Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14]CC)=O)[N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[CH:22][C:23]=1[F:24].C1COCC1>C1COCC1>[Cl:17][C:18]1[CH:19]=[C:20]([C:12]([C:4]2[N:3]=[C:2]([Cl:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:14])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: CCOC(=O)c1nc(Cl)c2ccccc2n1
Reactant: Fc1ccc([Mg]Br)cc1Cl
Solvent: C1CCOC1
Product: O=C(c1ccc(F)c(Cl)c1)c1nc(Cl)c2ccccc2n1
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 36.7 %

Procedure:
A mixture of ethyl 4-chloroquinazoline-2-carboxylate (1 g, 4.2 mmol) in THF (50 mL) was filtered, and to the filtrate at −30° C. under Ar was added 0.5 M (3-chloro-4-fluorophenyl)magnesium bromide/THF (10.4 mL, 5.2 mmol). After stirring at −30° C. for 0.75 h, additional 0.5 M (3-chloro-4-fluorophenyl)magnesium bromide/THF (4.2 mL). After 1 h, the reaction was quenched by addition of saturated aq ammonium chloride and allowed to warm to rt. The mixture was extracted with EtOAc, and the extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford (3-chloro-4-fluorophenyl)(4-chloroquinazolin-2-yl)methanone (495 mg, 37%) which was used directly in the next step. LC-MS (ESI) m/z 321 (M+H)+.
Reaction SMILES: Cl.C([O:9][CH2:10][CH2:11][C:12]1[N:13]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)[C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>>[Cl:27][C:25]1[CH:26]=[C:21]([S:20][C:14]2[N:13]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)[C:12]([CH2:11][CH2:10][OH:9])=[N:16][C:15]=2[CH:17]([CH3:19])[CH3:18])[CH:22]=[C:23]([Cl:28])[CH:24]=1
Reactant: CC(C)c1nc(CCOCc2ccccc2)n(Cc2ccc([N+](=O)[O-])cc2)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)c1nc(CCO)n(Cc2ccc([N+](=O)[O-])cc2)c1Sc1cc(Cl)cc(Cl)c1
Yield: 33 %

Procedure:
To 5 ml of concentrated hydrochloric acid was dissolved 1.3 g (2.34 mmol) of the benzyl compound (125a), the mixture was refluxed with heating for 4 hours and worked up. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with water and dried, distilled off, the residual oil was treated with ether, arid crystallized to give 5-(3,5-dichlorophenylthio)-2-(2-hydroxyethyl)-4-isopropyl-1-p-nitrobenzyl-1H-imidazole (126a). m.p. 169-171° C.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH2:7][CH:8]=[CH2:9])[C:3]([NH:5][NH2:6])=O.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:18][NH:19][C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=NC>CN1C(=O)CCC1>[CH3:1][C:2]([C:3]1[N:19]([CH3:18])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:6][N:5]=1)([CH3:10])[CH2:7][CH:8]=[CH2:9]
Reactant: CN=C(NC)c1ccccc1
Reactant: C=CCC(C)(C)C(=O)NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C=CCC(C)(C)c1nnc(-c2ccccc2)n1C
Temperature: 240 °C
Yield: 32.1 %

