Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[N:8]1([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])[CH:12]=[CH:11][CH:10]=[CH:9]1.N1C=CC=CC=1.Cl>ClCCCl.O.C(Cl)(Cl)Cl>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([C:12]1[N:8]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])[CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: COC(=O)c1cccc(-n2cccc2)c1
Agent: Cl
Solvent: O
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc(-n2cccc2C(=O)C(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
Trichloroacetyl chloride (15.5 ml) was added to a mixture of methyl 3-(pyrrol-1-yl)benzoate (14.0 g) and pyridine (16.9 ml) in 1,2-dichloroethane (70 ml) under ice-cooling and the mixture was stirred for 7 days at ambient temperature. The mixture was poured into a mixture of chloroform and water, and the mixture was adjusted to pH 1 with 6N-hydrochloric acid. The separated organic layer was washed with a saturated aqueous sodium bicarbonate solution and water. The mixture was dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give methyl 3-(2-trichloroacetylpyrrol-1-yl)benzoate (21.23 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[CH3:12].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C1(C)C=CC=CC=1.O.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>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: COC(=O)c1ccc(Br)c(C)c1
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of methyl 4-bromo-3-methylbenzoate (3.0 g; 13.1 mmol; 1 eq.), 2,4-dimethoxyphenylboronic acid (Aldrich 483486; 2.62 g; 14.4 mmol; 1.1 eq.), potassium carbonate (9.05 g; 65.5 mmol; 5 eq.) and Pd(PPh3)4 (1.51 g; 1.31 mmol; 0.1 eq.) in toluene (15 mL) and water (15 mL) was refluxed for 6 hours. The reaction mixture was cooled down to room temperature and filtered through a pad of CELITE which was further washed with toluene (200 mL). The filtrate was concentrated in vacuo and the residue taken up in Ethyl acetate (300 mL). The organic layer was washed with sat. aq. NaHCO3 (100 mL), water (100 mL) and brine (100 mL) then dried over magnesium sulfate and concentrated in vacuo. The residue (2.0 g; 6.99 mmol; 1 eq.) was taken up in EtOH (60 mL), sodium hydroxide (5M; 4.19 mL; 21 mmol; 3 eq.) was added and the reaction mixture was stirred at 60° C. for one hour. After concentration in vacuo, the residue was taken up in water (400 mL) and the aqueous phase was washed with Ethyl acetate then acidified to pH 2 with conc. HCl. The solution was concentrated to ca. 80 mL and the precipitate filtered off and dried to afford the title compound as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Si](Cl)(C(C)(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[B-](F)(F)(F)[F:29].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([F:29])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: F[B-](F)(F)F
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(O)C(F)c1cccc(Br)c1
Temperature: 0 °C
Yield: 40.7 %

Procedure:
A mixture of 3-bromophenyl acetic acid (1 g, 4.6 mmol), t-butyldimethylsilylchloride (1.6 g, 10.7 mmol) and THF (15 ml) were stirred at 0° C. under nitrogen. Lithium diisopropyl amide (5 ml-2M solution in heptane) was added to the mixture drop wise and the reaction was allowed to proceed first at 0° C., then at room temperature over night. The solvent was removed in vacuo and the crude material was redissolved in acetonitrile (20 ml). Selectfluor (2.1 g, 6.0 mmol) in acetonitrile (40 ml) was added drop wise and the reaction was allowed to stir at room temperature overnight. Solvent was removed under vacuum, redissolved in ethyl acetate and extracted with 1N HCl. The organic layer was dried with Na2SO4, decanted, and concentrated to dryness. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded (3-bromo-phenyl)-fluoro-acetic acid (436 mg, 40% yield). 1H NMR (500 MHz, DMSO-d6) δ 6.0-6.1 (d, 1H), 7.44 (m, 2H), 7.62 (m, 2H).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Brc1ncccn1
Product: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)c3ncccn3)c2)c1

