Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:10][C:9]2[NH:8][CH:7]=[C:6]([CH2:11][CH2:12][C:13](O)=[O:14])[C:5]=2[C:4](=[O:16])[CH2:3]1.[C:18](N1C=CN=C1)([N:20]1C=CN=[CH:21]1)=O.CNC>ClCCl.O1CCCC1>[CH3:1][C:2]1([CH3:17])[CH2:10][C:9]2[NH:8][CH:7]=[C:6]([CH2:11][CH2:12][C:13]([N:20]([CH3:21])[CH3:18])=[O:14])[C:5]=2[C:4](=[O:16])[CH2:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C)CC(=O)c2c(CCC(=O)O)c[nH]c2C1
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)CCc1c[nH]c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Yield: 76.2 %

Procedure:
To a suspension of 3-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (1.65 g, 7 mmol) in dichloromethane (15 mL) was added 1.36 g (8.4 mmol) of carbonyldiimidazole. The mixture was stirred at room temperature until the solution became clear. To the mixture was added dimethylamine (14 mL of a 2.0M solution in tetrahydrofuran). The mixture was stirred at room temperature overnight and then concentrated. The residue was redissloved in dichloromethane, washed with brine and concentrated. The solid was washed with ethyl acetate until it became white and dried to give 1.4 g (78% yield) of 3-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-N,N-dimethyl-propionamide. 1H-NMR (360 MHz, diemthylsulfoxide-d6) δ10.93 (br s, 1H, NH), 6.48 (s, 1H), 2.94 (s, 3H, CH3), 2.79 (s, 3H, CH3), 2.72 (m, 2H, CH2), 2.57 (s, 2H, CH2), 2.48 (m, 2H, CH2), 2.17 (s, 2H, CH2), 1.00 (m, 6H, 2×CH3). MS m/z 262 [M+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:10](=[O:12])/[CH:9]=[CH:8]/[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(O)/C=C/c1cccc(O)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(/C=C/c1cccc(O)c1)Nc1cccc(Cl)c1
Temperature: 5 °C
Yield: 8.4 %

Procedure:
A solution of (E)-3-(3-hydroxy-phenyl)-acrylic acid (1.0 g, 6.1 mmol) and thionyl chloride (0.53 mL, 7.32 mmol) in dry THF (15 mL) was stirred at 55° C. for 3 hrs. Then a further aliquot of thionyl chloride (0.1 mL, 1.38 mmol) is added and the mixture is stirred at reflux temperature for additional 1.5 hrs. After cooling to about 5° C., a solution of 3-chloro-aniline (0.65 mL, 6.1 mmol) and triethylamine (3.4 mL, 24.4 mmol) in dry THF (5 mL) was added dropwise. After stirring at RT for 16 hrs the reaction mixture was diluted with DCM and washed with water, aqueous hydrochloric acid, and brine. The organic layer was dried over sodium sulphate and evaporated. The resulting raw material was purified first by column chromatography (eluant petroleum ether/AcOEt 45/55) and then by trituration in DCM, yielding 140 mg of the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=2)[NH:3]1.[Si:13]([O:20][CH:21]1[CH2:30][CH2:29][CH2:28][C:27]2[N:26]=[C:25](Cl)[CH:24]=[CH:23][C:22]1=2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:13]([O:20][CH:21]1[CH2:30][CH2:29][CH2:28][C:27]2[N:26]=[C:25]([CH:10]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=4)[NH:3][C:2]3=[O:1])[CH:24]=[CH:23][C:22]1=2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: CC(C)(C)[Si](C)(C)OC1CCCc2nc(Cl)ccc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCCc2nc(C3C(=O)Nc4ccc(C#N)cc43)ccc21
Temperature: 80 °C
Yield: 40 %

