Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Sb](F)(F)(F)(F)[F:2].FC(O[C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18])=O>>[CH3:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]=1[F:2]
Reactant: F[Sb](F)(F)(F)F
Reactant: Cc1cccc(C)c1OC(=O)F
Product: Cc1cccc(C)c1F
Temperature: 200 °C
Yield: 40 %

Procedure:
3.9 g of antimony pentafluoride were added to 100 g of 2,6-dimethylphenyl fluoroformate and the mixture was heated at 200° C. for 5 hours at normal pressure. The reaction mixture was then cooled and worked up as described in Example 1. 2,6-Dimethylfluorobenzene was obtained in a yield of 40%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([NH:10][S:11]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])(=[O:13])=[O:12])[C:7]([OH:23])=[C:6]([Cl:24])[CH:5]=1.Br[CH2:27][CH2:28]Br>>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([Cl:24])[C:7]2[O:23][CH2:28][CH2:27][N:10]([S:11]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[O:21][CH3:22])(=[O:13])=[O:12])[C:8]=2[CH:9]=1)=[O:25]
Reactant: COC(=O)c1cc(Cl)c(O)c(NS(=O)(=O)c2cc(Cl)ccc2OC)c1
Reactant: BrCCBr
Product: COC(=O)c1cc(Cl)c2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCO2

Procedure:
The title compound, MS (ISP)=534.8 (M−H)−, was produced in analogy with example 36, steps 1-4. Step 1 was performed using 3-chloro-5-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acid methyl ester (example 50, step 2) and 1,2-dibromoethane, yielding 8-chloro-4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 2 to afford 8-chloro-4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 4-aminobenzoate in step 3 to produce 4-{[8-chloro-4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 4.
Reaction SMILES: CO[C:3]([CH:5]1[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[S:8](=[O:15])(=[O:14])[N:7]([CH3:16])[C:6]1=[O:17])=[O:4].[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>C1(C)C(C)=CC=CC=1>[CH3:16][N:7]1[C:6](=[O:17])[CH:5]([C:3](=[O:4])[NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[S:8]1(=[O:14])=[O:15]
Reactant: COC(=O)C1C(=O)N(C)S(=O)(=O)c2ccsc21
Reactant: Nc1nccs1
Solvent: Cc1ccccc1C
Product: CN1C(=O)C(C(=O)Nc2nccs2)c2sccc2S1(=O)=O

Procedure:
0.15 G. of 3,4-dihydro-4-methoxycarbonyl-2-methyl-3-oxo-2H-thieno[ 2,3-e] 1,2-thiazine 1,1-dioxide and 0.071 g. of 2-aminothiazole are dissolved in 30 ml. of absolute xylene and the solution is heated for half an hour under the reflux. After cooling, the crystals are removed by filtration, recrystallized from glacial acetic acid, and 3,4-dihydro-2-methyl-3-oxo-4-(2-thiazolyl-carbamoyl)2H-thieno[ 2,3-e] 1,2-thiazine 1,1-dioxide, melting point 236° C. to 238° C. (decomposition), is obtained.
Reaction SMILES: [C:1]([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12][C:13](=[O:16])[CH2:14][CH3:15])[O:9][C@@H:8]([N:17]2[CH:24]=[C:23]([F:25])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:7]1)(=[O:4])[CH2:2][CH3:3].C(N(CC)CC)C.[F:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38]>O1CCOCC1>[F:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([N:20]1[C:21](=[O:22])[C:23]([F:25])=[CH:24][N:17]([C@@H:8]2[O:9][C@H:10]([CH2:11][O:12][C:13](=[O:16])[CH2:14][CH3:15])[C@@H:6]([O:5][C:1](=[O:4])[CH2:2][CH3:3])[CH2:7]2)[C:18]1=[O:19])=[O:38]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(=O)CC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3cccc(F)c3)c2=O)C[C@@H]1OC(=O)CC
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
2.0 Grams of 2'-deoxy-3',5'-di-O-propionyl-5-fluorouridine are dissolved in 25 ml of dry dioxane and the solution is ice cooled. 2 Milliliters of triethylamine and 1.8 g of 3-fluorobenzoyl chloride are added to the solution and the mixture is subjected to reaction at room temperature for 15 minutes and then at 60° C. for 30 minutes. The reaction liquid is worked up in the same manner as described in Example 1 whereby 2.05 g (yield: 71.5%) of powdery 3-(3-fluorobenzoyl)-2'-deoxy-3', 5'-di-O-propionyl-5-fluorouridine are obtained.
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.[C:29]([C:31]1[CH:32]=[C:33]([NH:37][C:38](=[O:53])[O:39][CH2:40][CH2:41][C:42]2[C:47]([CH2:48][CH3:49])=[CH:46][C:45](Br)=[CH:44][C:43]=2[CH2:51][CH3:52])[CH:34]=[CH:35][CH:36]=1)#[N:30]>>[C:29]([C:31]1[CH:32]=[C:33]([NH:37][C:38]([O:39][CH2:40][CH2:41][C:42]2[C:47]([CH2:48][CH3:49])=[CH:46][C:45]([B:25]([OH:27])[OH:26])=[CH:44][C:43]=2[CH2:51][CH3:52])=[O:53])[CH:34]=[CH:35][CH:36]=1)#[N:30]
Reactant: CCc1cc(Br)cc(CC)c1CCOC(=O)Nc1cccc(C#N)c1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Product: CCc1cc(B(O)O)cc(CC)c1CCOC(=O)Nc1cccc(C#N)c1
Yield: 45 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 37D (670 mg, 1.7 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 37E (278 mg, 45%) as a brown oil. 1H NMR (400 MHz, CD3OD) δ ppm 1.16 (t, J=7.45 Hz, 6 H) 2.68 (q, J=7.41 Hz, 4 H) 3.03 (t, J=7.83 Hz, 2 H) 4.14 (t, J=7.82 Hz, 2 H) 7.13-7.29 (m, 2 H) 7.30-7.45 (m, 2 H) 7.59 (d, J=7.83 Hz, 1 H) 7.80 (s, 1 H) 9.42 (s, 1 H).
Reaction SMILES: CO[C:3]1[C:8]([C:9]#[N:10])=[C:7]([CH3:11])[N:6]=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13]>P(Cl)(Cl)(Cl)=O>[Cl:13][C:3]1[C:8]([C:9]#[N:10])=[C:7]([CH3:11])[N:6]=[CH:5][CH:4]=1
Reactant: COc1ccnc(C)c1C#N
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nccc(Cl)c1C#N
Reaction time: 0.17 h
Yield: 34.2 %

