Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][O:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:21]=[N:22][CH:23]=2)[C:19]=1Cl)=[O:13].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:21]=[N:22][CH:23]=2)[C:19]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1])=[O:13]
Reactant: COC(=O)c1ccc2cncn2c1Cl
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To a stirred suspension 2-fluoro-4-iodo aniline (53.95 g, 0.256 mol) and 5-chloro-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (62.0 g, 0.253 mol) in THF (500 mL) under nitrogen at −78° C., a solution of lithium bis(trimethylsilyl) amide (544 mL, 1M solution, 0.544 mol) was added dropwise over 1 hr, maintaining the temperature below −65° C., giving a red/brown solution. After stirring for 30 minutes at −78° C. the reaction mixture was allowed to warm to −30° C. and then quenched with addition water (100 mL). The solvent was removed in vacuo, before diluting with water (500 ml) and the mixture was extracted with 2-methyltetrahydrofuran (2×500 mL). The combined organic extracts were washed with water, then brine, dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was triturated tert-butyl methyl ether (600 mL) to yield product as yellow/brown solid (87.2 g 83%). LCMS (Method B): RT=3.54 min, [M+H]+=412.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12](N)=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([NH:8][CH3:9])=[O:7].[Cl:15][CH2:16][CH:17]1[O:19][CH2:18]1>FC(F)(F)CO>[Cl:15][CH2:16][CH:17]([OH:19])[CH2:18][NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[N:8]([CH3:9])[C:6](=[O:7])[C:5]2=[CH:10][CH:11]=1
Reactant: ClCC1CO1
Reactant: CNC(=O)c1ccc(N)cc1C(N)=O
Solvent: OCC(F)(F)F
Product: CN1C(=O)c2ccc(NCC(O)CCl)cc2C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.3 %

Procedure:
Twenty-five grams (0.142 mole) 4-amino-N-methylphthalamide, prepared according to the method described in J. Chem. Soc. 26: (1937), and 20.7 g (0.21 mole) 1-chloro-2,3-epoxypropane were added to 150 ml 2,2,2-trifluoroethanol and the reaction mixture was heated to reflux with stirring for 48 hrs. Seventy to eighty ml of 2,2,2-trifluoroethanol was removed by distillation and a heavy yellow precipitate formed when the remaining solution cooled to room temperature. This precipitate was triturated with ethyl acetate, collected by filtration and dried to give 29.5 g (77% yield) of the desired intermediate m.p. 136°-138.5° C. Calculated for C12H13ClN2O3 ; C, 53.64; H, 4.88; N, 10.45. Found: C, 53.87; H, 4.85; N, 10.81.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1.C(N(CC)CC)C.[N:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][CH2:48][CH:49]([OH:52])[CH:50]=[CH2:51])[CH:42]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:51][CH2:50][C:49](=[O:52])[CH2:48][CH2:47][C:43]1[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=1
Reactant: C=CC(O)CCc1cccnc1
Reactant: Brc1ccc2ccccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(CCc1cccnc1)CCc1ccc2ccccc2c1
Temperature: 100 °C
Yield: 47.8 %

Procedure:
Palladium(II) acetate (0.056 g), tri-o-tolylphosphine (0.148 g), 2-bromonaphthalene (0.49 g) and triethylamine (10 ml) were added to a solution of (±)-5-(3-pyridyl)-1-penten-3-ol (0.40 g) in acetonitrile (30 ml) and the mixture heated at 100° C. for 24 hours. The solvents were removed under reduced pressure and water was added to the residue. The mixture was extracted with dichloromethane, the combined extracts dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:ethyl acetate (2:1) to give the sub-title ketone as a brown oil (0.327 g).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:9]([CH:22]=[C:23]([CH2:25][O:26][C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)[N:24]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19](O)=[O:20])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:37][S:38]([NH:41][C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:10]2[N:9]3[CH:22]=[C:23]([CH2:25][O:26][C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)[N:24]=[C:8]3[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[N:12][CH:11]=2)=[CH:18][N:17]=1)=[O:20])(=[O:40])=[O:39]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 15c (400 mg, 0.790 mmol) in DCM (20 mL) was added methanesulfonamide (78.8 mg, 0.830 mmol), DCC (256 mg, 1.24 mmol) and 4-dimethylaminopyridine (152 mg, 1.24 mmol). The reaction mixture was stirred at rt overnight, and was quenched with H2O (40 mL). The resulting mixture was extracted with DCM (3×40 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with DCM/MeOH (10:1 v/v). The title compound 76 was obtained as a yellow solid (307 mg, 69% yield). 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 8.99 (s, 1H), 8.27-8.19 (m, 3H), 8.08 (s, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.68 (t, J=6.9 Hz, 1H), 7.56 (s, 1H), 7.47 (t, J=6.9 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 5.58 (s, 2H), 4.41-4.20 (m, 4H), 3.88-3.71 (m, 4H), 3.05 (s, 3H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H25N7O5S: 560.2 (M+H). Found 560.0.
Reaction SMILES: [CH3:1][C:2]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15](=[O:32])[NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(OC(=O)C(C)(OC1C=CC([O:60][C:61]([F:64])([F:63])[F:62])=CC=1)CC1C=CC(O)=CC=1)C>>[CH3:1][C:2]([O:33][C:34]1[CH:35]=[CH:36][C:37]([O:60][C:61]([F:64])([F:63])[F:62])=[CH:38][CH:39]=1)([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:32])[NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:21][CH:20]=2)=[CH:11][CH:12]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(Cc1ccc(OCC(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)(Oc1ccccc1)C(=O)O
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(OC(F)(F)F)cc1
Product: CC(Cc1ccc(OCC(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)(Oc1ccc(OC(F)(F)F)cc1)C(=O)O