Procedure:
This compound is prepared by method C using compound 12h and 2-bromopyrimidine
Reaction SMILES: C([O:5][C:6](=[O:37])[CH:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C:20]2[C:21]([O:26][C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:19])=[C:12]([F:36])[CH:11]=1)[CH3:8])(C)(C)C.COC(=O)COC1C=CC(CNC(C2C(OC3C=CC4OCOC=4C=3)=NC=CC=2)=O)=C(F)C=1>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([O:26][C:21]3[C:20]([C:18]([NH:17][CH2:16][C:13]4[CH:14]=[CH:15][C:10]([O:9][CH:7]([CH3:8])[C:6]([OH:37])=[O:5])=[CH:11][C:12]=4[F:36])=[O:19])=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(=O)OC(C)(C)C
Agent: COC(=O)COc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1
Product: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(=O)O

Procedure:
The compound of Formula (5.5.2) was prepared in a manner analogous to that described in Example 1, substituting (±)-2-[4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid tert-butyl ester for the corresponding [4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-acetic acid methyl ester material.
Reaction SMILES: C[O:2][P:3]([CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[C:19](=[O:20])[N:18]([C@H:21]([C:30](=[O:40])[NH:31][C:32]3[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=3[F:39])[C@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])[C:17](=[O:41])[NH:16]2)=[CH:11][CH:10]=1)(=[O:6])[O:4]C.Br[Si](C)(C)C>ClCCl>[F:39][C:33]1[CH:34]=[C:35]([I:38])[CH:36]=[CH:37][C:32]=1[NH:31][C:30]([C@@H:21]([N:18]1[C:19](=[O:20])[C@@H:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][P:3](=[O:2])([OH:6])[OH:4])=[CH:14][CH:13]=2)[NH:16][C:17]1=[O:41])[C@H:22]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH3:23])=[O:40]
Reactant: COP(=O)(COc1ccc([C@H]2NC(=O)N([C@H](C(=O)Nc3ccc(I)cc3F)[C@@H](C)c3ccccc3)C2=O)cc1)OC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: C[C@@H](c1ccccc1)[C@@H](C(=O)Nc1ccc(I)cc1F)N1C(=O)N[C@H](c2ccc(OCP(=O)(O)O)cc2)C1=O
Reaction time: 4 h
Yield: 69.5 %

Procedure:
To a solution of (4-{(R)-1-[(1S,2S)-1-(2-fluoro-4-iodo-phenylcarbamoyl)-2-phenyl-propyl]-2,5-dioxo-imidazolidin-4-yl}-phenoxymethyl)-phosphonic acid dimethyl ester (prepared as described in example 63) (79 mg, 0.11 mmol) in dichloromethane (2.0 mL) was added bromotrimethylsilane (0.12 mL, 0.88 mmol) at room temperature. After 4 hours, the reaction was concentrated in vacuo and diluted with water (5 mL). The precipitated solids were filtered and dried to give (4-{(R)-1-[(1S,2S)-1-(2-fluoro-4-iodo-phenylcarbamoyl)-2-phenyl-propyl]-2,5-dioxo-imidazolidin-4-yl}-phenoxymethyl)-phosphonic acid (51 mg, 68%).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[C:14]([C:16]([CH3:22])([CH3:21])[C:17](OC)=[O:18])[N:15]=2)[N:12]=1.[CH:23]([OH:26])([CH3:25])[CH3:24]>>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[C:14]([C:16]([CH3:22])([CH3:21])[C:17]([O:26][CH:23]([CH3:25])[CH3:24])=[O:18])[N:15]=2)[N:12]=1
Reactant: CC(C)O
Reactant: COC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1

Procedure:
In 18 ml of isopropanol, 995 mg of concentrated sulfuric acid was dissolved; 1.0 of methyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate was added, followed by thermal refluxing for 40 hours. After cooling, the mixture was concentrated under reduced pressure, neutralized by the addition of aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the crystal precipitated was collected, washed with hexane and dried to yield 794 mg of the title compound. The filtrate was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (5:1). The desired fraction was collected and dried to yield 215 mg of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(N(CC)CC)C.[F:17][C:18]([F:25])([F:24])[C:19](OCC)=[O:20]>CO>[F:17][C:18]([F:25])([F:24])[C:19]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:20]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCCCCC(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)CCCCCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 40 h
Yield: 84 %