Procedure:
To 4-methoxy-2-methylnicotinonitrile (Tet 6222, 2006) (100 mg, 0.67 mmol) in phosphoryl chloride (2 mL) was added phosphorus pentachloride (156 mg, 0.75 mmol). The mixture was heated to reflux under nitrogen for 15 h. The reaction was quenched with ice, stirred for 10 min, then neutralised with NaHCO3 and extracted with EtOAc. The combined organic extracts were dried (Na2SO4), evaporated to dryness and purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane). Product containing fractions were evaporated to give the title compound as a pale pink solid, (35 mg, 34%). 1H NMR δ (ppm) (CDCl3-d): 8.56 (1H, d, J=5.46 Hz), 7.32 (2H, d, J=5.46 Hz), 2.81 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][C:13]3[N:17]=[CH:18][C:19]([C:21]4[O:25][N:24]=[C:23]([C:26](Cl)=[O:27])[N:22]=4)=[CH:20][C:12]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:38]1([NH2:43])[CH2:42][CH2:41][CH2:40][CH2:39]1.C([O-])(O)=O.[Na+]>ClCCCl>[CH:38]1([NH:43][C:26]([C:23]2[N:22]=[C:21]([C:19]3[CH:18]=[N:17][C:13]4[O:14][CH2:15][CH2:16][N:11]([S:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)(=[O:10])=[O:9])[C:12]=4[CH:20]=3)[O:25][N:24]=2)=[O:27])[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: NC1CCCC1
Reactant: O=C(Cl)c1noc(-c2cnc3c(c2)N(S(=O)(=O)c2ccc(F)cc2)CCO3)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(NC1CCCC1)c1noc(-c2cnc3c(c2)N(S(=O)(=O)c2ccc(F)cc2)CCO3)n1
Reaction time: 72 h
Yield: 32.7 %

