Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[N:19][C:4]=2[CH:3]=1.[F:23][CH:24]([F:44])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][C:28]=1[O:42][CH3:43].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.O.CCOC(C)=O>[CH:20]1([N:17]2[C:5]3[C:6]([O:8][C@@H:9]([C@H:11]4[CH2:15][NH:14][C:13](=[O:16])[CH2:12]4)[CH3:10])=[N:7][C:2]([C:30]4[CH:31]=[CH:32][C:27]([O:26][CH2:25][CH:24]([F:44])[F:23])=[C:28]([O:42][CH3:43])[CH:29]=4)=[CH:3][C:4]=3[N:19]=[CH:18]2)[CH2:22][CH2:21]1
Reactant: C[C@@H](Oc1nc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCC(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2cc3ncn(C4CC4)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1OCC(F)F
Temperature: 105 °C

Procedure:
In a 50 mL 3-neck flask with a magnetic stir bar and condenser was placed (R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-on (125 mg, 0.34 mmol), 2-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (135 mg, 0.43 mmol) and Pd(PPh3)4 (40 mg, 0.027 mmol). Evacuated and filled with nitrogen 3×. Added 2.5 mL DME and 2N sodium carbonate (0.51 ml, 1.03 mmol) via syringe and heated in a 105° C. oil bath for 2 hrs at which time LC-MS indicated a complete reaction. Let cool, added EtOAc and water, separated, washed with brine, dried over Na2SO4, filtered and concentrated. Purified by chromatography: ISCO 50 g C18 reverse phase 0-30% water/acetonitrile/0.1% TFA. Partially concentrated under reduced pressure added EtOAc and sat.aq.bicarb, separated, washed with brine, dried over Na2SO4, filtered and concentrated to give a white solid.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]([CH3:34])=[C:25]([CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[N:26]=2)=[CH:18][CH:17]=1>>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:23][C:24]([CH3:34])=[C:25]([CH2:27][CH2:28][N:29]4[CH2:30][CH2:31][CH2:32][CH2:33]4)[N:26]=3)=[CH:18][CH:17]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Product: CCS(=O)(=O)c1ccc(-c2ccc(-c3nc(CCN4CCCC4)c(C)o3)cc2)cc1

Procedure:
The title compound is prepared in a mamler substantially analogous to Example 35 starting from 4-Ethylsulfonylbenzene boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 425.1 (M+1)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CS(O[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:21][C:22]1[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:25][CH:26]=1)(=O)=O>>[N:1]1([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][C:22]2[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:25][CH:26]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CS(=O)(=O)OCCCc1ccccc1OCc1coc(/C=C/c2ccccc2)n1
Reactant: c1c[nH]cn1
Product: C(=C/c1nc(COc2ccccc2CCCn2ccnc2)co1)\c1ccccc1
Yield: 80 %

Procedure:
In substantially the same manner as in Working Example 8, imidazole was allowed to react with 3-[2-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate to give 4-[2-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole as an oily product. The yield was 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[CH:17]=O.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[CH2:17][NH:22][CH:19]1[CH2:21][CH2:20]1
Reactant: O=Cc1cc(CNC(=O)CC(F)(F)F)ccc1Cl
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(CC(F)(F)F)NCc1ccc(Cl)c(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A mixture of N-(4-chloro-3-formyl-benzyl)-3,3,3-trifluoro-propionamide (840 mg, 3.00 mmol) and cyclopropylamine (0.320 mL, 4.51 mmol) in MeOH (30 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt. NaBH4 (170 mg, 4.51 mmol) was added in portions. The mixture was stirred for 1 h, and the solvents were removed under reduced pressure. The residue was diluted with EtOAc, and the resulting mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 90:10) yielded the title compound (929 mg, 96%). LC-MS: tR=0.64 min; ES+: 321.05.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[CH3:14][O:15][CH2:16][C@@H:17](O)[CH3:18]>>[F:1][C:2]1[C:3]([O:13][C@H:17]([CH3:18])[CH2:16][O:15][CH3:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2
Reactant: COC[C@H](C)O
Reactant: Cc1ccc2ccc(O)c(F)c2n1
Product: COC[C@@H](C)Oc1ccc2ccc(C)nc2c1F