Procedure:
6-Aminocaproic acid (1, 6.55 g, 50 mmol) was suspended in methanol (30 ml) and treated with triethylamine (6.9 ml, 100 mmol) followed by ethyl trifluoroacetate (7.2 ml, 60 mmol). The mixture was stirred at room temperature (r.t.) during 40 hours. The unreacted solid precipitate was filtered, the filtrate was evaporated in vacuo and crystallized from benzene-hexane mixture. Trifluoroacetyl derivative (2) had an 84% yield (9.5 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:32][C:30]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[C:23]([NH:22][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)[CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: NC(=O)c1ccc(Cl)cc1N
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cc(Cl)ccc4C(N)=O)nc(Cl)nc32)cc1

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 8.8 mmol) and 2-amino-4-chlorobenzamide (3.0 g, 17.6 mmol), 4-chloro-2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide was isolated as a yellow solid (0.650 g, 16% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3 H), 6.68 (d, J=4.03 Hz, 1 H), 7.23 (dd, J=8.51, 2.10 Hz, 1 H), 7.47 (d, J=8.23 Hz, 2 H), 7.79 (d, J=4.03 Hz, 1 H), 7.87 (d, J=8.42 Hz, 1 H), 7.91 (s, 1 H), 7.98 (d, J=8.42 Hz, 2 H), 8.41 (s, 1 H), 8.66 (d, J=2.20 Hz, 1 H), 12.65 (s, 1 H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10]C(=O)[C@@:8]1([N+]([O-])=O)[CH2:15][CH:16]=[C:17]([O:19]C)[CH2:18][C@@H:7]21.OS(O)(=O)=O>CCCCCCCCCCCCCCCC[N+](C)(C)C.[Br-].O>[F:3][C:4]1[CH:13]=[CH:12][C:11]2[O:10][C:8]3[CH2:15][CH2:16][C:17](=[O:19])[CH2:18][C:7]=3[C:6]=2[CH:5]=1
Reactant: COC1=CC[C@]2([N+](=O)[O-])C(=O)Oc3ccc(F)cc3[C@@H]2C1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: O=S(=O)(O)O
Agent: [Br-]
Solvent: O
Product: O=C1CCc2oc3ccc(F)cc3c2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
To a 250 mL flask were added CTABr (0.933 g, 2.56 mmol), NaOH (23.04 g, 576 mmol), and H2O (100 mL), and the resulting solution was warmed to 50° C. (6aR,10aS)-2-fluoro-9-methoxy-6a-nitro-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-6-one (3.75 g, 12.80 mmol) was rapidly added to the alkaline solution and left under stirring for 1 h. The green solution was then cooled to 0° C., and added dropwise to a solution of H2SO4 (3.75 M, 100 mL) also cooled to 0° C. The mixture was left stirring at 0° C. for 5 min, and was then allowed to stir at RT for 1 h. The mixture was then saturated with brine, and extracted with EtOAc. The organic layer was then dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash chromatography on silica gel afforded the product as a white solid (0.50 g, 19%); MS (EI) m/z=204 [M+].
Reaction SMILES: C([C:3]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]([OH:9])[CH2:7][CH2:6][CH2:5][C:4]1(CC)[CH:10]([C:14]([O-:16])=[O:15])[C:11]([O-:13])=[O:12])C.[OH-].[Na+].Cl>C1COCC1.O>[C:19]1([CH:3]2[CH:8]([OH:9])[CH2:7][CH2:6][CH2:5][CH:4]2[CH:10]([C:14]([OH:16])=[O:15])[C:11]([OH:13])=[O:12])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCC1(C(C(=O)[O-])C(=O)[O-])CCCC(O)C1(CC)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(C(=O)O)C1CCCC(O)C1c1ccccc1
Temperature: 70 °C
Yield: 96.7 %