Procedure:
To a suspension of 5-(1-(4-fluorophenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-1,2,4-oxadiazole-3-carbonyl chloride (21 mg, 0.049 mmol) in DCE (5 mL) was added DIPEA (21 μL, 120 μmol) to form a clear solution. To that solution was added cyclopentyl amine (40 μL, 0.099 mmol) and saturated aqueous NaHCO3 (1 mL). The reaction was stirred for 72 hours. LCMS analysis of the reaction mixture indicated consumption of starting material. The reaction was extracted with DCM (3×2 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting solid was purified by flash column chromatography to provide N-cyclopentyl-5-(1-(4-fluorophenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-1,2,4-oxadiazole-3-carboxamide (7.7 mg, 0.016 mmol, 32.2%) as a white solid. LCMS (+ESI) m/z=474.1 [M+H]+; 1H-NMR (CDCl3) δ 8.90 (d, 1H), 8.87 (d, 1H), 7.75 (m, 2H), 7.21 (m, 2H), 6.97 (m, 1H), 4.47 (m, 1H), 4.09 (dd, 2H), 3.92 (dd, 2H), 2.13 (m, 2H), 1.82-1.52 (m, 6H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:20]([CH2:23]Br)=[N:21][S:22][C:10]=2[C:9]=1[O:25]C(=O)C(C)(C)C)=[O:7])[CH2:2][CH2:3][CH3:4].[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33]1.[H-].[Na+].O>CN(C=O)C>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11]2[C:20]([CH2:23][N:32]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33]3)=[N:21][S:22][C:10]=2[C:9]=1[OH:25])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(-c2ccccc2)c2c(CBr)nsc2c1OC(=O)C(C)(C)C
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1nc(-c2ccccc2)c2c(Cn3ccc4ccccc43)nsc2c1O
Temperature: 25 °C
Yield: 14.1 %

Procedure:
To a solution of 3-bromomethyl-7-(2,2-dimethyl-propionyloxy)-4-phenyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester (86.1 mg) in DMF (0.85 mL) at 0° C. was added indole (39.9 mg) and 60% NaH (13.6 mg). The reaction mixture was allowed to warm up to r.t. and stirred for 2 h before water (20 mL) was added. The mixture was extracted with EtOAc (4×20 mL). The combined organic phases were washed with brine and water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel. Eluting with 1-50% EtOAc/hexanes gave the title compound (11 mg) as a white solid: MS (m/z) 458.2 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[N:22]=[C:21]([CH2:23][NH2:24])[CH:20]=[N:19][C:18]=1[O:25][CH2:26][C:27]([F:30])([F:29])[F:28]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:24]([CH2:23][C:21]3[CH:20]=[N:19][C:18]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[C:17]([CH3:16])[N:22]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1nc(CN)cnc1OCC(F)(F)F
Agent: Cl
Product: Cc1nc(CN2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Yield: 84 %

Procedure:
The title compound is prepared in 84% yield (560 mg, colorless solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and (6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methanamine hydrochloride (460 mg, 1.8 mmol, Amine-67) in a similar manner to Intermediate-2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:9]1[CH:10]=[C:11]([CH:15]2[O:19][CH2:18][CH2:17][O:16]2)[CH:12]=[CH:13][CH:14]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>CCOCC.C1(C)C=CC=CC=1>[O:16]1[CH2:17][CH2:18][O:19][CH:15]1[C:11]1[CH:10]=[C:9]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Brc1cccc(C2OCCO2)c1
Reactant: Nc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: c1ccc(Nc2cccc(C3OCCO3)c2)nc1

Procedure:
Combine 2-aminopyridine (8.25 g, 95 mmol), 2-(3-bromo-phenyl)-[1,3]dioxolane (13.8 mL, 90 mmol), sodium t-butoxide (12.2 g, 126 mmol), BINAP (210 mg, 0.62 mmol), Pd2(dbu)3 (630 mg, 0.21 mmol) and toluene (100 mL) and heat to reflux for 48 hours. Cool the reaction to room temperature, dissolve in ether and filter and concentrate the resulting solution. Purification by flash chromatography (hexanes/EtOAc (8.5:1.5) and then hexanes/EtOAc (7:3)) provides the title compound as a yellow oil.
Reaction SMILES: [F:1][CH:2]([CH3:14])[CH2:3][O:4][C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][N:6]=1>C1COCC1.CO.[Pd]>[F:1][CH:2]([CH3:14])[CH2:3][O:4][C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CC(F)COc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(F)COc1ncccc1N
Reaction time: 4 h

Procedure:
2-(2-fluoropropoxy)-3-nitropyridine (199.97 mg) was dissolved in a mixture of THF (10 ml) and methanol (5 ml). Pd/C (20 mg) was added and the mixture was hydrogenated at room temperature for 4 h and 3 bar. The mixture was concentrated in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12]1([CH2:15][NH2:16])[CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:16][CH2:15][CH:12]2[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: NCC1CC1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(Br)ccc1NCC1CC1
Temperature: 96 °C
Reaction time: 15 h
Yield: 105 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitrobenzene (9.25 g, 42 mmol), cyclopropanemethylamine (4.49 g, 63.1 mmol) and N,N-diisopropylethylamine (13.5 g, 105 mmol) in ethanol (100 mL) is stirred at 96° C. for 15 h. After cooling to room temperature, the mixture is concentrated under reduced pressure. The residue is purified by column chromatography (silica, eluent: ethyl acetate) to give 11.96 g of 4-bromo-N-(cyclopropylmethyl)-2-nitroaniline. Yield 100%, ES-MS: 271/273 [M+H].
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:12]([O:14]C)=O.O.[NH2:17][NH2:18]>CCO>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:12]([NH:17][NH2:18])=[O:14]
Reactant: COC(=O)c1cnc2cc(C)nn2c1N
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cc2ncc(C(=O)NN)c(N)n2n1
Temperature: 25 °C

