Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[CH2:2].[C:12]([O:16][C:17](=[O:38])[NH:18][C:19]([C:21]1[S:22][C:23]([S:36][CH3:37])=[C:24]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31](Br)[CH:30]=2)(=[O:28])=[O:27])[CH:25]=1)=[NH:20])([CH3:15])([CH3:14])[CH3:13].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.C1(C)C=CC=CC=1.CCO>[C:12]([O:16][C:17](=[O:38])[NH:18][C:19](=[NH:20])[C:21]1[S:22][C:23]([S:36][CH3:37])=[C:24]([S:26]([C:29]2[CH:30]=[C:31]([C:6]3[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=3)[CH:32]=[CH:33][CH:34]=2)(=[O:28])=[O:27])[CH:25]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Reactant: C=Cc1ccc(B(O)O)cc1
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: Cc1ccccc1
Solvent: CCO
Product: C=Cc1ccc(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)cc1
Yield: 44 %

Procedure:
Following the procedure outlined in Example 1, step c, reaction of 4-vinyl-phenyl-boronic acid (181 mg, 1.22 mmol), {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (300 mg, 0.61 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosphine)palladium(0) (141 mg, 0.122 mmol, Strem Chemicals, Inc., Newburyport, Mass.), Na2CO3 (2.4 mL, 2M aqueous), and toluene/EtOH mixture (2:1, 7.2 mL) afforded 138 mg (45%) of the title compound as a white glassy solid after SiO2 flash chromatography (1:3 EtOAc/hexanes). 1H-NMR (CDCl3): δ 8.21 (t, 1H, 1.7 Hz), 8.00 (brs, 1H), 7.92–7.95 (m, 1H), 7.79–7.81 (m, 1H), 7.48–7.58 (m, 5H), 6.75 (dd, 1H, J=17.7, 10.9 Hz), 5.82 (d, 1H, J=17.5), 5.31 (d, 1H, J=10.9 Hz), 2.54 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][N:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.S(=O)(=O)(O)O.[CH3:21]O>>[N:1]1([C:6]2[N:7]=[CH:8][C:9]([CH2:12][C:13]([O:15][CH3:21])=[O:14])=[CH:10][N:11]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CO
Reactant: O=C(O)Cc1cnc(-n2cnnn2)nc1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cnc(-n2cnnn2)nc1
Temperature: 25 °C
Reaction time: 0.04 h

Procedure:
To a solution of 2-(2-(1H-tetrazol-1-yl)pyrimidin-5-yl)acetic acid (100 mg, 0.485 mmol) in methanol (30 mL) was added sulfuric acid (1 mL, 18.8 mmol). Stirred at room temperature and sonicated to dissolve all acid starting material. Reaction was complete within about 2-3 min. The reaction was concentrated under reduced pressure, neutralized with saturated aqueous sodium bicarbonate, extracted with DCM (2 times), washed organics with brine, dried over magnesium sulfate. Solvent was removed under reduced pressure and residue dried on high vacuum overnight. LC/MS: [(M+1)]+=221.0;
Reaction SMILES: [F:1][C:2]([F:10])=[C:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][SH:8].[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][N:13]=1.C(N(CC)CC)C>O1CCCC1.O>[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([S:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([CH3:9])=[C:2]([F:10])[F:1])=[O:17])=[CH:14][N:13]=1
Reactant: CC(CCCCS)=C(F)F
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CCCCSC(=O)c1ccc(Cl)nc1)=C(F)F
Reaction time: 1 h
Yield: 87.2 %

Procedure:
A mixture consisting of 1.00 g (6.3 mmol) of 6-chloronicotinic acid, 5 ml of thionyl chloride and three drops of N,N-dimethylformamide was stirred under heating and refluxing for 3 hours. After the reaction, excess thionyl chloride was removed under reduced pressure, followed by the addition of 10 ml of toluene and removing the solvent again under reduced pressure to obtain crystal of 6-chloronicotinoyl chloride. In a separate vessel, 0.50 g (3.0 mmol) of 6,6-difluoro-5-methyl-5-hexene-1-thiol and 0.80 g (4.5 mmol) of 6-chloronicotinoyl chloride were dissolved in 10 ml of tetrahydrofuran, followed by the drop-wise addition of 0.50 g (4.9 mmol) of triethylamine at room temperature and stirring at the same temperature for 1 hour. The reaction liquid was then poured in water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (diisopropyl ether:hexane=1:6) to obtain 0.80 g (yield: 87%) of S-(6,6-difluoro-5-methyl-5-hexenyl) 6-chlorothionicotinate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:10][N:11]1[CH2:19][CH2:18][CH2:17][CH:13]([C:14](O)=O)[CH2:12]1.[OH-].[Na+].C(Cl)Cl>O>[CH3:10][N:11]1[CH2:19][CH2:18][CH2:17][CH:13]([C:14]2[NH:1][C:2]3=[N:3][CH:4]=[CH:5][CH:6]=[C:7]3[N:8]=2)[CH2:12]1
Reactant: CN1CCCC(C(=O)O)C1
Reactant: Nc1cccnc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CN1CCCC(c2nc3cccnc3[nH]2)C1