Procedure:
A solution of 0.87 g (2.6 mmole) of diethyl-2-(SR)-phenyl-3-(SR)-hydroxy-(SR)-cyclohexylmalonate in 12 mL of THF and 7 mL of water was treated with 3.1 mL (7.8 mmole) of 10% aqueous sodium hydroxide and the mixture was heated in an oil bath at 70° C. under nitrogen for 24 hr. The mixture was cooled, 10 mL of water was added and the pH was adjusted to 2 with 2N aqueous HCl. The mixture was extracted with 3×35 mL of ethyl acetate, and the organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo to give 700 mg of a light yellow foam. This material was carried on in Step F below.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:18][Si](C=[N+]=[N-])(C)C.CCCCCC>C1C=CC=CC=1.CO>[CH3:18][O:16][C:15](=[O:17])[C@H:12]([CH2:13][OH:14])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Solvent: CO
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of N-carbobenzyloxy-L-serine (4.0 g, 16.7 mmol) in benzene (200 ml) and methanol (50 ml) was added a solution of 2M trimethylsilyldiazomethane in hexane (10.9 ml, 21.7 mmol) in an ice bath, and the mixture was stirred at room temperature for 3 hours. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1→1:3) as the eluant to afford N-carbobenzyloxy-L-serine methyl ester (4.40 g, yield 100%) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[OH:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:18]([O:20][C:21](=O)[C:16]=12)=[O:19]>>[OH:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:16]=1[C:21](=[O:20])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:18]2=[O:19]
Reactant: COC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1OC(=O)c2c(O)cccc21
Product: COC(=O)C(CN1C(=O)c2cccc(O)c2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.84 g, 45%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (1.00 g, 5.54 mmol) and 3-hydroxyphthalic anhydride (1.00 g, 6.09 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:9]=2[CH:10]=1)=O)C.[C-:28]#[N:29].[Na+].CN>>[CH3:28][NH:29][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:9]=2[CH:10]=1)=[O:3]
Reactant: CCOC(=O)c1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2o1
Reactant: [C-]#N
Agent: CN
Agent: [Na+]
Product: CNC(=O)c1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2o1

Procedure:
tert-Butyl 4-(2-(ethoxycarbonyl)benzofuran-4-yl)piperazine-1-carboxylate (6.17 g, 16.5 mmol) and sodium cyanide (0.081 g, 1.6 mmol) were stirred overnight at rt in methyl amine (8 M in ethanol) (62 mL, 490 mmol). The solvent was removed by rotary evaporation, the residue was dissolved in dichloromethane and transferred to a separatory funnel. The mixture was washed with 2 M sodium hydroxide and water. The organic phase was separated, dried over potassium carbonate, filtered and the solvent was removed by rotary evaporation to give the title compound. Yield: 5.8 g, 98%. The crude product was used in the subsequent step iii) without further purification. 1H NMR (500 MHz, CDCl3) δ ppm 1.51 (s, 9H) 3.06 (d, 3H) 3.15-3.23 (m, 4H) 3.61-3.70 (m, 4H) 6.59-6.66 (m, 1H) 6.71 (d, 1H) 7.13 (d, 1H) 7.29-7.35 (m, 1H) 7.51 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N-]1C=CN=C1.[CH2:16]([C:20]1[C:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38](=[O:41])(=[O:40])[NH2:39])=[CH:28][C:27]=2[F:42])=[C:23]([C:43]#[N:44])[N:22]([C:45]2[CH:50]=[C:49]([NH:51][C:52](=[O:55])[CH2:53][CH3:54])[CH:48]=[CH:47][C:46]=2[Cl:56])[N:21]=1)[CH2:17][CH2:18][CH3:19]>>[CH2:16]([C:20]1[C:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38](=[O:41])(=[O:40])[NH:39][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])=[CH:28][C:27]=2[F:42])=[C:23]([C:43]#[N:44])[N:22]([C:45]2[CH:50]=[C:49]([NH:51][C:52](=[O:55])[CH2:53][CH3:54])[CH:48]=[CH:47][C:46]=2[Cl:56])[N:21]=1)[CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(C#N)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Agent: c1c[n-]cn1
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(C#N)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1F
Yield: 74 %

