Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1Cl)([O-:3])=[O:2].C(N(CC)C(C)C)C.[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>ClCCl>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][N:29]([C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: CCN(CC)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccncc2[N+](=O)[O-])CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Nitro-4-Chloro pyridine (10 mmol) dissolved in dichloromethane (25 mL) and diethyl iso propyl amine (20 mmol) followed Boc piperazine(10 mmol) was added to the above solution while cooling at 0° C. and the reaction mixture was stirred at room temperature for overnight . The dichloromethane was evaporated under vacuum. The resulting solid is extracted in to dichloromethane and washed with citric acid and brine solution. The evaporation of dichloromethane gave a yellow solid, 4-(3-Nitro-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester which is used for next step without purification.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.P(=O)([O-])[O-].[K+].[K+].Br[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[F:21])[NH2:17]>O.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH:1]1([C:14]2[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=2[F:21])[NH2:17])[CH2:3][CH2:2]1
Reactant: OB(O)C1CC1
Reactant: Nc1ccc(F)c(Br)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(F)c(C2CC2)c1
Temperature: 100 °C
Reaction time: 15 h
Yield: 65.4 %

Procedure:
558 mg of cyclopropylboronic acid, 3.7 g of tribasic potassium phosphonate, 70 mg of tricyclohexylphosphane and 56 mg of palladium(2+) diacetate in 1.5 ml of water are added to a solution of 950 mg of 3-bromo-4-fluoroaniline in 20 ml of toluene, with stirring and under argon. The mixture is degassed and then heated to a temperature of 100° C. After 15 hours, the reaction medium is cooled to a temperature in the region of 20° C., run into 100 ml of water, and then extracted with four times 60 ml of diethyl ether. The combined organic phases are dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified on a silica column, eluent: 7030 cyclohexaneethyl acetate. 494 mg of 3-cyclopropyl-4-fluoroaniline are obtained in the form of a brown oil, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20]>>[NH2:16][C:15]1[CH:14]=[C:13]([C:19]([F:21])([F:22])[F:20])[C:12]([O:11][CH3:10])=[CH:18][C:17]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: COc1ccc(N)cc1C(F)(F)F
Reactant: O=Cc1ccccc1Cl
Product: COc1cc(C(=O)c2ccccc2Cl)c(N)cc1C(F)(F)F

Procedure:
(2-amino-5-methoxy-4-trifluoromethylphenyl)-(2-chlorophenyl)-methanone (Xee) was prepared by reacting 2-chlorobenzaldehyde with 0.0263 moles of 4-methoxy-3-trifluoromethyl aniline in a manner analogous to Example 1. MH+/Z=330.
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][C:35]#[CH:36]>CN(C=O)C.[Cu](I)I>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][C:35]#[C:36][C:12]1[CH:13]=[CH:14][C:9]([S:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:8])=[O:7])=[CH:10][CH:11]=1
Reactant: C#CCCOCCCCCCBr
Reactant: O=S(=O)(c1ccc(Br)cc1)C1CCCC1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(C#CCCOCCCCCCBr)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A stirred solution of 4-bromophenyl cyclopentyl sulfone (EP683172 A1) (0.5 g) and N,N-diisopropylethylamine (3.33 ml) in DMF (15 ml) was treated with dichlorobis(triphenylphosphine) palladium (II) (50 mg) and copper iodide (13.68 mg). The solution was heated to 70° under nitrogen and a solution of 4-[(6-bromohexyl)oxy]but-1-yne (DE 3513885 A1) and N,N-diisopropylethylamine (1.66 ml) in DMF (5 ml) was added dropwise. The mixture was stirred at 70° for 19 h. The reaction mixture was cooled to room temperature, poured onto water and extracted 3 times with EtOAc. The extracts were dried (MgSO4) and evaporated in vacuo. The residual oil was purified on a silica SPE bond elut cartridge (100 g), using a gradient of 0% to 30% diethyl ether in cyclohexane (Gradmaster™). The appropriate fractions were evaporated to give the title compound (280 mg). LCMS RT=3.93 min