Procedure:
To a solution of 2,2-dimethyl-4-pentenohydrazide (360 mg) in NMP(2.5 ml) were added K2CO3 (348 mg) and N,N′-dimethylbenzenecarboximidamide hydrochloride (463 mmol). The solution was heated to the microwave at 240° C. for 30 minutes. Volatiles were evaporated in vacuo, the crude dissolved in DCM, washed with water and dried over Na2SO4. After filtration and concentration to dryness in vacuo, the crude was purified by column chromatography (DCM:MeOH=98 to 2) to give 196 mg of the title compound. MS (m/z): 242[MH]+.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)=[O:2].C(Cl)(=O)C([Cl:15])=O>O1CCCC1.CN(C)C=O>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:15])=[O:8])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=Cc1ccc(C(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Commercially available 4-formylbenzoic acid (5.0 g, 33.3 mmol) was dissolved in a mixture of anhydrous tetrahydrofuran (100 ml) and anhydrous N,N-dimethylformamide (1 ml) and the mixture was cooled with stirring to 0° C. To the resulting mixture was added dropwise oxalyl chloride (3.8 ml, 43.3 mmol). The mixture was stirred at room temperature for 30 minutes and then at 40° C. for 20 minutes. The reaction mixture was concentrated under reduced pressure and then in vacuo to afford 4-formylbenzoyl chloride. 4-(2,2,3,3-Tetrafluoropropoxy)aniline (646 mg, 2.9 mmol), described in Chem. Pharm. Bull., 44 (2), 314 (1996), and N,N-diisopropylethylamine (1.21 ml, 7.0 mmol) were dissolved in anhydrous tetrahydrofuran (8 ml) and the mixture was cooled to 0° C. with stirring. To the resulting mixture was added dropwise a solution of 4-formylbenzoyl chloride (561 mg, 3.33 mmol) obtained above in anhydrous tetrahydrofuran (2 ml). This mixture was stirred at room temperature for 17 hours and then at 40° C. for 20 minutes. At the end of this time, saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture in an ice bath and the mixture was partitioned between ethyl acetate and water. The organic layer was washed sequentially with 0.5N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution, water, and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystalline residue was recrystallized from a mixture of ethyl acetate and hexane to give 4-formyl-4′-(2,2,3,3-tetrafluoropropoxy)benzanilide (634 mg, yield 62%) as pale yellow crystals.
Reaction SMILES: [CH:1]1([N:5]2[CH2:8][CH:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4([C:23]#[N:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH:1]1([N:5]2[CH2:8][CH:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4([CH2:23][NH2:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#CC1(c2ccc(OCC3CN(C4CCC4)C3)cc2)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC1(c2ccc(OCC3CN(C4CCC4)C3)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
4-{4-[(1-cyclobutylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-carbonitrile (0.29 g, 0.89 mmol), was dissolved in THF (5 mL). The solution was cooled to 0° C. under nitrogen. Lithium aluminiumhydride (2.7 mL, 1.0M solution in diethyl ether) was added dropwise. The reaction was stirred at 0° C. for 30 minutes, then warmed up to ambient temperature for 4 hours under a nitrogen atmosphere until complete. The reaction was cooled to 0° C., water (0.1 mL) was added dropwise followed by sodium hydroxide (2.0M, 0.1 mL) and water (0.3 mL). The mixture was filtered (using dichloromethane:methanol (90:10)) through celite. The organics were dried over sodium sulphate, filtered and concentrated in vacuo to provide a clear oil. This was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4 to 90:10:1) to provide the title compound (0.175 g, 59%) as a clear colourless oil. 1H NMR (400 MHz, CDCl3) δ 1.60-1.70 (m, 2H), 1.70-1.85 (m, 2H), 1.85-1.95 (m, 2H), 1.95-2.06 (m, 2H), 2.1-2.18 (m, 2H), 2.79 (s, 2H), 2.9 (m, 1H), 3.1 (t, 2H), 3.2 (m, 1H), 3.48 (m, 2H), 3.54 (m, 2H), 3.8 (m, 2H), 4.10 (d, 2H), 6.9 (d, 2H), 7.2 (d, 2H). HRMS ESI+ m/z 331.2374 [MH]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH:9]=[O:10])[CH2:3][CH2:2]1.[N:11]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[N:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1CN[C@@H](C(O)=O)C1.[BH4-].[Na+]>CC#N.C(O)C>[OH:10][CH2:9][C@@H:8]([N:11]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=CCCC1CCOCC1
Agent: O=C(O)[C@H]1CCCN1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Product: O=C(NN(C(=O)OCc1ccccc1)[C@H](CO)CC1CCOCC1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 88.9 %

Procedure:
To a stirred solution of 3-(tetrahydro-pyran-4-yl)-propionaldehyde (8.59 g, 0.06 mol) and dibenzyl azodicarboxylate (12.8 g, 0.042 mol) in MeCN (250 mL) at 0° C. was added (R-proline) (0.48 g, 0.0042 mol). After stirring the mixture at 0° C. for 15 h, ethanol (100 mL) and NaBH4 (1.56 g, 0.042 mol) were added, and the mixture was stirred at 0° C. for 40 min. The reaction was quenched by slow addition of 10% aq citric acid (15 mL), and the whole solution was concentrated in vacuo. This residue was diluted with EtOAc (200 mL), washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give crude product which was purified by column chromatography to give (S)-dibenzyl 1-(1-hydroxy-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)hydrazine-1,2-dicarboxylate (16.52 g, 89%). 1H NMR (CD3OD) δ 1.0-1.5 (m, 8H), 2.9-3.3 (m, 2H), 3.4-3.6 (m, 2H), 3.7-3.9 (m, 2H), 4.4-4.7 (m, 2H), 5.1-5.4 (m, 4H), 7.2-7.4 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[NH:12][C:11](=O)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:14]=[C:13]([CH3:15])[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(=O)[nH]1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(Cl)n1