Procedure:
The title compound was prepared using same method for 2-Methyl-2-phenoxy-3-(4-{[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-propionic acid from 3-(4-Hydroxy-phenyl)-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionic acid ethyl ester.
Reaction SMILES: [S:1]([O:5][C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8])([OH:4])(=[O:3])=O.[CH:13]1([NH2:17])[CH2:16][CH2:15][CH2:14]1>C(Cl)Cl.CN(C=O)C>[OH:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[O:5][S:1](=[O:3])(=[O:4])[NH:17][CH:13]1[CH2:16][CH2:15][CH2:14]1
Reactant: O=S(=O)(O)Oc1ccccc1O
Reactant: NC1CCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=S(=O)(NC1CCC1)Oc1ccccc1O
Reaction time: 3 h

Procedure:
Cyclobutyl-sulfamic acid 2-hydroxy-phenyl ester was prepared by adding a solution of catechol sulphate (1.32 g, 7.7 mmol) in DCM (2 ml) to a stirred solution of cyclobutylamine (600 μl, 7.0 mmol) and TEA (1.07 ml, 7.7 mmol) in DMF at 0° C., and stirring for 3 hours at this temperature. The mixture was quenched with 1M HCl (50 ml) and extracted with diethyl ether. The organic extract was washed with water, brine, dried and concentrated to dryness. Quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]([CH3:26])([CH3:25])[CH2:9][C:10]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#N)=[CH:14][CH:13]=2)[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1C[O:38]CC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]([CH3:26])([CH3:25])[CH2:9][C:10]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:38])=[CH:14][CH:13]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1ccc(C#N)cc1)C(F)(F)F
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1ccc(C=O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 18 %

Procedure:
To a solution of 79 mg (0.2 mmol) of 4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]benzonitrile in 10 mL of THF was added 11.3 mg (0.3 mmol) of lithium aluminum hydride and the mixture was warmed to reflux. After 18 hours, all the solvent escaped. The reaction was cooled to room temperature, THF was added, and the reaction was quenched with water and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (silica gel, toluene-EtOAc (95:5)) to leave an oil. A second purification by preparative TLC (silica gel, hexanes-EtOAc (9:1)) afforded 15 mg (18%) of the title compound as an oil which partially solidified.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[C:3]=1[CH2:14]O.S(Cl)([Cl:18])=O>>[Cl:18][CH2:14][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([Cl:13])[CH:5]=2)[C:10]([Cl:12])=[CH:11][C:2]=1[Cl:1]
Reactant: OCc1c(Cl)cc(Cl)c2ccc(Cl)cc12
Reactant: O=S(Cl)Cl
Product: ClCc1c(Cl)cc(Cl)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2,4,7-Trichloronaphthalen-1-yl)methanol (1.0 g, 3.8 mmoles) was added portionwise to thionyl chloride (10 ml) with cooling (ice bath). The reaction mixture was stirred at room temperature for 30 minutes and at reflux for 2 hours and then concentrated to dryness in vacuo. The oily residue was taken up in methylene chloride and the solution dried over MgSO4. The solution was filtered and concentrated in vacuo to give 1.0 g of the title compound.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:10].Cl.[Cl:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][SH:27])[CH2:20][CH2:19]2)=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:12].[ClH:10].[C:1]1([NH:7][C:8](=[SH:27][CH2:26][CH2:25][CH2:24][N:21]2[CH2:22][CH2:23][N:18]([CH2:17][C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:29][CH:28]=3)[CH2:19][CH2:20]2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OC(Nc1ccccc1)=[SH]CCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 107.1 %