Reaction SMILES: [F:1][C:2]1([C:20]([O:22]CC)=[O:21])[CH2:7][CH2:6][N:5]([CH:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[Li+].[OH-].Cl>C1COCC1>[CH2:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][CH:8]([N:5]2[CH2:4][CH2:3][C:2]([F:1])([C:20]([OH:22])=[O:21])[CH2:7][CH2:6]2)[CH2:9][CH2:10]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)N1CCCC(N2CCC(F)(C(=O)OCC)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCCC(N2CCC(F)(C(=O)O)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 148.1 %

Procedure:
Ethyl 4-[4-fluoro-4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (2.26 g, 6.85 mmol) was dissolved in THF (60 mL) at rt and 1M LiOH sol. (6.5 mL) was added. The reaction mixture was stirred at rt overnight. The pH was carefully adjusted to pH 6 by addition of concentrated hydrochloric acid, the solvents were removed in vacuo, to give 1-[1-(ethoxycarbonyl)azepan-4-yl]-4-fluoropiperidine-4-carboxylic acid (3.21 g) as a white waxy solid, Intermediate 3, which was used crude in subsequent reactions.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=3[N:10]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:11](=[O:14])[CH2:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:48]=[N+:49]=[N-:50])(=O)=O)(C)C.C(O)(=O)C.C([O-])(O)=O.[Na+]>C1COCC1>[N:48]([CH:12]1[C:11](=[O:14])[N:10]([CH2:15][C:16]([F:18])([F:19])[F:17])[C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:13]1)=[N+:49]=[N-:50]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: O=C1CN=C(c2ccccc2)c2ccccc2N1CC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: [N-]=[N+]=NC1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of 5-phenyl-1-(2,2,2-trifluoroethyl)-1H-benzo[e][1,4]diazepine-2-one (66 g,0.209 mole) in THF (1200 mL) cooled to -78° C. was added potassium tert-butoxide (229 mL of a 1N solution in THF dropwise over 30 min. A solution of the anion was obtained. A solution of 2,4,6-triisopropylbenzenesulfonylazide (71 g, 0.229 mole) in THF (200 mL) was added over 20 min. This was stirred for 10 min, acetic acid (50 g, 48 ml, 0.834 mole) was added and the reaction allowed to warm to ambient temperature over 4 hours. The reaction was poured into sat. NaHCO3 (1 L) and extracted with ethyl acetate (2×500 mL). The organic layers were combined, washed once with water then brine, dried with Na2 SO4 and evaporated at reduced pressure. The residue was dissolved in THF (500 mL) and then filtered to give a solid which was discarded. The solution of crude azide was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32](=[O:35])[N:31]([CH3:36])[CH:30]=3)=[CH:25][CH:24]=2)=[CH:4][C:5]2[N:9]=[C:8]([O:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=3)[C:16]([O:18]C)=[O:17])[NH:7][C:6]=2[CH:22]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:3]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][C:32](=[O:35])[N:31]([CH3:36])[CH:30]=3)=[CH:27][CH:28]=2)=[CH:4][C:5]2[N:9]=[C:8]([O:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=3)[C:16]([OH:18])=[O:17])[NH:7][C:6]=2[CH:22]=1
Reactant: COC(=O)c1cc(Oc2nc3cc(-c4ccc(-c5ccc(=O)n(C)c5)cc4)c(Cl)cc3[nH]2)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(Oc2nc3cc(-c4ccc(-c5ccc(=O)n(C)c5)cc4)c(Cl)cc3[nH]2)cc1C(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Methyl 5-({6-chloro-5-[4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1H-benzimidazol-2-yl}oxy)-2-methylbenzoate (43 mg, 0.086 mmol) was dissolved in MeOH (1.7 mL). Then 2.5 M aqueous NaOH (0.5 mL, 1.250 mmol) was added, and the reaction was stirred at 50° C. for 2 h. The reaction mixture was concentrated, and then partitioned between EtOAc and water. The aqueous phase was acidified to pH=1 with 2 N aqueous HCl and extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated to give the desired product as an off-white solid. LC-MS: calculated for C27H20ClN3O4 485.11, observed m/e 486.25 (M+H)+ (Rt: 1.85 min). 