Procedure:
By the procedure of Example 1, Step H, 2-chlorobenzoic acid was converted to its imidazolide and reacted with 3-n-butyl-1-[2-chloro-5-(propionylamino)phenyl]-4-[[3-fluoro-2'-sulfamoylbiphenyl-4-yl]methyl]-1H-pyrazole-5-carbonitrile (from Step K). The crude product was purified by semipreparative HPLC on a Zorbax C8 reverse phase column (elution with 75:25 acetonitrile-H2O containing 0.1% TFA), affording a 74% yield of the title compound as a cream-colored, stiff foam; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 732 (M+1)+. 400 MHz 1H NMR (CDCl3) δ0.93 (t, J=7.3 Hz, 3H), 1.22 (t, J=7.5 Hz, 3H), 1.40 (m, 2H), 1.68 (m, 2H), 2.39 (q, J=7.5 Hz, 2H), 2.67 (t, J=7.8 Hz, 2H), 3.93 (br s, 2H), 7.1-7.7 (m, 12H), 7.77 (d, J=2.3 Hz, 1H), 8.37 (dd, J=7.9, 1.4 Hz, 1H), 9.10 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[O:9]=[C:10]1[CH2:15][CH2:14][C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:16]#[N:17])[CH2:12][CH2:11]1>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]2([OH:9])[CH2:15][CH2:14][C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)([C:16]#[N:17])[CH2:12][CH2:11]2)=[N:3][CH:4]=1
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Reactant: Fc1ccc(Br)nc1
Product: N#CC1(c2ccccc2)CCC(O)(c2ccc(F)cn2)CC1
Yield: 89.1 %

Procedure:
According to the process described in Example 260, 25 mmol of 2-bromo-5-fluoropyridine were converted into the Grignard reagent and reacted with 25 mmol of 4-oxo-1-phenylcyclohexanecarbonitrile (dissolved in 100 ml of THF). The chromatographic separation of the crude product (silica gel flash column; HEP/EA 3:1) afforded two main fractions (TLC (HEP/EA 1:1): Rf 0.58 and 0.49), which were combined. 6.6 g of the title compound (cis/trans mixture) were obtained as a viscous yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].C([O:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][C:33](Cl)=[N:32][C:31]=1[C:37]([F:40])([F:39])[F:38])C.[Li+].[OH-].Cl>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:13])([F:14])[F:12])[O:8][C:33]1[CH:34]=[CH:35][C:30]([C:29]([OH:41])=[O:28])=[C:31]([C:37]([F:38])([F:40])[F:39])[N:32]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1C(F)(F)F
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C(=O)O)c(C(F)(F)F)n3)cc2Cl)C(F)(F)F)cn(C)c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5, 60 mg) in N,N-dimethylacetamide (2 ml) were added potassium-tert.-butylate (21.5 mg) and 6-chloro-2-trifluoromethyl-nicotinic acid ethyl ester (81 mg). The mixture was stirred at room temperature for 1.5 h. A 0.2 M aqueous LiOH solution (4.79 ml) was added and the mixture was stirred at room temperature for 3 h and then cooled in an ice bath. The mixture was acidified with 1 M aqueous HCl and extracted with ethyl acetate. The organic phase was concentrated to dryness and the product was purified by chromatography ((SiO2, CH2Cl2/MeOH 1:0=>3:1). Off-white solid (22 mg). MS (m/e)=565.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>CCO.[Ni]>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[C:3]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=1
Reactant: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)Cc1cc(N)c(F)cc1Cl
Yield: 95.2 %

Procedure:
A solution of ethyl 2-(2-chloro-4-fluoro-5-nitrophenyl)acetate (22.5 g, 86.2 mmol) in EtOH (200 mL) was stirred with Raney Ni (20% slurry in water, 5.0 g, 17 mmol) under a hydrogen atmosphere (30 psi) for 5 h. The catalyst was removed by filtration and the filtrate was concentrated to give ethyl 2-(5-amino-2-chloro-4-fluorophenyl)acetate (19 g, 95% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.10 (d, J=11.2 Hz, 1H), 6.71 (d, J=9.2 Hz, 1H), 5.27 (s, 2H), 4.05 (q, J=6.8 Hz, 2H), 3.57 (s, 2H), 1.14 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 232.0 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=O)[C:4]=2[CH:3]=[CH:2]1.[Cl-].[OH:12][NH3+:13]>N1C=CC=CC=1>[NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[N:13][OH:12])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1CCCc2[nH]ccc21
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: c1ccncc1
Product: ON=C1CCCc2[nH]ccc21
Reaction time: 2 h

Procedure:
To a stirred solution of 1,5,6,7-tetrahydro-indol-4-one (5.4 g) in pyridine (40 mL) was added hydroxyammonium chloride (2 eq.) at rt. After 2 hours, the solvent was removed and the residue was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried and concentrated to give 5.5 g of 1,5,6,7-tetrahydro-indol-4-one oxime as a pale yellow solid.