Procedure:
A 250 mL flask containing the Methyl 7-amino-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (2.1 g, 20 mmol), EtOH (55 mL), and hydrazine hydrate (20 mL) was heated to reflux for 6 hours. The mixture was allowed to cool to room temperature. The precipitated solid was filtered and washed with water (2×10 mL) to provide Compound (10-1) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([NH:35]O)=[NH:34])=[CH:31][N:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[N:15]3[N:22]=[CH:23][C:24]([C:25]4[O:27][N:35]=[C:33]([C:32]5[CH:37]=[CH:38][C:29]([NH2:28])=[N:30][CH:31]=5)[N:34]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:9])[F:11]
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(Cl)c3)nc12
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)c(Cl)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 5-(3-chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.17) (205 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (90 mg, 34%). MS (ISP) 526.1 [(M+H)+]; mp 234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16]C(C)(C)C)=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:21][CH3:22].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:21][CH3:22]
Reactant: COc1cc(N2CCC(C(=O)OC(C)(C)C)CC2)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCC(C(=O)O)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of tert-butyl 1-(4-chloro-3-methoxyphenyl)piperidine-4-carboxylate (0.500 g, 1.535 mmol; this starting material was isolated as a reaction product in Example 1a, Step 1) in anhydrous CH2Cl2 (5 mL) was treated with trifluoroacetic acid (3 mL, 38.9 mmol) and the mixture stirred at RT for 2 h. After this time, the mixture was concentrated on the a rotary evaporator and the resultant residue was neutralized by first treating it with 2 M NaOH and then 0.1 M pH 7 phosphate buffer. The resultant mixture was extracted with EtOAc, and the extract was washed with brine, dried (MgSO4) and concentrated to give 1-(4-chloro-3-methoxyphenyl)piperidine-4-carboxylic acid (0.45 g, 1.668 mmol, >100% yield) as a pale yellow solid. LC-MS: 270, [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].CN(C=O)C.[Br:18][CH2:19][C:20](Br)=[O:21]>O1CCOCC1>[CH3:1][O:2][C:3]1[C:4]([NH:12][C:20](=[O:21])[CH2:19][Br:18])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: COc1cccc(C(=O)O)c1N
Reactant: O=C(Br)CBr
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1cccc(C(=O)O)c1NC(=O)CBr
Temperature: -5 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A solution of 3-methoxy-2-aminobenzoic acid (5.0 g, 30 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL-3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled with an ice-bath to -5° C. Bromoacetyl bromide (6.66 g, 2.90 mL, 30 mmol) was added dropwise, keeping the internal temperature between -5° to 0° C. over a 1/2 h period. After the addition of bromoacetyl bromide was completed, the solution was warmed to room temperature and then stirred overnight. To the solution was slowly added 150 mL of ice-water, causing a pale white solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum oven overnight to afford 6.26 g (72%) of the title compound as a pale-white solid, mp 178°--180° C. (decomp): 1H NMR (DMSO-d6) δ12.80 (bs, 1H), 9.80 (s, 1H), 7.30-7.25 (m, 3H), 4.05 (s, 2H), 3.81 (s, 3H); 13C NMR (DMSO-d6) δ167.37, 164.54, 153.67, 129.76, 126.56, 124.39, 121.18, 114.66, 56.03, 29.63; MS (EI, m/z) 287 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:19])[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:5]O.C1(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:19])[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:5][N:34]=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccc(Cl)cc1)c1c(Cl)cc(CO)cc1Cl
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1