1H NMR (500 MHz, C2D6OS): δ 8.20 (s, 1H), 7.90 (d, 1H), 7.80 (s, 1H), 7.65 (d, 2H), 7.55 (s, 1H), 7.45-7.50 (m, 3H), 7.41 (d, 1H), 7.35 (s, 1H), 6.5 (d, 1H), 3.5 (s, 3H). 2.55 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[C:14]([O:16][Si](C(C)(C)C)(C)C)[CH:13]=[CH:12][C:11]=2[F:24])[OH:9])=[C:4]([Cl:25])[CH:3]=1.C(#N)C.C[N+]1([O-])CCOCC1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=2[F:24])=[O:9])=[C:4]([Cl:25])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(C(O)c2ccc(Br)cc2Cl)c1
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: O=C(c1cc(O)ccc1F)c1ccc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Compound 510 (15.9 g, 35.6 mmol) was dissolved in dry DCM (80 mL) and dry acetonitrile (10 mL) under an argon atmosphere. The mixture was cooled to 0° C. and added 4-methyl-morpholine 4-oxide (6.27 g, 53.5 mmol), grinded molecular sieve (4 Å, 17.8 g). Tetra-N-propylammonium perruthenate (VII) (250 mg, 0.71 mmol) was added in 5 portions (5×50 mg) and the reaction mixture was stirred for 10 min. at 0° C., evaporated to ⅓ volume and filtered through silica. The silica was washed with EtOAc (300 mL). The organic phase was concentrated in vacuo affording the crude product. Purified by continuously gradient flash chromatography using EtOAc/petroleum ether (40-60)(v:v=1:80 to 1:10) as the eluent, affording the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH2:5]2.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:28]([O:30][CH:31]([O:35][CH2:36][CH3:37])[CH:32](Cl)[CH3:33])[CH3:29]>CN(C=O)C.O>[C:16]1([CH2:15][CH2:14][CH2:13][N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:33][CH2:32][CH:31]([O:35][CH2:36][CH3:37])[O:30][CH2:28][CH3:29])[CH:3]=3)[C:8]2=[O:12])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(OCC)C(C)Cl
Reactant: O=C1c2ccc(O)cc2CCN1CCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CCOc1ccc2c(c1)CCN(CCCc1ccccc1)C2=O)OCC

Procedure:
A solution of 6-hydroxy-2-(3-phenylpropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline (7.55 g, 26.87 mmol), Cs2CO3 (18 g, 53.74 mmol) and chloropropionaldehyde diethyl acetal (5.4 mL, 32.2 mmol) in DMF (100 mL) is stirred for 48 hours. After this time the reaction is diluted with H2O (400 mL) and the resulting mixture extracted with EtOAc (2×200 mL). The combined organic phases are washed with saturated NaCl solution (2×400 mL), dried over MgSO4 and concentrated in vacuo. The residue is chromatographed (silica gel, 1:9 EtOAc/hexane) to give 2-(3-phenylpropyl)-6-(3,3-diethoxypropyloxy)-1-oxo-1,2,3,4-tetrahydroisoquinoline which is hydrolyzed with 6N HCl in tetrahydrofuran at room temperature to yield β-[2-(3-phenylpropyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy]-propionaldehyde
Reaction SMILES: [C:1]([NH:5][Si:6](Cl)([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].[CH3:10][C:11]([CH:13]=[C:14]([CH3:16])[CH3:15])=[CH-:12].[K+]>C1COCC1>[C:1]([NH:5][Si:6]([CH3:8])([CH3:7])[CH2:12][C:11]([CH3:10])=[CH:13][C:14]([CH3:16])=[CH2:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: [CH-]=C(C)C=C(C)C
Reactant: CC(C)(C)N[Si](C)(C)Cl