Procedure:
The procedure described in Example 2 was followed, using 4.3 g of phenyl isocyanate, 12.7 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 7.3 g of triethylamine and 100 ml of methylene chloride, to give 9.1 g (53% of theory) of N-phenyl-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. >230° C. (dec.).
Reaction SMILES: C([NH:4][C:5]1[CH:21]=[CH:20][C:8]([N:9]([CH2:17][CH2:18][OH:19])[CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:7][CH:6]=1)(=[O:3])C.[ClH:22]>O>[OH2:3].[ClH:22].[ClH:22].[OH:19][CH2:18][CH2:17][N:9]([CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:8]1[CH:7]=[CH:6][C:5]([NH2:4])=[CH:21][CH:20]=1
Reactant: CC(=O)Nc1ccc(N(CCO)CCNS(C)(=O)=O)cc1
Agent: Cl
Solvent: O
Product: CS(=O)(=O)NCCN(CCO)c1ccc(N)cc1
Reaction time: 2 h

Procedure:
0.0178 mol (5.6 g) of 4-acetylamino-N-(β-hydroxyethyl)-N-mesylaminoethylaniline in 12 ml of a 5N aqueous solution of hydrochloric acid is heated for 30 minutes in a boiling water bath. The water is then driven off in vacuo. The residue is kept for two hours in vacuo at 60° C. and is then obtained in crystalline form.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=C/N(C)C.O.CC[O:18]C(C)=O>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]=[O:18]
Reactant: CN(C)/C=C/c1nc2ccccc2o1
Reactant: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1nc2ccccc2o1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To (E)-2-(benzo[d]oxazol-2-yl)-N,N-dimethylethenamine (1 g, 5.32 mmol) in THF (15 mL) at 0° C. was added water (15 mL) and NaIO4 (3.4 g, 16 mmol). The resulting mixture was stirred at 0° C. for 10 min, then at room temperature for 2 h. To the solution was added H2O and EtOAc and then the mixture was filtered. The clear solution was extracted with EtOAc and the organic phase was washed with aqueous NaHCO3 solution. The organic phase was concentrated and the residue was purified by column chromatography to give the title compound (120 mg). MS (ESI) m/z 148 (M+H+).
Reaction SMILES: Br[C:2]1[C:7]2[O:8][C:9]([CH3:13])([CH3:12])[O:10][CH2:11][C:6]=2[CH:5]=[C:4]([CH3:14])[CH:3]=1.[C:15]1([C:21]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:22]2[CH:26]=[C:25]([CH:27]=[O:28])[N:24]=[CH:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:12][C:9]1([CH3:13])[O:8][C:7]2[C:2]([CH:27]([C:25]3[N:24]=[CH:23][N:22]([C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:26]=3)[OH:28])=[CH:3][C:4]([CH3:14])=[CH:5][C:6]=2[CH2:11][O:10]1
Reactant: Cc1cc(Br)c2c(c1)COC(C)(C)O2
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: Cc1cc2c(c(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c1)OC(C)(C)OC2
Yield: 31 %

Procedure:
Starting from 8-bromo-2,2,6-trimethyl-4H-1,3-benzodioxin and 1-triphenylmethyl-1H-imidazole-4-carboxaldehyde. The organomagnesium compound is added at ambient temperature. The reaction product is purified by chromatography on silica (15 μm) (eluent: 98:2 v/v dichloromethanemethanol). Yield: 31% of theory; M.P.: 205°-215° C. (recrystallized from acetonitrile).
Reaction SMILES: O=[C:2]1[NH:6][N:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3]1.C(#N)C.P(Cl)(Cl)([Cl:23])=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:23][C:2]1[CH2:3][CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1
Reactant: CCOC(=O)C1CC(=O)NN1c1cccnc1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1CC(Cl)=NN1c1cccnc1
Temperature: 60 °C
Yield: 79.7 %