Procedure:
Prepared as described in Example 140, Step A, using 8-fluoro-2-methylquinolin-7-ol (0.30 g, 1.69 mmol) in place of 2-methylquinolin-8-ol and using (S)-1-methoxypropan-2-ol (0.196 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:16][N:17]4C(=O)C5=CC=CC=C5C4=O)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[C:6]=2[CH:35]=1.O.NN>>[NH2:17][CH2:16][CH2:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:35][C:6]=3[C:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])=[N:8][CH2:9][C:10]2=[N:14][N:13]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: NN
Solvent: O
Product: NCCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 21, a mixture of 8-chloro-6-(o-chlorophenyl)-1-(2-phthalimidoethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with hydrazine hydrate to give 1-(2-aminoethyl)-8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: CC(C1C=C2C[CH2:11][CH:12]3[C:17]([C:19](O)=[O:20])(C)[CH2:16][CH2:15][CH2:14][C:13]3(C)C2CC1)C.C(OCC1C=CC=CC=1)(=O)C1C=CC=CC=1.C(OC(C)C)(=O)CCCCCCCCCCCCC>>[CH:19](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CC(C)C1C=C2CCC3C(C)(C(=O)O)CCCC3(C)C2CC1
Agent: CCCCCCCCCCCCCC(=O)OC(C)C
Solvent: O=C(OCc1ccccc1)c1ccccc1
Product: CCCCCCCC=O

Procedure:
The foregoing formula may require a solubilizing agent, e.g., the methyl ester of dihydroabietic acid (commercial name: HERCOLYN D® , benzyl benzoate, isopropyl myristate and/or C12 -C14 isoparaffin hydrocarbons.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17]([CH3:22])=[C:18]([F:21])[CH2:19][OH:20])[C:3]=1[O:23][CH2:24][CH3:25].C[N+]1([O-])CCOCC1.ClCCl>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:22])=[C:18](/[F:21])\[CH:19]=[O:20])[C:3]=1[O:23][CH2:24][CH3:25]
Reactant: CCOc1c(C(C)=C(F)CO)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CCOc1c(/C(C)=C(/F)C=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure H-1, (2E>3-(4-bromo-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)- 2-fluoro-but-2-en-1-ol (Compound A-136, 908 mg, 2.2 mmol), tetrapropylammonium perruthenate (20 mg, 0.057 mmol) and 4-methylmorpholine N-oxide (516 mg, 4.4 mmol) were reacted in acetonitrile and dichloromethane to give the title compound after purification by flash column chromatography (silica gel, 5% ethyl acetate in hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([NH:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[C:14]([OH:17])(=O)[CH3:15]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]([CH2:12][CH3:13])[C:14](=[O:17])[CH:15]=[C:7]2[OH:8]
Reactant: CC(=O)O
Reactant: CCNc1ccc(Cl)cc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCn1c(=O)cc(O)c2cc(Cl)ccc21
Temperature: 0 °C