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)C=C(C)C[Si](C)(C)NC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of 0.612 g (3.69 mmol) of (N-t-butylamino)(chloro)dimethylsilane in 50 mL of THF was added 0.500 g (3.72 mmol) of potassium 2,4-dimethylpentadienide (prepared in a manner similar to that reported in J. Am. Chem. Soc. 1978, 100, 3258). The reaction mixture was stirred overnight. The solvent was removed, the residue was extracted with pentane and filtered. The pentane was removed in vacuo to give the product as a pale yellow oil. The yield was 0.733 g, 88.2 percent. 1H NMR (C6D6) δ 5.64 (s, 1H), 5.01 (s, 1H), 4.97 (s, 1H), 1.88(s, 2H), 1.85(s, 3H), 1.76(s, 3H), 1.09(s, 9H), 0.17 (s, 6H). 13C NMR (C6D6) δ 142.7, 136.5, 125.3, 113.2, 49.5, 34.0, 27.9, 26.5, 24.6, 2.8.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:15]([NH:17][C@H:18]([C:27]([NH:29][C@@H:30]([C:32]([NH:34][C@H:35]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH:37]([CH3:39])[CH3:38])=[O:33])[CH3:31])=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:16])[CH2:13][OH:14])=O)C1C=CC=CC=1.[ClH:44].O.[H][H]>CO.[Pd]>[ClH:44].[NH2:11][C@H:12]([C:15]([NH:17][C@H:18]([C:27]([NH:29][C@@H:30]([C:32]([NH:34][C@H:35]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH:37]([CH3:38])[CH3:39])=[O:33])[CH3:31])=[O:28])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)=[O:16])[CH2:13][OH:14]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CO

Procedure:
A solution of 3 g. of Nα -benzyloxycarbonyl-L-seryl-L-tyrosyl-D-alanyl-L-leucine, methyl ester in 100 ml. of methanol containing 3.7 ml. of 1.35 N hydrogen chloride in methanol is stirred with 200 mg. of 20% palladium on carbon under one inch of water pressure of hydrogen for three hours. Thin layer chromatography of samples of the solution shows disappearance of the starting material in about two hours. The reaction mixture is filtered to remove the catalyst and the filtrate evaporated at 30°-40° C. to yield the product as a foam. The product is used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[O:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:26]1([O:25][C:19]2[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([NH:16][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=3)[CH2:7]2)=[O:30])[CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccc(F)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccc(F)cc3C2)c1OC1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
The mixture of 2-(2-cyclobutoxy-3-methyl-benzoylamino)-5-fluoro-indan-2-carboxylic acid ethyl ester (102) (510 mg, 1.24 mmol) and KOH (1 g, 18 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give a pure product (103) as white solid (469 mg, 99%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].BrBr.[Na].Cl.C[OH:16]>[Cl-].[Al+3].[Cl-].[Cl-].CCOCC>[C:5]1([C:1](=[O:4])[C:2](=[O:16])[CH3:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCC(=O)c1ccccc1
Reactant: CO
Agent: BrBr
Agent: Cl
Agent: [Al+3]
Solvent: CCOCC
Product: CC(=O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
6.0 kg (44.78 moles) of propiophenone and 92 g of anhydrous aluminum chloride were added to 6 liters of ether followed by 17.2 kg (107.5 mole) of bromine at a rate to maintained a gentle reflux. When the addition was complete (approximately 6 hours), the mixture was heated to reflux overnight and then the solvent was removed under vacuum to obtain a lachrymatory dark red/orange oil. The oil was slowly added to a solution of 2.81 kg (122.2 mmole)of sodium in 45 l of methanol while maintaining the temperature below 20° C. When the addition was complete, 12.5 liters of concentrated hydrochloric acid were added and the mixture was stirred at room temperature for 1 hour. The precipitate was filtered off and the filtrate reduced in volume to approximately 25 liters by distillation of the methanol. The residue was partitioned between 10 liters of chloroform and 10 liters of water. Then, the organic phase was separated and the aqueous phase extracted twice with 5 liters of chloroform. The combined chloroform solutions were dried over sodium sulfate and evaporated to dryness. The residue was fractionally distilled under vacuum through a 30 cm Fenske column to obtain 5.7 kg of 1-phenylpropane-1,2-dione (86% yield) and a boiling point of 77°-85° C. at 1-2 mm Hg.