Procedure:
3,5-dichloro-4-(4-chlorobenzoyl)benzyl alcohol (858.B) (l mole) is reacted with diphenylphosphoryl azide (diphenylphosphonic azide) (DPPA) (1.2 mole, and 1,8-Diazabicyclo [5.4.0] undec-7-ene, (Synonym: DBU) (1.2 mole)) in toluene at cold temperature, followed by aqueous work-up and alcohol titration, to give 3,5-dichloro-4-(4′-chlorobenzoyl)benzyl azide (858.D). DPPA is an organic compound that is used in the synthesis of other organic compounds. Aust. J. Chem 26:1591-1593 (1973). The stability of DPPA towards heating is shown by its distillation at 157° C. and by the fact that vigorous evolution of nitrogen is not observed until a temperature of 175° C. is reached.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:31])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([N:18]2[CH2:19][CH2:20][CH:15]([C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([F:31])[CH:11]=4)[CH:6]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[CH:14]=3)[CH2:16][CH2:17]2)(=[O:22])=[O:23])=[CH:29][CH:28]=1
Reactant: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccc(Cl)cc3)CC2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1cc(C2CCN(S(=O)(=O)c3ccc(Cl)cc3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.6 %

Procedure:
To a stirred solution of {4-[1-(4-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (80 mg, 0.17 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (35 mg, 0.83 mmol) in water (1 mL) and the reaction mixture was stirred for 24 h at RT. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether (3×5 mL). The washings were discarded. Water (5 mL) was added to the residue, and the mixture acidified (pH ˜2-3) with an aqueous solution of hydrochloric acid (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to give {4-[1-(4-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid (57 mg, 65%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.27 (br s, 1H), 7.95 (dd, J=9.0, 6.1 Hz, 1H), 7.88 (d, J=10.3 Hz, 1H), 7.76-7.85 (m, 4H), 7.68 (s, 1H), 7.34-7.41 (m, 2H), 3.80 (d, J=11.2 Hz, 2H), 3.71 (s, 2H), 2.59 (t, J=11.2 Hz, 2H), 1.87-1.94 (m, 3H), 1.73-1.82 (m, 2H); MS cald. for C23H20ClFNO4S [(M−H)−]: 460, obsd. 460.3.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:12][CH2:11][C:10]3([CH2:21][CH2:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]([O:24][CH3:25])=[O:23])[CH:18]=4)[CH2:13]3)[C:9]2=[O:26])=CC=1>CC#N.O>[O:26]=[C:9]1[C:10]2([CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]([O:24][CH3:25])=[O:23])[CH:18]=3)[CH2:13]2)[CH2:11][CH2:12][NH:8]1
Reactant: COC(=O)c1ccc2c(c1)CCC1(CCN(Cc3ccc(OC)cc3)C1=O)C2
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc2c(c1)CCC1(CCNC1=O)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (±)-methyl 1′-(4-methoxybenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate from Step E (270 mg, 0.712 mmol) in CH3CN (9 mL) was added dropwise a solution of ceric ammonium nitrate (1.95 g, 3.56 mmol) in H2O (9 mL). The resulting mixture was stirred at ambient temperature for 18 h, then at 50° C. for 4 h, then allowed to cool. The CH3CN was removed under reduced pressure, and the residual mixture was partitioned between dilute aqueous NaHCO3 (100 mL) and EtOAc (200 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with EtOAc to give the title compound. MS: m/z=260 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[C:16]2[CH:17]=[N:18][CH:19]=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH3:10])=[CH:5][CH:4]=1.[C:31]([O:35][C:36]([N:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40](Br)=[CH:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C(O)C>[C:31]([O:35][C:36]([N:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]([C:20]2[CH:19]=[N:18][CH:17]=[C:16]([C@@H:12]3[CH2:13][CH2:14][CH2:15][N:11]3[CH:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH3:10])[CH:21]=2)=[CH:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)n1cc(Br)c2ccccc21
Reactant: COc1ccc([C@@H](C)N2CCC[C@H]2c2cncc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C(C)N2CCC[C@H]2c2cncc(-c3cn(C(=O)OC(C)(C)C)c4ccccc34)c2)cc1
Temperature: 80 °C
Yield: 58.6 %

Procedure:
A mixture of 3-{(S)-1-[(R)-1-(4-Methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine 4 (crude, 6.93 mmole), 3-bromo-indole-1-carboxylic acid tert-butyl ester (2.46 g, 8.32 mmole), Na2CO3 (35 mL, 35 mole, 1 M aqueous) in a mixed solution of 50 mL of toluene and 20 mL of ethanol was degased under vacuum. After heat at 80° C. for 1.5 hours, the reaction mixture was cooled to room temperature and dilutied with 150 mL of EtOAc, and washed by 2×100 mL of water. The organic layer was filtered and concentrated. The crude producte was purified by flash chromatography (Hexane 70%, EtOAc 30%) to give 3-(5-{(S)-1-[1-(4-Methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridin-3-yl)-indole-1-carboxylic acid tert-butyl ester 5 (2.02 g, 59% in two steps) as light brown gum.