Procedure:
Grams 10.9 of 2,3-diaminopyridine and 17,9 g N-methylnipecotic acid hydrochloride are heated at 190° C. for 6 hours. The reaction mixture is cooled and diluted with a small amount of water, then is made alkaline to pH 10 by addition of NaOH and extraction is repeated several times with methylene chloride. The organic extracts, collected together, are evaporated to dryness. The obtained residue, is extracted several times with diethyl ether and the ethereal extracts are evaporated to dryness. The obtained residue, crystallized from acetonitrile, provides 5 g (23% of the theoretical value) 2-(1-methylpiperidin-3-yl)-3H-imidazo-[4,5-b] pyridine melting at 141°-144° C.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20]N1C(=O)CCC1=O.O[C:29]1[C:30]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36][CH2:35][C:31]=2[N:32]=[CH:33][N:34]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:20][C:29]1[C:30]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36][CH2:35][C:31]=2[N:32]=[CH:33][N:34]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCc2ncnc(O)c2C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2ncnc(Cl)c2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of PPh3 (81.4 g, 310 mmol) and N-chlorosuccinimide (41.4 g, 310 mmol) in dioxane (850 mL) was stirred at ambient temperature for 30 minutes. To this suspension was added tert-butyl 4-hydroxy-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate and the mixture stirred at 50° C. for 18 hours. The mixture was subsequently treated with triethylamine (25 mL, 183 mmol) and the resulting brown solution concentrated. The black oil was dry packed onto silica gel and purified by chromatography eluting with 15-20% EtOAc/Hexanes to give the title compound as a yellow gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:29])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:29])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:13]([C:11]2[O:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH:23]=1)[CH3:17]
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)o1
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3ccc(F)cc3)o2)c1

Procedure:
5-(4-Fluoro-phenyl)-furan-2-carboxylic acid (54 mg, 0.26 mmol) was coupled to ethyl ester (60) (50 mg, 0.26 mmol) using Method C. The crude residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][C:10]([CH:13](OC)[O:14]C)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)=O>O>[Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)c1ccn(-c2ncccc2Cl)n1
Solvent: O=CO
Solvent: O
Product: O=Cc1ccn(-c2ncccc2Cl)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A mixture of 3.35 g of 3-chloro-2-[3-(dimethoxymethyl)-1H-pyrazol-1-yl]pyridine, 24 ml of formic acid and 6 ml of water was stirred at 60° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. Ice water was poured into the residue, and a precipitated solid was collected by filtration to obtain 2.38 g of 1-(3-chloro-2-pyridinyl)-1H-pyrazole-3-carbaldehyde of the formula:
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[N:16]=[CH:15][C:14]([F:17])=[CH:13][C:9]=1[C:10]([OH:12])=O)[CH3:2].[NH2:21][CH2:22][C:23]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([S:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[N:16]=[CH:15][C:14]([F:17])=[CH:13][C:9]=1[C:10]([NH:21][CH2:22][C:23]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:12])[CH3:2]
Reactant: CCSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Reactant: NCC1(O)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCSc1cccc(Oc2ncc(F)cc2C(=O)NCC2(O)CCCCC2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 41.7 %