Procedure:
A 3-neck round bottomed flask (100 mL) was charged with ethyl 5-oxo-2-(pyridin-3-yl)pyrazolidine-3-carboxylate (8.50 g, 36.1 mmol) and acetonitrile (40 mL). Phosphoryl trichloride (4.05 mL, 43.4 mmol) was charged and the reaction was heated at 60° C. for 2 hours. The reaction was cooled to 20° C. and water (100 mL) was added. Sodium carbonate was added to adjust pH to 8 and the mixture was extracted with ethyl acetate (3×100 mL). The organic layers were concentrated to dryness and the residue was purified by flash column chromatography using 30-80% ethyl acetate/hexanes as eluent to provide the title compound as a yellow oil (7.30 g, 79%): 1H NMR (400 MHz, CDCl3) δ 8.30 (dd, J=2.9, 0.8 Hz, 1H), 8.17 (dd, J=4.7, 1.4 Hz, 1H), 7.38 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.18 (ddd, J=8.4, 4.7, 0.7 Hz, 1H), 4.79 (dd, J=12.4, 6.9 Hz, 1H), 4.24 (qd, J=7.1, 1.1 Hz, 2H), 3.55 (dd, J=17.7, 12.4 Hz, 1H), 3.33 (dd, J=17.8, 6.9 Hz, 1H), 1.25 (t, J=7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.65, 141.90, 141.33, 141.09, 135.13, 123.53, 120.37, 62.89, 62.35, 42.45, 14.03; ESIMS m/z 254 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:19]=[N:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl[Sn]Cl.O.[OH-].[Na+]>C(Cl)(Cl)Cl>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:18]=[CH:19][C:10]=1[C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(-c2cnc3ccccc3n2)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
A solution of 2-(3-nitrophenyl)quinoxaline (9.4 g, 37.4 mmol), SnCl2.H2O (28 g, 13.48 mmol) in CHCl3 (95 mL) was heated to 90° C. for 15 minutes, cooled to room temperature, added to ice water (190 mL), and basified to pH 10 with 50% aqueous NaOH, adding ice as necessary to maintain the temperature below 10° C. The mixture was extracted with ethyl acetate (500 mL), and the organic phase was filtered through a Celite pad, which was washed once with ethyl acetate (150 mL). The combined organics phases were washed with brine and dried, and then solvent was evaporated in vacuo. The resulting solid was recrystallized from toluene to afford (3-quinoxalin-2-ylphenyl)amine (5.6 g, 68% yield). LCMS calculated for C14H11N3 (M+H): 222.26. found 222. 1H-NMR (400 MHz, DMSO-d6) δH: 9.42 (1H, s), 8.11-8.00 (2H, m), 7.94-7.75 (2H, m), 7.55 (1H, s), 7.42 (1H, d, J=7 Hz), 7.22 (1H, m), 6.72 (1H, m), 5.42 (2H, br. s).
Reaction SMILES: [CH:1]1([NH:4][S:5]([NH:8][C@@H:9]([CH2:20][C:21]2[O:22][C:23]([CH2:26][C:27]3[S:28][C:29]4[CH:35]=[C:34]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH:33]=[CH:32][C:30]=4[N:31]=3)=[N:24][N:25]=2)[C:10]([O:12]CC2C=CC=CC=2)=O)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C[O-].[Na+].CO.Cl>C1COCC1>[CH:1]1([N:4]2[C:10](=[O:12])[C@H:9]([CH2:20][C:21]3[O:22][C:23]([CH2:26][C:27]4[S:28][C:29]5[CH:35]=[C:34]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[CH:33]=[CH:32][C:30]=5[N:31]=4)=[N:24][N:25]=3)[NH:8][S:5]2(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1)NS(=O)(=O)NC1CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1[C@H](Cc2nnc(Cc3nc4ccc(-c5ccccc5)cc4s3)o2)NS(=O)(=O)N1C1CC1
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
To a solution of Compound 181b (41 mg, 0.070 mmol) in THF (3 mL) at 0° C. was slowly added a solution of 25% NaOMe in MeOH (0.035 mL, 0.15 mmol) dissolved in THF (0.5 mL) and the mixture was stirred for 30 min. The reaction was quenched with the addition of cold 1.0 M HCl (0.70 mL, 0.70 mmol) at 0° C., then the mixture was extracted with DCM. The extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes to give Compound 181c (12 mg, 36% yield) as a yellow foam. 1H NMR (400 MHz, CDCl3) δ 8.08-8.03 (m, 2H), 7.73 (dd, J=8.6, 1.8 Hz, 1H), 7.66-7.59 (m, 2H), 7.51-7.43 (m, 2H), 7.42-7.35 (m, 1H), 4.73 (s, 2H), 4.69 (dd, J=9.0, 3.5 Hz, 1H), 3.54 (dd, J=16.8, 3.6 Hz, 1H), 3.41-3.30 (m, 1H), 2.70 (dt, J=7.1, 3.4 Hz, 1H), 1.21-1.05 (m, 2H), 1.04-0.86 (m, 2H). LCMS=1.9 min using analytical method (M), 482.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[C:4]([F:29])[C:3]=1[CH2:30][C:31](O)=[O:32].CO>O1CCCC1>[F:29][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][C@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[N:21]=[CH:22][C:23]([CH2:26][O:27][CH3:28])=[CH:24][N:25]=3)[CH2:18][CH2:19]2)[CH:7]=[C:2]([F:1])[C:3]=1[CH2:30][CH2:31][OH:32]
Reactant: COCc1cnc(N2CCC([C@H]3C[C@@H]3CCOc3cc(F)c(CC(=O)O)c(F)c3)CC2)nc1
Solvent: C1CCOC1
Solvent: CO
Product: COCc1cnc(N2CCC([C@H]3C[C@@H]3CCOc3cc(F)c(CCO)c(F)c3)CC2)nc1
Temperature: 50 °C