Procedure:
4-(3,4-Dichloro-phenyl)-6-methyl-1H-pyridin-2-one: The compound was prepared from the above described (E)-4-(3,4-dichloro-phenyl)-but-3-en-2-one (26.7 g, 124 mmol), commercially available 1-ethoxycarbonylmethyl-pyridinium bromide [CAS-No. 17282-40-5] (33.6 g, 137 mmol) and ammonium acetate (47.8 g, 621 mmol) in EtOH (150 mL) according to general procedure Ib step 1. Obtained as a light brown solid (25.4 g, 81%). MS (ISP) 254.1 [(M+H)+], 256.2 [(M+2+H)+] and 258.0 [(M+4+H)+]0.3) The title compound was prepared from the above described 4-(3,4-dichloro-phenyl)-6-methyl-1H-pyridin-2-one (25.4 g, 100 mmol) and phosphoryl chloride (45.6 mL, 500 mmol) according to the general procedure Ia to d preparation of chlorides. Obtained as an off-white solid (23.7 g, 87%). MS (ISP) 272.1 [(M+H)+], 274.0 [(M+2+H)+], 276.0 [(M+4+H)+] and 278.0 [(M+6+H)+].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH:10]=[CH:11][N:12]([CH3:14])C)[CH:5]=[CH:6][C:7]=1[CH3:8].N[C:17]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=C[NH:19][N:18]=1>C(O)(=O)C>[C:4]1([C:9]2[N:19]3[N:18]=[CH:17][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:14]3[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: Cc1ccc(C(=O)C=CN(C)C)cc1C
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3ccc(C)c(C)c3)ccnc12

Procedure:
A mixture of 4.06 g. of 3',4'-dimethyl-3-dimethylaminoacrylophenone and 3.10 g. of ethyl 3-aminopyrazole-4-carboxylate in 25 ml. of glacial acetic acid is refluxed for 6 hours. The desired compound is recovered as in previous examples except that the compound as first observed is amorphous and then crystallizes on standing in the crystallization solvent, m.p. 187°-188° C.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[C:21]4[C:27](I)=[N:26][N:25]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]4=[N:23][CH:24]=3)[CH:14]=2)=[O:12])[CH2:7][CH2:6]1.[F:38][C:39]1[CH:40]=[CH:41][C:42]([O:48][CH3:49])=[C:43](B(O)O)[CH:44]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[CH3:1][N:2]([CH3:37])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[C:21]4[C:27]([C:41]5[CH:40]=[C:39]([F:38])[CH:44]=[CH:43][C:42]=5[O:48][CH3:49])=[N:26][N:25]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]4=[N:23][CH:24]=3)[CH:14]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: CN(C)CCN1CCN(C(=O)c2cccc(-c3cnc4c(c3)c(I)nn4COCC[Si](C)(C)C)c2)CC1
Reactant: COc1ccc(F)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(=O)N4CCN(CCN(C)C)CC4)c3)cc12
Temperature: 90 °C

Procedure:
A mixture of (4-(2-(dimethylamino)ethyl)piperazin-1-yl)(3-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)methanone (50 mg, 0.079 mmol), 5-fluoro-2-methoxyphenylboronic acid (20 mg, 0.118 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (7.9 mg, 0.10 mmol) and sodium carbonate (2M aqueous solution, 0.119 mL, 0.237 mmol) in acetonitrile (1 mL) was heated in a Personal microwave at 90° C. for 30 min. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography purification of the crude product afford (4-(2-(dimethylamino)ethyl)piperazin-1-yl)(3-(3-(5-fluoro-2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)methanone as a light yellow oil. MS: m/z 633.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>CN(C=O)C>[Cl:24][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]1[CH2:18][CH2:19][CH3:20]
Reactant: O=S(Cl)Cl
Reactant: CCCN1C(=O)c2ccccc2C1(O)c1ccc(F)cc1
Solvent: CN(C)C=O
Product: CCCN1C(=O)c2ccccc2C1(Cl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
Distilled THF (20 mL) was added to 3-(4-fluorophenyl)-3-hydroxy-2-propyl-2,3-dihydroisoindol-1-one (200 mg, 0.7 mmol) followed by thionyl chloride (0.06 mL, 0.84 mmol) and a catalytic amount of DMF (3 drops). The mixture was stirred at room temperature under nitrogen for 4 h and monitored by TLC. Removal of the solvent under vacuum gave 3-chloro-3-(4-fluorophenyl)-2-propyl-2,3-dihydroisoindol-1-one as a colourless oil (212 mg, 0.69 mmol, 100%) which was used immediately without further purification.
Reaction SMILES: ClC1C(C2C=C3C(=CC=2)NN=C3)=CC=CN=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[CH3:27].Br[C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[Cl:35][C:34]1[C:29]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[C:19]([CH3:27])[CH:20]=2)=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: Clc1cccnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Clc1ncccc1-c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(-c2ncccc2Cl)ccc1F
Yield: 54.8 %