Procedure:
To a suspension of 2-oxoindoline-5-carbonitrile (30 mg, 0.190 mmol) in THF placed in a microwave vial were added sequentially 5-(tert-butyldimethylsilyloxy)-2-chloro-5,6,7,8-tetrahydroquinoline (67.8 mg, 0.228 mmol), K2CO3 (52.4 mg, 0.379 mmol), X-PHOS (7.23 mg, 0.015 mmol), and Pd2(dba)3 (3.47 mg, 3.79 μmol). The vial was sealed and flushed with argon. The mixture was heated in a microwave oven at 80° C. for 95 min. The mixture was cooled to RT and diluted with water and ethyl acetate. The organic layer was separated and the remaining aqueous layer was extracted with dichloromethane. The combined dichloromethane extracts were dried over sodium sulfate, filtered, and evaporated to dryness. Amount 32 mg. Yield 40%.
Reaction SMILES: CN([CH2:4][CH:5]([CH:15]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[CH3:35])[C:16](=[CH2:27])[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=[O:18])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])=[O:7])C.IC.C(N(C(C)C)CC)(C)C.[OH-].[K+]>C(#N)C>[F:34][C:30]1[C:29]([CH3:35])=[C:28]([CH:15]([C:16](=[CH2:27])[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[O:18])[C:5](=[CH2:4])[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[O:7])[CH:33]=[CH:32][CH:31]=1
Reactant: C=C(C(=O)c1cccc(OC)c1)C(c1cccc(F)c1C)C(CN(C)C)C(=O)c1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: CI
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C(=O)c1cccc(OC)c1)C(C(=C)C(=O)c1ccccc1F)c1cccc(F)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a solution of crude 2-((dimethylamino)methyl)-3-(3-fluoro-2-methylphenyl)-1-(2-fluorophenyl)-5-(3-methoxyphenyl)-4-methylenepentane-1,5-dione (7.5 g, 15.7 mmol) in acetonitrile (60 mL) was added iodomethane (11.7 mL, 187 mmol) and diisopropylethylamine (5.4 mL, 31.3 mmol). The mixture was stirred at room temperature for 2 h, during which time a precipitate formed. To this heterogeneous mixture was added 2 M KOH (26 mL, 52 mmol), and the resulting mixture was refluxed for 6 h and then allowed to stand for 48 h. The mixture was partitioned between dichloromethane and water. The layers were separated and the aqueous phase extracted twice with dichloromethane. The combined organic layers were dried over MgSO4 and evaporated to dryness. The residue was purified over silica gel using 30% EtOAc/hexanes to give 3-(3-fluoro-2-methylphenyl)-1-(2-fluorophenyl)-5-(3-methoxyphenyl)-2,4-dimethylenepentane-1,5-dione (3.2 g, 47% yield), (characterized by LCMS and 1H NMR), LRMS (M+H+) m/z=433.4.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:12](=[O:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]#[CH:3].S(Cl)([Cl:18])(=O)=O>C(O)(=O)C>[Cl:18][CH2:13][C:12](=[O:14])[C:6](=[N:5][O:4][CH2:1][C:2]#[CH:3])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: C#CCON=C(C(C)=O)C(=O)OCC
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: C#CCON=C(C(=O)CCl)C(=O)OCC
Yield: 73.7 %

Procedure:
Ethyl 2propargyloxyimino-3-oxobutyrate (syn isomer, 71.2 g.), acetic acid (81 ml.) and sulfuryl chloride (50.2 g.) were treated in a similar manner to that of Example F-(2) to give ethyl 4-chloro-3-oxo-2-propargyloxyiminobutyrate (syn isomer, 61.6 g.), oil.
Reaction SMILES: [CH2:1]([Zn]CC)C.C1(C)C=CC=CC=1.ClCI.[CH3:16]/[C:17](=[CH:20]\[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)[CH3:22])/[CH2:18][OH:19].S(=O)(=O)(O)O>>[CH3:16][C@@:17]1([CH2:18][OH:19])[CH2:1][C@H:20]1[C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)[CH3:22]
Reactant: C/C(=C\C(C)c1cccc(C)c1)CO
Reactant: CC[Zn]CC
Agent: ClCI
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1cccc([C@H](C)[C@@H]2C[C@@]2(C)CO)c1
Temperature: -25 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 6.92 g, 8.4 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to −25° C. Chloroiodomethane (2.96 g, 16.8 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between −20 and −25° C. After completion of the dropwise addition, the mixture was stirred at −10 to −20° C. for 15 minutes, and then cooled to −25° C. At the same temperature, (E)-2-methyl-4-(3-methylphenyl)pent-2-en-1-ol (0.80 g, 4.2 mmol) was added dropwise over a period of 20 minutes. After completion of the dropwise addition, the stirring was continued at −10 to −25° C. for 20 minutes. Next, a 20% aqueous sulfuric acid solution (3.1 ml) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1). [(1R*,2S*)-1-Methyl-2-((R*)-1-(3-methylphenyl)ethyl)cyclopropyl]methanol (0.38 g, 1.9 mmol, 45% yield) was obtained as the main isomer, and [(1R*,2S*)-1-methyl-2-((S*)-1-(3-methylphenyl)ethyl)cyclopropyl]methanol (0.014 g, 0.069 mmol, yield 1.6%) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH:14]([NH:16][C:17]1[S:18][CH:19]=[C:20]([C:22](=[N:53][O:54][CH3:55])[C:23]([NH:25][CH:26]2[C:51](=[O:52])[N:28]3[C:29]([C:35]([O:37][CH:38]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:36])=[C:30]([CH2:33][OH:34])[CH2:31][S:32][C@H:27]23)=[O:24])[N:21]=1)=[O:15]>CC(C)=O>[CH:14]([NH:16][C:17]1[S:18][CH:19]=[C:20]([C:22](=[N:53][O:54][CH3:55])[C:23]([NH:25][CH:26]2[C:51](=[O:52])[N:28]3[C:29]([C:35]([O:37][CH:38]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:36])=[C:30]([CH:33]=[O:34])[CH2:31][S:32][C@H:27]23)=[O:24])[N:21]=1)=[O:15]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12)c1csc(NC=O)n1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=O)CS[C@H]12)c1csc(NC=O)n1
Yield: 70.5 %