Procedure:
To a solution of {2,6-difluoro-4-[2-((1R,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetic acid (72.0 mg, 0.125 mmol) in 1 ml anhydrous tetrahydrofuran at 0° C. was added 1 M borane-tetrahydrofuran complex (0.375 ml, 0.375 mmol) dropwise. The reaction mixture was stirred at 50° C. for an hour. The mixture was diluted by addition of 1 ml of methanol, concentrated under reduced pressure, and the residue purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 25-95% acetonitrile in 0.1% formic acid in water gradient) to afford the title compound. LC/MS (m/z): 448.4 (M+H)+. Human EC50: 7.2 nM
Reaction SMILES: [CH:1]([O-:3])=O.C(OC(=O)C)(=O)C.[F:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>O1CCCC1>[CH:1]([NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=1[F:11])=[O:3]
Reactant: Nc1ccccc1F
Reactant: O=C[O-]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: O=CNc1ccccc1F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Under argon gas, formate (6.1 mL) was added to acetic anhydride (15.5 mL) at 0° C. and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with tetrahydrofuran (10 mL). Tetrahydrofuran (20 mL) solution containing 2-fluoroaniline (5.56 g) was added into the diluent at room temperature and stirred at room temperature for 1 hour. A title compound having the following physical properties was obtained by concentrating the reaction mixture. The obtained title compound was used for the following reaction without further purification.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.S(Cl)([Cl:23])=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:23][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: CN1C(=O)CCc2nc(-c3cncc(CO)c3)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1C(=O)CCc2nc(-c3cncc(CCl)c3)ccc21
Temperature: 3.5 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
At 0° C., 6-(5-hydroxymethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one (170 mg, 0.63 mmol) in DCM (15 mL) was treated with thionyl chloride (0.32 mL, 4.0 mmol). After the addition, the reaction mixture was allowed to stir at 2-5° C. for 2 hours before it was poured into satd. aq. NaHCO3 solution (50 mL). After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give 6-(5-chloromethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one (156 mg, 86.3%) as yellow oil. MS: 288.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18]([OH:20])=[O:19])=[CH:9][C:8]2=[O:21])=[CH:4][CH:3]=1.[N+:24]([O-])([O-:26])=[O:25].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][C:13]([N+:24]([O-:26])=[O:25])=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18]([OH:20])=[O:19])=[CH:9][C:8]2=[O:21])=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccc([N+](=O)[O-])cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
1-(4-Chlorobenzyl)-1,2-dihydro-2-oxoquinol-4-ylacetic acid (33 g.) was added to concentrated sulphuric acid (210 ml.) at 0° C. The mixture was stirred at 0° C. and potassium nitrate(11g.) was added in small portions over 8 minutes. The mixture was then stirred at 0° C. for a further 10 minutes and then for 2 hours at room temperature. The mixture was poured into an ice-water mixture (2.5 l.), and the precipitated solid was filtered off. The dried solid was crystallised from 3/1 v/v dimethylformamide-ethanol to give 1-(4-chlorobenzyl)-1,2-dihydro-6-nitro-2-oxoquinol-4-ylacetic acid, m.p. 217-9° C., in 85% yield.