl)cc2)c(F)c1
Reactant: c1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC(c1ccc(OCc2ccc(Cl)cc2)c(F)c1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1H-Pyrrolo[2,3-b]pyridine (6, 100.0 mg, 0.85 mmol) in methanol (50.0 mL) were added 4-(4-chloro-benzyloxy)-3-fluoro-benzaldehyde (46, 250.0 mg, 0.94 mmol, prepared as described in Example 15) and potassium hydroxide (1.00 g, 17.82 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give the compound (P-1895, 55 mg, 17.0%). MS (ESI) [M+H+]+=383.3.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH:13]=[CH:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH:13]3[O:27][CH:12]3[CH2:11]2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C1(NC(=O)c2ccc(Cl)s2)CC=CC1
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)c2ccc(Cl)s2)CC2OC2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.85 g (2.9 mmol) methyl 1-[(5-chloro-thiophen-2-yl)-carbonylamino]-cyclopent-3-ene-1-carboxylate and 20 ml methylene chloride is combined with 0.92 g 70% meta-chloroperbenzoic acid at 0° C. and stirred for 3 h at room temperature. The mixture is washed with sat. Sodium hydrogen carbonate solution and concentrated.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[Br:11]Br.O>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:9][Br:11])=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccccc1C
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccccc1C(=O)CBr
Reaction time: 1.5 h
Yield: 92.5 %

Procedure:
A solution of 13.42 g of ortho-methylacetophenone in 15 ml of acetic acid was treated with 15.98 g of bromine in 15 ml acetic acid. After being kept at ca 100° C. for 90 minutes, the mixture was poured into 300 ml water and extracted with ether. Removal of solvent from the dried (MgSO4) extract provided 19.70 g of residual oil, which by GLC was 75% pure. This crude product was used without further purification.
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]([NH:10][C:11]([C:13]1[CH:22]=[C:21]([Cl:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[O:24][CH2:25][C:26]1[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][CH:31]=1)=[O:12])([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>O>[Cl:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([O:24][CH2:25][C:26]2[CH:31]=[N:30][C:29]([C:32]([F:34])([F:35])[F:33])=[N:28][CH:27]=2)=[C:13]([C:11]([NH:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:36])=[O:5])=[O:12])[CH:22]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)NC(=O)c1cc(Cl)c2ccccc2c1OCc1cnc(C(F)(F)F)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(NC(=O)c1cc(Cl)c2ccccc2c1OCc1cnc(C(F)(F)F)nc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
0.015 g 2-{[4-chloro-1-(2-trifluoromethyl-pyrimidin-5-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid tert-butyl ester was dissolved in 5 mL of a mixture consisting of 95% trifluoroacetic acid, 2.5% triethylsilanes and 2.5% of water. This was left stirring at room temperature for 30 minutes, and then it was concentrated in vacuo. Purification was performed by flash chromatography on silica using methanol/dichloromethane to give 0.007 g (53%) of 2-{[4-Chloro-1-(2-trifluoromethyl-pyrimidin-5-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=[O:18].[CH3:19][Mg]Br.[NH4+].[Cl-].O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([CH3:19])[OH:18]
Reactant: O=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(O)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Temperature: 0 °C
Yield: 93.5 %

Procedure:
A suspension of 7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one (35 g, 107 mmol) in dry THF (210 mL) under nitrogen atmosphere was cooled to 0° C. and a solution of methylmagnesium bromide (3.0M solution in diethyl ether; 107 mL, 320 mmol) in dry THF (70 mL) was added over 10 minutes via an addition funnel. After complete addition a saturated aqueous solution of NH4Cl (125 mL) was added slowly to the stirring reaction mixture, keeping the internal temperature below 30° C. Water was added and the mixture was extracted twice with EtOAc. The combined organic layers were dried over sodium sulfate before concentrating under reduced pressure to afford 7-bromo-3-chloro-1-fluoro-5-methyl-5H-chromeno[2,3-c]pyridin-5-ol (34.33 g, 100 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH2:10])=[O:4].C1OC1C.CN(C)C(=O)C.[N:21]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[N:24][N:23]=[N:22]1>C(OCC)C>[CH3:1][O:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:27](=[O:28])[CH2:26][N:21]1[CH:25]=[N:24][N:23]=[N:22]1)=[O:4]
Reactant: COC(=O)[C@H]1NC(=O)[C@H]1N
Reactant: O=C(Cl)Cn1cnnn1
Agent: CC1CO1
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: COC(=O)[C@H]1NC(=O)[C@H]1NC(=O)Cn1cnnn1
Temperature: -30 °C
Yield: 79.3 %

Procedure:
To a mixture of 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester, 4 ml of propylene oxide and 3 ml of N,N-dimethylacetamide, which is stirred previously under ice-cooling, is added dropwise 400 mg of 1H-tetrazol-1-yl acetyl chloride, followed by stirring for 30 minutes. To the mixture is added 50 ml of ethyl ether, followed by stirring under cooling at -30° C., and then the upper layer is removed by decantation. The lower layer is subjected to the same procedure as above twice, followed by addition of 10 ml of acetone. The resultant solution is developed and purified by column-chromatography on silica-gel (40 g, 3×10 cm) using a mixture of acetone:methylene chloride (1:1) as eluent, followed by drying to give 403 mg (84%) of cis-3-(1H-tetrazol-1-ylacetamido)-2-oxoazetidine-4-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[CH3:19][C@H:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([CH3:26])[NH:21]1.Cl>C(Cl)Cl>[CH3:19][C@H:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([CH3:26])[N:21]1[C:2]([Cl:1])=[O:4]
Reactant: C[C@@H]1CCC[C@H](C)N1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CCC[C@H](C)N1C(=O)Cl
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 256.2 %

Procedure:
To a solution of triphosgene (20.8 g, 70.0 mmol) in DCM (400 mL) at 5° C. was added pyridine (16.2 mL, 200 mmol) dropwise over 10 min, maintaining the temperature below 10° C. The solution was then stirred between 5-10° C. for 1 h, then cis-2,6-dimethyl piperidine (CAS: 766-17-6, 27.0 mL, 200 mmol) was added dropwise over 10 min and the resulting red solution stirred at RT for 4 days (reaction complete within <4 h). The solution was cooled to 3° C., then a pre-cooled (3° C.) 1M aqueous HCl solution (400 mL) was added and the mixture stirred at 5° C. for 30 min. The mixture was separated and the aqueous layer was extracted with DCM (200 mL), then the combined organic extracts passed through a hydrophobic fit and concentrated under vacuum affording Intermediate 3a as a red oil (31.5 g, 90%). 1H NMR (300 MHz, CDCl3): 1.30 (6H, d, J=7.09 Hz), 1.49-1.87 (6H, m), 4.46-4.56 (2H, m).