Procedure:
Jones reagent (14.5 ml) was dropwise added to a suspension of benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-hydroxymethyl-3-cephem-4-carboxylate (syn isomer) (19.5 g) in acetone (300 ml) at 0° to 3° C. under stirring and the mixture was stirred for 20 minutes at the same temperature. The reaction mixture was filtered and the filtrate was washed with acetone. To the mixture of the filtrate and washings was added ethyl acetate (300 ml) and washed with brine and dried over magnesium sulfate. The solution was evaporated and the residue was pulverized in diethyl ether to give benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-formyl-3-cephem-4-carboxylate (syn isomer) (13.7 g).
Reaction SMILES: [OH-].[K+].[N:3](OCCCC)=[O:4].[CH3:10][C:11]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:12]=1[O:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH2:17][C:18]#[N:19].Cl>O.C1(C)C=CC=CC=1>[CH3:10][C:11]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:12]=1[O:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([C:18]#[N:19])=[N:3][OH:4]
Reactant: Cc1ccc(C)c(OCc2ccccc2CC#N)c1
Reactant: CCCCON=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C)c(OCc2ccccc2C(C#N)=NO)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
85% Potassium hydroxide (0.40 g, 6 mmol), toluene (5 ml) and butyl nitrite (0.62 g, 6 mmol) were added to 2-(2,5-dimethylphenoxymethyl)benzyl cyanide (1.26 g, 5 mmol). The mixture was stirred at room temperature for 8 hours. After completion of the reaction, water (100 ml) was added. The mixture was neutralized with hydrochloric acid, extracted with ether (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)-α-hydroxyiminobenzyl cyanide (1.30 g, Yield: 92.8%, E/Z=15/85).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]=1[C:21]([OH:23])=O.C(N(CC)CC)C.Cl.[CH3:32][O:33][C:34](=[O:38])[CH2:35][NH:36][CH3:37]>C(Cl)Cl.CN(C)C=O.O>[CH3:32][O:33][C:34](=[O:38])[CH2:35][N:36]([C:21]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[O:8][CH3:7])=[O:23])[CH3:37]
Reactant: CNCC(=O)OC
Reactant: COc1ccc2c(C(=O)O)c(OC)ccc2c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CN(C)C(=O)c1c(OC)ccc2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.7 %

Procedure:
A solution of oxalyl chloride (0.95 mL, 11 mmol) in CH2Cl2 (10 mL) was added to a suspension of 2,6-dimethoxy-1-naphthalenecarboxylic acid (2.32 g, 10 mmol, described in Example 1) and N,N-dimethylformamide (2 drops, catalyst) in CH2Cl2 (50 mL) under nitrogen. After 1.5 hours, triethylamine (5 mL, 36 mmol) and N-methylglycine methyl ester hydrochloride (2.1 g, 15 mmol) were added. The resulting mixture was stirred at room temperature overnight and then poured into water (200 mL) and CH2Cl2 (200 mL). The aqueous phase was washed with CH2Cl2 (100 mL) and the combined CH2Cl2 phases were washed successively with 1M H3PO4 (2×100 mL), water (100 mL), saturated NaHCO3 (50 mL), brine (100 mL) and dried over Na2SO4. Filtration and concentration left a pale brown foam which was filtered through a short column of silica gel with 1:1 ethyl acetate:hexane to obtain 2.53 g of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][S:10]([C:13]1[N:17]=[C:16]([CH3:18])[NH:15][N:14]=1)(=[O:12])=[O:11].[H-].[Na+].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24](Cl)[N:23]=1.O>CN(C)C=O.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][S:10]([C:13]1[N:17]=[C:16]([CH3:18])[N:15]([C:24]2[N:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[N:23]=2)[N:14]=1)(=[O:11])=[O:12]
Reactant: Cc1nc(S(=O)(=O)Nc2c(F)cccc2F)n[nH]1
Reactant: Cc1cc(C)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(-n2nc(S(=O)(=O)Nc3c(F)cccc3F)nc2C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.5 %