Reaction SMILES: [CH3:1][C@@:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@H:19]4[CH2:24][CH2:23][C@@H:22]([C:25]([F:28])([F:27])[F:26])[CH2:21][CH2:20]4)[CH:14]=3)[CH:9]=2)[CH2:6][O:5]C(=O)[NH:3]1.[OH-].[Li+].C(O)C>>[NH2:3][C@@:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@H:19]3[CH2:24][CH2:23][C@@H:22]([C:25]([F:26])([F:27])[F:28])[CH2:21][CH2:20]3)[CH:14]=2)[CH:9]=1)([CH3:1])[CH2:6][OH:5]
Reactant: C[C@@]1(c2ccc3cc(O[C@H]4CC[C@@H](C(F)(F)F)CC4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: C[C@](N)(CO)c1ccc2cc(O[C@H]3CC[C@@H](C(F)(F)F)CC3)ccc2c1

Procedure:
The mixture of (R)-4-Methyl-4-[6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-oxazolidin-2-one (30.6 mg, 0.0000778 mol) and 4.20 M aqueous lithium hydroxide (0.300 mL, 0.00126 mol) and ethanol (0.900 mL, 0.0154 mol) was heated to reflux for 4.5 h. The reaction was evaporated to remove organics. The aqueous phase was extracted with methylene chloride, and the organics were evaporated. The residue was purified by silica gel chromatography using 0-100% methanol in methylene chloride to yield the product in 13.4 mg yield (47%). MS: m/z=351.20 [M-NH2]+. 1H NMR (400 MHz, METHANOL-d4) δ ppm: 7.87 (d, J=2.0 Hz, 1H), 7.80 (d, J=9.0 Hz, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.57 (dd, J=8.5, 2.0 Hz, 1H), 7.25 (d, J=2.3 Hz, 1H), 7.18 (dd, J=8.8, 2.5 Hz, 1H), 4.77-4.82 (m, 1H), 3.74 (d, J=10.8 Hz, 1H), 3.70 (d, J=10.8 Hz, 1H), 2.25-2.34 (m, 1H), 2.18-2.25 (m, 2H), 1.65-1.88 (m, 6H), 1.54 (s, 3H).
Reaction SMILES: CC(OC([NH:8][C:9]1[C:14]([C:15]([O:17]C)=[O:16])=[C:13]([F:19])[C:12]([F:20])=[CH:11][CH:10]=1)=O)(C)C.FC(F)(F)C(O)=O.[OH-].[Li+].Cl>C(Cl)Cl.C(OCC)(=O)C.O>[NH2:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([F:19])[C:12]([F:20])=[CH:11][CH:10]=1
Reactant: COC(=O)c1c(NC(=O)OC(C)(C)C)ccc(F)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(F)c(F)c1C(=O)O
Reaction time: 8 h
Yield: 114.6 %

Procedure:
To a solution of methyl 6-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2,3-difluorobenzoate (5.5 g, 19.2 mmol) in methylene chloride (150 mL) was added trifluoroacetic acid (25 mL, Aldrich). The resulting solution was stirred overnight and then concentrated to an oily residue under reduced pressure. The oil was dissolved in tetrahydrofuran (150 mL) and water (100 mL) and lithium hydroxide (2.3 g, 100 mmol, 5 equiv.) were added. The resulting mixture was rapidly stirred overnight. The next morning the reaction was poured into ethyl acetate and 1.0N HCl was added until the pH is adjusted to 7. The organic layer was washed twice with brine and taken to a residue under reduced pressure to afford 6-amino-2,3-difluorobenzoic acid (3.78 g, 22 mmol) of sufficient purity for use directly in the next transformation. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.51 (ddd, J=9.35, 4.22, 2.20 Hz, 1 H), 7.21-7.31 (m, 1 H), 8.71 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13]Cl)[CH:6]=[C:5]2[CH:15]=[O:16].[I-:17].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][I:17])[CH:6]=[C:5]2[CH:15]=[O:16]