Procedure:
5-Chloro-N-ethyl anthranilic acid (13.1g; 0.006 mole) in acetic acid (35 ml) and acetic anhydride (35 ml) was refluxed for 24 hours. The cooled mixture was poured into ice-water and basified to pH 14. The precipitated red oil was separated and the supernatant acidified to pH 5 to give the title compound as a white crystalline solid. m.p. (EtOH) 305°-8° C (Found: C, 58.80; H, 4.64; N, 6.49; Cl, 15.95; C11H10CINO2 requires, C, 59.07; H, 4.51; N, 6.26; Cl, 15.85%).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH2:34][C:35]#[N:36])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.CO.Cl>O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH2:34][C:35]#[N:36])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: N#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: N#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.8 g.), methanol (12 ml.), conc hydrochloric acid (0.55 g.) and tetrahydrofuran (10 ml.) was stirred at room temperature for 3 hours. After concentrating the resultant solution in vacuo, the residue was dissolved in an aqueous solution of sodium bicarbonate. The solution was adjusted to pH 3.5 with 10% hydrochloric acid and stirred for 30 minutes. The precipitates were collected by filtration, washed with water and dried to give 7-[2-(2-aminothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.56 g.).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH:9]([C:12]2[CH2:18][C@H:17]3[N:14]([C:15](=[O:29])[C@@H:16]3[C@H:19]([O:21][Si](C(C)(C)C)(C)C)[CH3:20])[C:13]=2[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH2:8]1)=[O:6])[CH:2]=[CH2:3].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH:9]([C:12]2[CH2:18][C@H:17]3[N:14]([C:15](=[O:29])[C@@H:16]3[C@H:19]([OH:21])[CH3:20])[C:13]=2[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(C2CCN(C(=O)OCC=C)C2)C[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CCOC(=O)C1=C(C2CCN(C(=O)OCC=C)C2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 14 h
Yield: 41.9 %

Procedure:
To a solution of allyl (5R,6S)-3-(1-allyloxycarbonylpyrrolidin-3-yl)-6-[(1R)-1-t-butyldimethylsilyoxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (2.9 g) in tetrahydrofuran (30 ml) were added acetic acid (3.3 ml) and a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (28.7 ml) at 0° C. under nitrogen. After standing at ambient temperature for 7 hours and additionally at 5° C. for 14 hours, the reaction mixture was taken up into a mixture of ethyl acetate and water. After adjusting pH to around 7 with an aqueous sodium hydrogen carbonate, the organic layer was separated, washed in turn with water and brine, and dried over magnesium sulfate. Removal of the solvent gave a residue, which was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (1:2, V/V) to give allyl (5R,6S)-3-(1-allyloxycarbonylpyrrolidin-3-yl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.94 g).
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[C:1]1([CH:7]([CH3:11])[C:8]([Cl:20])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(=O)O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C(=O)Cl)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-phenylpropionic acid (0.36 mL; 2.6 mmol) and a catalytic amount of dry dimethylformamide (ca. 10 μL) in 3.0 mL of dry methylene chloride under nitrogen at room temperature was added oxalyl chloride (0.34 mL; 3.9 mmol) dropwise. After 30 minutes, the mixture was concentrated in vacuo and used immediately for Step 2.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[S:7]1[CH:11]=[CH:10][C:9]2[C:12]([C:16]#[N:17])=[CH:13][CH:14]=[CH:15][C:8]1=2.O.[OH-].[Na+]>C1COCC1>[NH2:17][CH2:16][C:12]1[C:9]2[CH:10]=[CH:11][S:7][C:8]=2[CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1cccc2sccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1cccc2sccc12
Temperature: 0 °C
Reaction time: 17 h
Yield: 91.9 %