Procedure:
N-(2,6-difluorophenyl)-5-methyl-1,2,4-triazole-3-sulphonamide (5 g) (Compound A81) was added in portions to a suspension of sodium hydride (1.37 g in 80% suspension in oil) in dry dimethylformamide (40 ml). The mixture was stirred for 30 minutes at 25° C., 4,6-dimethyl-2-chloropyrimidine (2.6 g) was added, and the mixture was then stirred at 100° C. for 18 hours. The cooled reaction mixture was poured into water, acidified with glacial acetic acid and then extracted with dichloromethane (3×100 ml). The organic phases were dried and evaporated, and the residue was chromatographed (silica/dichloromethane). The product was recrystallised from ethanol to give 0.8 g of the desired product, mp 228°-230° C., identical to that of Example A63.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:20]=[C:13]([C:14]([O:16][CH:17](Cl)[CH3:18])=[O:15])[C:12]([OH:21])=[CH:11][CH:10]=1.[C:22](=[O:27])([O-:26])[O:23][CH2:24][CH3:25].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:20]=[C:13]([C:14]([O:16][CH:17]([O:27][C:22]([O:23][CH2:24][CH3:25])=[O:26])[CH3:18])=[O:15])[C:12]([OH:21])=[CH:11][CH:10]=1
Reactant: CCOC(=O)[O-]
Reactant: CC(Cl)OC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)OC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 25 °C

Procedure:
To a solution of 1-chloroethyl 5-(2,4-difluorophenyl)salicylate (5.0 g) in about 40 ml of DMF is added portionwise 3.0 g of sodium ethyl carbonate. The reaction is stirred at room temperature and then concentrated in vacuo. The concentrate is partitioned between ether/ethyl acetate and acidified water. The organic layer is separated and the aqueous layer is again extracted with ether, the organic layers are pooled and washed with water followed by drying and concentration to the crude product. After further purification by chromatography as described in Example 1, the product is crystallized from hexane to afford pure 1-(ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)salicylate.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[F:13][C:14]1[CH:15]=[C:16]([NH2:24])[C:17](=[CH:21][C:22]=1[F:23])[C:18]([OH:20])=[O:19]>O1CCOCC1>[CH:21]1[CH:17]2[C:16](=[N:24][C:2]([O:19][C:18]2=[O:20])=[O:4])[CH:15]=[C:14]([F:13])[C:22]=1[F:23]
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=C1N=C2C=C(F)C(F)=CC2C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 828.7 %

Procedure:
Triphosgene (0.65 g, 0.22 mmol) was added to 4,5-difluoroanthranilic acid (0.34 g, 0.2 mmol) in dry 1,4-dioxane (30 ml), and the mixture was stirred at rt. for 1 h. Solvent was slowly distilled off at ca. 50° C., and the residue distributed between ethyl acetate (100 ml) and the pH 7 buffer (50 ml). The aqueous layer was extracted with more ethyl acetate (2×50 ml), and combined organic layers washed with diluted aq. citric acid (pH ca. 4-5), water (30 ml), brine (50 ml), and dried (MgSO4). Solvent was removed in vacuo to yield 0.33 g (83%) of 6,7-difluoroisatoic anhydride. The intermediate thus obtained (0.29 g, 1.45 mmol) was stirred with dry potassium carbonate (0.20 g, 1.45 mmol) in dry methanol (30 ml) for 1 h. Most of the solvent was removed in vacuo, and the residue distributed between ethyl acetate (100 ml) and the pH 7 buffer (50 ml). Aqueous layer was adjusted to pH ca. 7 with additional aq. HCl, and extracted with ethyl acetate (2×30 ml). Combined organic layers were washed with water (2×30 ml), brine (50 ml), and dried (MgSO4). Solvent was removed in vacuo to yield 0.24 g (89%) of methyl 4,5-difluoroanthranilate. 1H NMR in CDCl3 (δ,ppm): 3.86 (s, 3 H), 5.72 (br. s, 2 H), 6.43 (m, 1 H), 7.66 (m, 1 H).
Reaction SMILES: [Mg].[CH:2]1(Br)[CH2:4][CH2:3]1.[CH:6]([O:9][CH2:10][CH2:11][C:12](=[O:14])[CH3:13])([CH3:8])[CH3:7].[Cl-].[NH4+]>O1CCCC1>[CH:2]1([C:12]([OH:14])([CH2:11][CH2:10][O:9][CH:6]([CH3:8])[CH3:7])[CH3:13])[CH2:4][CH2:3]1
Reactant: CC(=O)CCOC(C)C
Reactant: BrC1CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)OCCC(C)(O)C1CC1