Reactant: [I-]
Reactant: O=Cc1cn(CCCCl)c2ccc(Cl)cc12
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1cn(CCCI)c2ccc(Cl)cc12
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A stirred solution of 5-chloro-1-(3-chloropropyl)indole-3-carboxaldehyde (3.8 g, 15 mmol) and sodium iodide (4.5 g, 30 mmol) in acetonitrile (50 mL) under argon was heated under reflux for 18 h, cooled to room temperature and partitioned between ether (3×30 mL) and water (50 mL). The combined organic extracts were washed (aqueous sodium metabisulfite solution, water, brine), dried (sodium sulfate) and concentrated in vacuo to give the product as a yellow oil (5.0 g, 96%) which was used immediately.
Reaction SMILES: CCN(CC)CC.[C:8]([O:11][CH2:12][C:13]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=O)=O)(=[O:10])[CH3:9].[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1.Cl>CCO>[C:8]([O:11][CH2:12][C:13]1[N:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[N:30]=[C:16]2[C:15]=1[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:10])[CH3:9]
Reactant: CC(=O)OCC(=O)C1CCCCC1=O
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)OCc1c2c(nn1-c1ccc(F)cc1)CCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.8 %

Procedure:
Et3N (0.717 mL, 0.520 g, 5.14 mmol) was added to a stirring suspension of 1.00 g (5.04 mmol) of 2-acetoxyacetylcyclohexanone (Dolmazon, R.; Gelin, S. J. Heterocyclic Chem., 1982, 19, 117-121) and 0.820 g (5.04 mmol) of 4-fluorophenylhydrazine·HCl in 20 mL of absolute EtOH. The resulting solution was stirred under N2 for 4 h at room temperature and refluxed for 6 h. The mixture was concentrated and the residue was partitioned between 100 mL of Et2O and 50 mL of dilute aqueous HCl. The Et2O layer was washed with water, saturated aqueous NaHCO3, and brine. After drying over Na2SO4, the solution was concentrated to give 1.43 g of light brown solid. Recrystallization from EtOAc:hexanes afforded 0.753 g (52%) of the title compound as a white solid, m.p. 128.5°-129.5° C.; 1H NMR (CDCl3, 400 MHz) 1.85 (m, 4), 2.07 (s, 3), 2.60 (t, 2, J=6 Hz), 2.73 (t, 2, J=6 Hz), 5.00 (s, 2), 7.15 (t, 2, J=9 Hz), 7.45 (dd, 2, J=5, 9 Hz); IR (KBr) 1740, 1220 cm-1 ; MS (DCI) m/z 289 (base), 228 . Anal. Calcd. for C16H17FN2O2 : C, 66.65; H, 5.94; N, 9.72. Found: C, 66.74; H, 5.89; N, 9.61.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([F:22])[CH:16]=1>>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[C:3]([C:11]([OH:13])=[O:12])=[CH:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=2[CH3:8])=[C:17]([F:22])[CH:16]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: Cc1c(Cl)c(C(=O)O)cn(C)c1=O
Product: Cc1c(Nc2ccc(Br)cc2F)c(C(=O)O)cn(C)c1=O

Procedure:
The title compound is prepared from 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid by the procedure described in step e for Example 5, using 4-bromo-2-fluoroaniline instead of 2-fluoro-4-iodoaniline The title compound is used for the next reaction without further purification.