Procedure:
Add lithium aluminum hydride (1M solution in THF, 7.5 mL) to benzo[b]thiophene-4-carbonitrile (prepared as described in WO 0168653) (0.6 g, 3.8 mmol) at 0° C. in THF (38 mL). After 17 h at ambient temperature, cool to 0° C. and add sequentially water (1.89 mL), 2N aqueous NaOH (1.89 mL) and water (2.69 mL). Filter the solids and evaporate the filtrate to obtain the crude amine. Purify by SCX chromatography. Rinse the column with methanol, add a solution of the crude amine in methanol, wash the column with methanol and then elute with 1N ammonia in methanol. Concentrate to give the title compound (0.57 g, 93%). GC-MS m/z: 163 (M+).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.Br[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1>O1CCCC1.CCOCC.[Cl-].[Zn+2].[Cl-].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1
Reactant: Brc1ccncc1
Reactant: Fc1cccc(F)c1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1cccc(F)c1-c1ccncc1
Temperature: -50 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
A. 1.6 M solution of n-butyl lithium (14 ml) was added dropwise to a stirred solution of 1,3-difluorobenzene (2.17 g) in 34 ml dry tetrahydrofuran at -78° C. After 1 hour at -78° C., the solution was warmed to -50° C. and a solution of anhydrous zinc chloride (3.0 g) in 34 ml tetrahydrofuran was added. After a further 30 minutes at -50° C., a solution of 4-bromopyridine (1.62 g) in 10 ml ether was added followed by 1.0 g of tetrakis(triphenylphosphine) palladium. The solution was then allowed to warm slowly to room temperature and it was then heated at 40° C. for 12 hours. The mixture was cooled to room temperature and was first quenched with saturated aqueous ammonium chloride and then extracted with ethyl acetate. The organic extracts were dried and evaporated yielding a yellow crystalline solid. This material was purified by elution on silica gel with ethyl acetate/hexane to give 1.4 g (73% yield) of the required product as a pale yellow solid of m.p. 113°-114° C. NMR (CDCl3, 60 MHZ): 8.65 (m, 2H), 6.8-7.6 (m, 5H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:20])[CH2:11][N:10]=2)[CH:4]=1.[CH3:23]OS(OC)(=O)=O>CC(C)=O>[CH3:23][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:9]([C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:8]=[CH:7][CH:6]=2)=[N:10][CH2:11][C:12]1=[O:20]
Reactant: O=C1CN=C(c2cccc(C(F)(F)F)c2)c2ccccc2N1
Reactant: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CN1C(=O)CN=C(c2cccc(C(F)(F)F)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 15.2 g. of 1,3-dihydro-5-(α, α, α-trifloro-m-tolyl)-2H-1,4-benzodiazepin-2-one in 360 ml. of acetone is treated with 7.5 ml. of dimethylsulfate and 45 g. of finely triturated, dry potassium carbonate and stirred intensively at room temperature for 15 hours. The mixture is then poured into 400 ml. of ice-water, the acetone is evaporated under reduced pressure and the separated oil extracted with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated to dryness. The resulting oil crystallizes on trituration with hexane, and there is obtained 1,3-dihydro-1-methyl-5-(α, α, α-trifluoro-m-tolyl)-2H-1,4-benzodiazepin-2-one having a melting point of 117°-119° C., which can be employed in the next stage without further purification. A sample for analysis is obtained by crystallization from ethanol; melting point 121°-122° C.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1>>[N:1]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=3)=[O:19])=[CH:21][CH:22]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccc(O)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Product: O=C(Nc1cccc(O)c1)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 3-aminophenol (29 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 0-50 EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(3-hydroxyphenyl)benzamide as an off-white solid. Yield: 38 mg (35%). 1H-NMR: 8.21 (d, J=8.5 Hz, 2H), 7.80 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.24-7.08 (m, 3H), 7.06 (t, J=8.0 Hz, 1H), 6.48 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 6.41 (t, J=2.0 Hz, 1H), 6.36 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 3.84-3.80 (m, 2H), 2.45 (t, J=7.0, 2H), 1.67-1.59 (m, 2H).
Reaction SMILES: [C:1]1([C:8]([O:10]C)=[O:9])([C:4]([O:6]C)=[O:5])[CH2:3][CH2:2]1>O>[C:1]1([C:8]([OH:10])=[O:9])([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)C1(C(=O)OC)CC1
Solvent: O
Product: O=C(O)C1(C(=O)O)CC1
Reaction time: 9.5 h