Procedure:
2-(3-Ethylsulfanyl-phenoxy)-5-fluoro-nicotinic acid (150 mg, 0.51 mmol) was added to a solution of 1-aminomethyl-cyclohexanol (93 mg, 0.56 mmol) and triethylamine (0.21 ml, 1.5 mmol) in dimethylformamide (3 ml) under nitrogen at room temperature. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (108 mg, 0.56 mmol) followed by 1-hydroxybenzotriazole (76 mg, 0.56 mmol) were then added and the reaction was stirred at room temperature for 20 h. The mixture was concentrated under reduced pressure, partitioned between ethyl acetate (20 ml) and water (20 ml) and the organic phase was removed, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on a silica gel eluting with a solvent gradient of dichloromethane:methanol (99:1 changing to 98:2, by volume) to give 2-(3-ethylsulfanyl-phenoxy)-5-fluoro-N-(1-hydroxy-cyclohexylmethyl)-nicotinamide (86 mg) as an off-white solid.
Reaction SMILES: [CH2:1]([C@@:3]12[CH2:16][C@:15]([OH:18])([CH3:17])[C@:14]([OH:25])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][C@H:12]1[CH2:11][CH2:10][C:9]1[CH:8]=[C:7]([O:26][CH2:27][C:28](O)=[O:29])[CH:6]=[CH:5][C:4]2=1)[CH3:2].[NH2:31][CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>>[CH2:1]([C@@:3]12[CH2:16][C@:15]([OH:18])([CH3:17])[C@:14]([OH:25])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][C@@H:12]1[CH2:11][CH2:10][C:9]1[CH:8]=[C:7]([O:26][CH2:27][C:28]([NH:31][CH2:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)=[O:29])[CH:6]=[CH:5][C:4]2=1)[CH3:2]
Reactant: CC[C@@]12C[C@@](C)(O)[C@](O)(c3ccccc3)C[C@H]1CCc1cc(OCC(=O)O)ccc12
Reactant: NCc1ccncc1
Product: CC[C@@]12C[C@@](C)(O)[C@](O)(c3ccccc3)C[C@@H]1CCc1cc(OCC(=O)NCc3ccncc3)ccc12

Procedure:
The title compound was prepared from the compound of Example 70 according to the procedure of Example 97 using 4-(aminomethyl)pyridine in place of 1-methylpiperazine. Mass spectrum (m/e) 501 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[C:9]3=[CH:19][CH:20]=[CH:21][N:8]3[CH2:7][C:6]=2[CH:22]=1.[Br:23]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:23][C:21]1[N:8]2[C:9]([CH:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[O:11][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][C:6]=3[CH2:7]2)=[CH:19][CH:20]=1
Reactant: CN1CCC(C2Oc3ccc(Cl)cc3Cn3cccc32)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(C2Oc3ccc(Cl)cc3Cn3c(Br)ccc32)CC1

Procedure:
A solution of 7-chloro-11-[(1-methyl)piperidin-4-yl]-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (5.5 g; 0.017 mole) and N-bromosuccinimide (3.7 g; 0.021 mole) in 150 ml of tetrahydrofuran was stirred for 20 hours at ambient temperature. The reaction mixture was then diluted with ethyl acetate and washed twice with a dilute Na2SO3 solution and once with water and dried (saturated NaCl solution, anhydrous MgSO4).
Reaction SMILES: [NH:1]1[CH:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:4][CH:3]=[N:2]1.C([BH3-])#N.[Na+].[CH:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:25](Cl)=[O:26])=[CH:19][CH:18]=1>C(O)(=O)C>[N:2]1([C:25]([O:24][CH2:23][C:20]2[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=2)=[O:26])[CH2:3][CH2:4][CH:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[NH:1]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)C1CC=NN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)N1
Reaction time: 2 h
Yield: 62.2 %