Procedure:
To the Grignard reagent [production according to E. Renk et al. J. Am. Chem. Soc. 83, 1987 (1961)], from 9.06 g (0.37 mol) of magnesium and 42.8 g (0.35 mol) of cyclopropyl bromide in 460 cc of absolute tetrahydrofurane, is added dropwise at 5°C over the course of 10 minutes, in an atomosphere of nitrogen and while stirring, a solution of 46 g (0.35 mol) of 4-isopropoxy-2-butanone in 100 cc of absolute tetrahydrofurane. After stirring the reaction mixture at room temperature for 20 hours, saturated ammonium chloride solution and ice are added and the mixture is extracted with ether. The ether extract is washed with saturated salt solution, dried over sodium sulphate and the ether evaporated off. The resulting 2-cyclopropyl-4-isopropoxy-2-butanol is obtained after distillation at 75°-79°/12 mm as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[C:12]([F:15])([F:14])[F:13].[Br:17]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[C:5]([C:12]([F:14])([F:13])[F:15])=[CH:6][C:7]([Cl:11])=[CH:8][C:9]=1[CH2:10][Br:17]
Reactant: COC(=O)c1c(C)cc(Cl)cc1C(F)(F)F
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)cc(Cl)cc1C(F)(F)F

Procedure:
A mixture of 4-chloro-2-trifluoromethyl-6-methyl-benzoic acid methyl ester (1.6 g, 6.3 mmol), N-bromosuccinamide (1.23 g, 6.93 mmol), and benzoyl peroxide (0.050 g, 0.20 mmol) in carbon tetrachloride (50 mL) was heated at reflux until majority of ester was consumed (as analyzed by GC/MS). The resulting mixture was filtered and the filtrate concentrated to afforded 2-bromomethyl-4-chloro-6-trifluoromethyl-benzoic acid methyl ester. The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:12][CH:13]([C:20](=[O:35])[N:21]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:14][CH2:15][C:16]([O:18]C)=[O:17])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:12][CH:13]([C:20](=[O:35])[N:21]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCCCCN(CCc1ccccc1)C(=O)C(CCC(=O)OC)CS(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCN(CCc1ccccc1)C(=O)C(CCC(=O)O)CS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a solution of methyl 5-(3,4-dichlorophenylsulfonyl)-4-(N-pentyl-N-phenethylcarbamoyl)pentanoate (57 mg) in ethanol (1 ml) was added a 1N sodium hydroxide solution (0.12 ml). After stirring at room temperature for 16 hours, the reaction mixture was concentrated in vacuo, acidified with a dilute hydrochloric acid, and extracted with chloroform. The organic layer was washed with water, dried over MgSO4, and evaporated at reduced pressure. The residue was purified by preparative thin-layer chromatography on silica by developing with chloroform/ethanol (10:1) to give 45 mg of 5-(3,4-dichlorophenylsulfonyl)-4-(N-pentyl-N-phenethylcarbamoyl)pentanoic acid as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([N:8]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:7])=[CH:4][CH:3]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[C:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27](=[O:35])[C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:25][CH2:26]2)[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:7])=[CH:36][CH:37]=1)(=[O:40])[CH3:39]
Reactant: COc1ccc(OC)c(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)c1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(OC)c(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(NC(C)=O)cc2)c1
Yield: 70.9 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(2,5-dimethoxyphenyl)benzamide (170.0 mg, 0.34 mmol) and acetic anhydride (0.16 ml, 1.70 mmol), the procedure of Inventive Example 94 was repeated to obtain 132.0 mg (71.5%) of the title compound in a colorless amorphous form.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH:29]([CH:32]([CH3:34])[CH3:33])[CH2:30][OH:31])[CH2:25][CH2:24]3)[N:18]2[CH3:21])=[C:14]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:13]=1>>[CH3:33][CH:32]([CH3:34])[C@H:29]([N:26]1[CH2:25][CH2:24][N:23]([CH2:22][C:17]2[N:18]([CH3:21])[C:19]3[C:15]([N:16]=2)=[C:14]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)[N:13]=[C:12]([N:3]2[C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=[C:2]2[CH3:1])[N:20]=3)[CH2:28][CH2:27]1)[CH2:30][OH:31]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: CC(C)C(CO)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN([C@H](CO)C(C)C)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and racemic 2-(4-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)-3-methylbutan-1-ol were reacted. The enantiomers were separated by SFC to give 361. LCMS m/z: 534.3 (MH+)