Procedure:
The glass pipe of the above-described apparatus is charged with 600 ml of the ion exchanger LEWATIT® SP 112 (in the H+ form) and closed on both sides by sintered glass disks. The glass flask contains 500 g of dimethyl cyclopropane-1,1-dicarboxylate (MOD, 98.8%, 3.12 mol) and 750 ml of demineralized water. At a reduced pressure of 700 mbar the contents is heated to boiling (89°-92° C.), the liquids being recirculated by pumping from the flask via the ion exchanger column. At a reflux ratio of from 8:1-15:1 methanol distills off at from 56°-58° C. After 9-10 hours the saponification is complete. After cooling, the apparatus is flushed with water. The combined aqueous solutions are then extracted with 750 ml and twice with 250 ml of methyl t-butyl ether. The ether removed by largely distillation and replaced by 850 ml of toluene. The ether is then removed by distillation completely, and CDA crystallizes in the process. The crystals are removed by filtration, washed with toluene and dried. The final weight and the analytical data are shown in Table 1.
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].[CH3:16][C:17]1[CH:18]=[CH:19][C:20]2[N+:25]([O-:26])=[N:24][C:23]([NH:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N:22][C:21]=2[CH:37]=1.FC(F)(F)C(O)=O>C(Cl)Cl.C(Cl)(Cl)Cl.N>[CH3:16][C:17]1[CH:18]=[CH:19][C:20]2[N+:25]([O-:26])=[N:24][C:23]([NH:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N+:22]([O-:6])[C:21]=2[CH:37]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc2c(c1)nc(NCCCN1CCOCC1)n[n+]2[O-]
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)[n+]([O-])c(NCCCN1CCOCC1)n[n+]2[O-]
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 32.5 %

Procedure:
H2O2 (ca. 70%, 3.0 mL, 59.2 mmol) was added dropwise to a stirred solution of trifluoroacetic anhydride (8.4 mL, 59.2 mmol) in DCM (50 mL) at 5° C. The solution was stirred at 5° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 5° C. and added to a stirred solution of 1-oxide 4 (1.48 g, 5.1 mmol) and trifluoroacetic acid (2.2 mL, 28.0 mmol) in CHCl3 (20 mL) at 5° C. The solution was stirred at 5° C. for 16 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was chromatographed, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 5 (529 mg, 32%) as a red solid, mp (MeOH/EtOAc) 155-158° C.; 1H NMR δ 8.54 (brs, 1 H, NH), 8.19 (d, J=9.0 Hz, 1 H, H-8), 8.08 (brs, 1 H, H-5), 7.38 (dd, J=9.0, 1.5 Hz, 1 H, H-7), 3.82-3.85 (m, 4 H, 2×CH2O), 3.66-3.70 (m, 2 H, CH2N), 2.55-2.59 (m, 5 H, CH2N, CH3), 2.49-2.54 (m, 4 H, 2×CH2N), 1.85-191 (m, 2 H, CH2); 13C NMR δ 150.0, 147.9, 138.3, 129.1, 128.7, 121.4, 116.1, 66.9 (2), 57.8, 53.9 (2), 41.7, 24.7, 22.3. Anal. Calcd for C15H21N5O3¼CH3OH: C, 56.0; H, 6.8; N, 21.4. Found: C, 55.9; H, 6.7; N, 21.0%.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[CH2:9]([O:16][C:17](Cl)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:9]([O:16][C:17](=[O:18])[NH:1][C@H:2]([CH2:7][OH:8])[C@@H:3]([CH3:4])[CH2:5][CH3:6])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC[C@H](C)[C@H](N)CO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
To a solution of L-isoleucinol (2.20 g, 18.8 mmol) in methylene chloride (66 ml) were added chloroformic acid benzyl ester (3.22 ml, 22.5 mmol) and triethylamine (3.15 ml, 22.5 mmol) in an ice bath, and the mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:1) as the eluant to afford [(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]carbamic acid benzyl ester (4.17 g, yield 88%) as a colorless oil.