Procedure:
3-Chloro-2-(4-fluoro-3-methylphenyl)pyridine was synthesized analogous to the reaction conditions used in the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole by heating the mixture of 4-fluoro-3-methylphenyl boronic acid (1.0 g, 6.5 mmol), 2-bromo-3-chloropyridine (1.4 g, 7.1 mmol), Pd(PPh3)4 (0.45 g, 0.38 mmol) and 2M aq. Na2CO3 (8 mL, 16 mmol) in 1,4-dioxane (125 mL) under argon atmosphere for 3 h. Upon work-up of the reaction mixture, as discussed in the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole, the crude concentrate was purified by flash silica gel column chromatography [Combiflash® companion System® with RediSep® silica gel column 40 g, 10-30% EtOAC/hexanes eluting solvent gradient upon liquid loading on to column] to obtain 3-chloro-2-(4-fluoro-3-methylphenyl)pyridine as a white solid (790 mg, 54%). 1H NMR (DMSO-d6): δ 8.60 (dd, 1H, J=1.4 and 4.7 Hz), Hz), 8.02 (dd, 1H, J=1.4 and 8.2 Hz), 7.57 (app d, 1H, J=7.3 Hz), 7.54-7.49 (m, 1H), 7.42 (dd, 1H, J=4.7 and 8.2 Hz), 7.23 (t, 1H, J=8.8 Hz), 2.28 (s, 3H).LCMS: 97%, MS (m/e) 222.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[C:6]=1[F:17].Br[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][N:21]=1>>[F:17][C:6]1[C:7]2[C:12](=[CH:11][C:10]([F:16])=[CH:9][CH:8]=2)[C:13]([O:15][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:27])=[O:28])=[CH:22][N:21]=2)=[CH:14][C:5]=1[CH2:4][C:3]([OH:2])=[O:18]
Reactant: CCS(=O)(=O)c1ccc(Br)nc1
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1F
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)c(F)c3ccc(F)cc23)nc1
Yield: 12.4 %

Procedure:
Starting with (1,6-difluoro-4-hydroxy-naphthalen-2-yl)acetic acid methyl ester (50 mg, 0.198 mmol) and 2-bromo-5-ethanesulfonyl-pyridine (52 mg, 0.208 mmol), using a method analogous to the one described for example 4-1, [1,6-difluoro-4-(5-ethanesulfonyl-pyridin-2-yloxy)-naphthalen-2-yl]-acetic acid (10 mg, 12%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (d, 1H), 8.34 (dd, 1H), 8.19 (dd, 1H), 7.42-7.76 (m, 4H), 3.78-3.86 (m, 2H), 3.37-3.40 (m, 2H), 1.12 (t, 3H); MS cald. for C19H15F2NO5S 407, obsd. (ESI+) [(M+H)+] 408.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14])([O-])=O.C(O)C.[H][H]>CCOCC.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14]
Reactant: [H][H]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: Nc1cccc(C(=O)O)c1C(=O)O
Yield: 84 %