Procedure:
To a solution of 1,1-dimethylethyl 4,5-dihydro-1H-pyrazole-5-carboxylate (5 g, 29.4 mmol) dissolved in acetic acid (75 mL) was added sodium cyanoborohydride (3.69 g, 58.8 mmol) over 10 minutes. After 30 min. the reaction mixture was concentrated. The intermediate was diluted with ethyl acetate and basified with sat. Na2CO3. The ethyl acetate was dried over sodium sulfate, filtered, and concentrated. The intermediate was diluted with tetrahydrofuran (THF) (75 mL), and triethylamine was added (8.19 mL, 58.8 mmol), followed by Cbz-Cl (2.1 mL, 14.69 mmol). After 2 h, the organic salts were filtered and the crude product was purified by silica gel column using 20-80% EtOAc/hexanes to afford 2.8 g (9.14 mmol) of 3-(1,1-dimethylethyl) 1-(phenylmethyl) 1,3-pyrazolidinedicarboxylate. LC-MS (ES) m/e 307.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].N1C=CC=CC=1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25])([O-:20])=[O:19]>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([NH:11][C:24]([C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)=[O:25])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1c(O)cccc1C(=O)O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Thionyl chloride (25 mL) was added to 3-nitrobenzoic acid (3 g, 18 mmol) and the mixture was stirred at reflux for 6 hr. Thionyl chloride was evaporated under reduced pressure and the residues was dried to obtain 3-nitrobenzoyl chloride as a yellow solid. 3-Hydroxyanthranilic acid (0.92 g, 6.0 mmol) and pyridine (1.45 mL, 18.0 mmol) were added to toluene (30 mL) and the mixture was stirred at room temperature for 30 min. Then 3-nitrobenzoyl chloride prepared above (3.34 g, 18 mmol) was added. The mixture was stirred at room temperature for 30 min and then at 80° C. for 2 hr. The solvents was evaporated under reduced pressure and the residue was washed with 5% aqueous hydrochloric acid (100 mL×3), filtered, the solid was washed with water (100 mL×3), dried in vacuum at 50° C. to obtain 3-hydroxy-2-(3-nitrobenzeneamido)benzoic acid as a yellow solid (1.8 g, yield 100%). LC-MS (ESI) m/z 303 [M+1]+.
Reaction SMILES: I(O)(=O)(=O)=[O:2].[CH2:6]([O:9][N:10]1[C:16](=[O:17])[N:15]2[CH2:18][C@H:11]1[C:12]([CH3:21])=[CH:13][C@H:14]2[CH2:19][OH:20])[CH:7]=[CH2:8]>C(#N)C.[O-2].[Cr+6].[O-2].[O-2]>[CH2:6]([O:9][N:10]1[C:16](=[O:17])[N:15]2[CH2:18][C@H:11]1[C:12]([CH3:21])=[CH:13][C@H:14]2[C:19]([OH:2])=[O:20])[CH:7]=[CH2:8]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2CO
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC#N
Product: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of periodic acid (2 g, 10.42 mmol) in wet acetonitrile (20 mL) (0.75% water by volume) at room temperature was added chromium(VI) oxide (4 mg, 0.04 mmol). The mixture was stirred until complete dissolution was achieved. This solution (5.47 mL, 3 eq) was added dropwise at 0° C. to a solution of (2S,5R)-6-(allyloxy)-2-(hydroxymethyl)-4-methyl-1,6-diazabicyclo[3.2.1]oct-3-en-7-one (Intermediate 14, 0.212 g, 0.95 mmol) in wet acetonitrile (10 mL) (0.75% by volume). The reaction mixture went from clear orange to cloudy brownish color to cloudy green suspension. After 30 minutes, LC/MS showed desired product mass and some remaining starting material. Another equivalent of the oxidizing agent solution (1.82 mL) was added. After 30 minutes, the reaction mixture was diluted with ethyl acetate and washed with 1 to 1 brine/water. The organics were dried over magnesium sulfate, filtered and concentrated to afford a green foam (0.193 g, 86%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:14][CH:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16]([OH:18])=O)([CH2:6][N:7]1[C:11](=[O:12])[CH2:10][NH:9][C:8]1=[O:13])=[O:5])[CH3:2].[CH3:23][NH:24][C:25](=[O:32])[C@H:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH2:27]>ClCCl.O1CCCC1>[CH2:1]([O:3][P:4]([CH2:6][N:7]1[C:11](=[O:12])[CH2:10][NH:9][C:8]1=[O:13])([CH2:14][CH:15]([C:16](=[O:18])[NH:27][C@H:26]([C:25](=[O:32])[NH:24][CH3:23])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:5])[CH3:2]
Reactant: CNC(=O)[C@@H](N)CC(C)C
Reactant: CCOP(=O)(CC(CC(C)C)C(=O)O)CN1C(=O)CNC1=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOP(=O)(CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC)CN1C(=O)CNC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.1 %

Procedure:
0.22 g (0.64 mmol) of 2(RS)-[[(RS)-(ethoxy)[(2,5-dioxo-1 -imidazolidinyl)methyl]phosphinyl]methyl]-4-methylvaleric acid and 0.116 g (0.81 mmol) of L-leucine methylamide were taken up in 5 ml of dichloromethane and 2.5 ml of tetrahydrofuran. The solution was treated at -8° C. with 0.3 g (1.2 mmol) of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline. The mixture was stirred at room temperature for 24 hours and was then left to stand at 0° C. for 48 hours. The solvent was removed by evaporation. The residue was taken up in 50 ml of chloroform. The solution was washed in sequence with 5% citric acid solution, 5% sodium hydrogen carbonate solution and sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to give a gum. This gum was chromatographed on silica gel using chloroform/methanol(19:1) for the elution to give 0.08 g of [(2,5-dioxo-1-imidazolidinyl)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester as a gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[SH:9].C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])Br>CN(C)C=O>[Br:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[S:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8]
Reactant: Sc1c(Cl)cccc1Cl
Reactant: FC(F)(Br)C(F)(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(Br)C(F)(F)Sc1c(Cl)cccc1Cl
Yield: 35.2 %