Procedure:
After a mixture of 10% Pd/C (2.5 g), 3-nitrophthalic acid (75.0 g, 355 mmol) and ethanol (1.5 L) was charged to a 2.5 L Parr hydrogenator under nitrogen, hydrogen was charged to the reaction vessel for up to 55 psi (379 kPa). The mixture was shaken for 13 hours while the hydrogen pressure was maintained at between 50 psi (245 kPa) and 55 psi (379 kPa). Hydrogen was released and the mixture was purged with nitrogen 3 times. The suspension was filtered through a celite bed and rinsed with methanol. The filtrate was concentrated in vacuum to yield a solid. The solid was suspended in ether and isolated by vacuum filtration. The solid was dried in vacuum to a constant weight to afford 54 g (84% yield) of 3-aminopthalic acid as a yellow product. The product in DMSO-d6 was characterized by a 1H NMR spectrum showing the following chemical shifts (δ in ppm): 3.17 (s, 2H), 6.67 (d, 1H), 6.82 (d, 1H), 7.17 (t, 1H), 8-10 (brs, 2H). The product in DMSO-d6 was characterized by a 13C-NMR spectrum showing the following chemical shifts (δ in ppm): 112.00, 115.32, 118.20, 131.28, 135.86, 148.82, 169.15, 170.09.
Reaction SMILES: C(N(CC)CC)C.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH2:16]([O:23][C:24]([N:26]1[CH2:30][C@H:29]([O:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH2:28][C@H:27]1[CH2:42][OH:43])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:16]([O:23][C:24]([N:26]1[CH2:30][C@H:29]([O:31][S:32]([C:35]2[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH2:28][C@H:27]1[CH2:42][O:43][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](CO)N(C(=O)OCc3ccccc3)C2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
37.4 ml (269 mmol) of triethylamine, 38.76 g (257 mmol) of t-butyldimethylsilyl chloride and 2.99 g (24.5 mmol) of 4-dimethylaminopyridine were added, in turn, to a solution of 104.98 g (245 mmol) of (2S,4R)-1-benzyloxycarbonyl-2-hydroxymethyl-4-(p-toluenesulfonyloxy)pyrrolidine [obtained as described in Preparative Example 12(i)′ above] in 610 ml of methylene chloride, and the resulting mixture was then stirred at room temperature overnight. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was partitioned between ethyl acetate and water. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was purified by chromatography on a silica gel column using a 1:1 by volume mixture of hexane and ethyl acetate as the eluant to afford 119.34 g (yield: 94%) of (2S,4R)-1-benzyloxycarbonyl-2-(t-butyldimethylsilyloxy)methyl-4-(p-toluenesulfonyloxy)pyrrolidine as a yellow oil.
Reaction SMILES: Cl.[CH2:2]([NH:6][CH2:7][C:8]([O:10]CC)=[O:9])[CH:3]([CH3:5])[CH3:4].Cl.[OH-].[Na+].[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:6]([CH2:7][C:8]([OH:10])=[O:9])[CH2:2][CH:3]([CH3:4])[CH3:5])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CCOC(=O)CNCC(C)C
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)CN(CC(=O)O)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of isobutylamino-acetic acid, ethyl ester hydrochloride (0.359 g, 0.00183 mol) in. 6 M hydrochloric acid (10 mL) was refluxed for 20 hours and allowed to cool. The mixture was made basic with 50% wt/wt sodium hydroxide and 1 M sodium hydroxide to pH=5, and the volatiles were rotary evaporated. The residue was triturated 3 times with boiling methanol, and the triturates were combined and rotary evaporated. The residue was triturated 3 times with hot acetic acid, and the triturates were combined and rotary evaporated. The residue was dissolved in water and freeze-dried to give a white solid. This solid was combined with 4-fluoro-benzenesulfonyl chloride (0.3334 g, 0.001713 mol) and sodium carbonate (0.547 g, 0.00516 mol) in water, and the mixture was stirred at room temperature for 3 days. The mixture was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was dried (MgSO4) and rotary evaporated to a white solid. The solid was chromatographed on silica gel (15 g, 230-400 mesh) eluting with dichloromethane-methanol (10:1, 10×15 mL). Fractions containing product were combined and rotary evaporated to give a white solid. The solid was dried in vacuo; yield 0.32 g (64% overall).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:8]=[C:7]([CH2:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][C:4]=1[S:13](Cl)(=[O:15])=[O:14]>O1CCCC1>[Cl:2][C:3]1[CH:8]=[C:7]([CH2:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][C:4]=1[S:13]([NH2:1])(=[O:15])=[O:14]
Reactant: N
Reactant: CC(=O)Cc1ccc(S(=O)(=O)Cl)c(Cl)c1
Solvent: C1CCOC1
Product: CC(=O)Cc1ccc(S(N)(=O)=O)c(Cl)c1

Procedure:
Aqueous ammonia solution (5 ml) is added to a stirred solution of the crude sulfonyl chloride (23b) (0.70 g, 2.62 mmol) in tetrahydrofuran (100 ml) at 0° C. After 2 hours the reaction mixture is concentrated in vacuo. The residue is diluted with water (100 ml) and extracted with ethyl acetate (100 ml). The organic extract is dried (MgSO4) and the solvent removed to give an oil. Purification by chromatography on silica, eluting with ethyl acetate, affords the title compound (0.154 g).