Procedure:
In a manner similar to Step A of Example 1, the reaction of 26.0 g (0.25 mole) 2,6-dichlorothiophenol, 20.0 g (0.15 mole) potassium carbonate and 75.4 g (0.30 mole) 1,2-dibromotetrafluoroethane in 200 ml of N,N-dimethylformamide produced 31.5 g of 2-(2-bromo-1,1,2,2-tetrafluoroethylthio)-1,3-dichlorobenzene as an oil. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][CH2:17][C:18](O)=O>O>[CH2:1]([N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]=[C:18]1[CH2:17][Cl:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1NCc1ccccc1
Reactant: O=C(O)CCl
Solvent: O
Product: ClCc1nc2ccccc2n1Cc1ccccc1
Temperature: 120 °C
Yield: 73.3 %

Procedure:
N-benzyl-o-phenylenediamine (3 g, 15 mmol), which is a known compound, was added to polyphosphoric ester (10 g), to which monochloroacetic acid (1.1 g, 12 mmol) was added and heated at 120° C. for 1 hour. Then water was added to the mixture to decompose remaining polyphosphoric ester. The resultant was refined in a conventional process and the title intermediate (2.25 g, 8.8 mmol) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=[O:23])[CH:17]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([F:25])=[CH:4][N:3]=1.CC(C)=O.[NH4+].[Cl-].CCCCCC.C(OCC)(=O)C>O.[Zn]>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][OH:23])[CH:17]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([F:25])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N(c1cccc([N+](=O)[O-])c1)c1nc(Cl)ncc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(c1cccc(NO)c1)c1nc(Cl)ncc1F
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl (2-chloro-5-fluoropyrimidin-4-yl)(3-nitrophenyl)carbamate (0.78 g) in mixture of acetone (3 ml) and water (2 ml) was added NH4Cl (0.22 g) and the reaction mixture was heated to 60° C. Zn dust (289 mg) was added to the reaction mixture at 60° C. portion wise. The reaction mixture was stirred for 45 minute at 60° C. and monitored on TLC using hexane:ethyl acetate (3:7) as mobile phase. After completion of the reaction, the reaction mixture was poured in water. The product was extracted into ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate and concentrated completely under reduce pressure to give crude product. Crude material was purified by using column chromatography. Desired product eluted with 5% ethyl acetate in hexane to give, after concentration, 0.409 g of tert-butyl (2-chloro-5-fluoropyrimidin-4-yl)(3-(hydroxyamino)phenyl)carbamate. M+1=354.8. 1H NMR: DMSO-d6 (400 MHz): 1.400 (s, 9H), 6.612 (d, 1H, J=7.6), 6.688 (s, 1H), 6.774 (d, 1H, J=8.4), 7.170-7.210 (t, 1H, J=8), 8.434 (d, 2H, J=6.4), 8.95 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25](=[O:36])[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].O>CCO>[F:35][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[F:34])[CH2:27][NH:26][C:25]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)[N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:11]=1[CH:22]([CH3:24])[CH3:23])=[O:36]
Reactant: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccn3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)O)cc2n1Cc1ccccn1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
Following General Procedure F, ethyl3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1 H-indole-6-carboxylate (Compound 45, 117 mg, 0.238 mmol) in EtOH (10 ml) was added NaOH (47 mg, 1.20 mmol) and H2O (1 ml). The reaction was stirred at 50° C. for 12 h, concentrated in vacuo to an oil then acidified to PH=5 with 10% HCl, diluted with EtOAc, washed organic with H2O, brine, dried over Na2SO4 and concentrated in vacuo to yield the title compound as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:15]([C:16]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[O:17])=[C:14]([CH3:23])[N:13]=[C:12]([CH3:24])[C:11]=1[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>CO>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:10]1[C:15]([C:16]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[O:17])=[C:14]([CH3:23])[NH:13][C:12]([CH3:24])=[C:11]1[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]
Reactant: COCCOC(=O)c1c(C)nc(C)c(C(=O)OC(C)C)c1-c1cccc(C#N)c1Cl
Solvent: CO
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(C#N)c1Cl
Yield: 66.4 %

Procedure:
The procedure as described for Example 17 is followed. Starting from 120 mg of (-)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyanophenyl)-2,6-dimethylpyridine-3,5-dicarboxylate (atropisomer ratio in the elution sequence from chiral HPLC 98: 2; [α]20 D =7.2 (c=0.9, MeOH)), after electrolysis at 10-40 mA, 80 mg (67% of theory) of isopropyl 2-methoxyethyl 4-(2-chloro-3-cyanophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate are obtained in the enantiomer ratio 61.3:38.7.