Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[N:16][S@@:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.B(F)(F)F.CCOCC.[CH2:39]([Mg]Cl)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@@:15]([NH:16][S@@:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:11])[F:12])[CH:7]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CC(C)(C)[S@@](=O)N=C(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)[S@@](=O)N[C@@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
(R)—N-((3-Fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(4-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (150 mg, 0.34 mmol) was stirred in anhydrous CH2Cl2 (7 mL) at −78° C. for 5 min under Argon. BF3.Et2O (0.10 mL, 2.0 eq) was added dropwise. The mixture was stirred at −78° C. for 10 min. Benzylmagnesium chloride (1.0 M in Et20, 1.4 mL, 3.0 eq) was added slowly at −78° C., and the resulting mixture was stirred at −78° C. for 1.5 h. The reaction mixture was quenched with sat. NH4Cl and then extracted with Et2O (2×). The combined organic portion was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, EtOAc/hexanes=0-30%) to give the fast eluting fraction corresponding to (R)—N-((5)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (29 mg): 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (s, 9H) 3.63 (d, J=12.4 Hz, 1H), 3.94 (d, J=12.4 Hz, 1H), 4.21 (s, 1H), 6.90 (m, 1H), 5.90 (m, 1H), 6.94-7.09 (m, 4H), 7.16-7.20 (m, 4H), 7.31-7.39 (m, 2H); LC-MS (ESI) 530.36 (M+H), retention time=4.11 min (10-90% MeOH in H2O with 0.1% TFA in a 4-min run); and the slow eluting fraction corresponding to (R)—N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (146 mg, total yield: 96.4%): 1H NMR (400 MHz, CDCl3) δ ppm 7.35-7.43 (m, 2H), 7.13-7.20 (m, 3H), 7.07 (t, J=8.72 Hz, 2H), 6.93 (dd, J=7.58, 1.77 Hz, 2H), 6.84 (d, J=8.59 Hz, 1H), 6.70 (m, 2H), 5.85 (tt, J=52, 4 Hz, 1H), 4.25 (s, 1H), 4.02 (d, J=12.63 Hz, 1H), 3.58 (d, J=12.63 Hz, 1H), 1.20 (s, 9H); 13C NMR (CDCl3) δ ppm 23.02, 46.99, 56.53, 65.70, 104.55, 104.96, 105.37, 107.06, 107.47, 107.92, 108.17, 109.56, 109.97, 112.32, 112.55, 115.37, 115.58, 116.13, 116.41, 116.69, 119.12, 127.21, 128.14, 130.91, 130.99, 132.07, 134.34, 137.48, 137.51, 149.09, 149.21, 150.52, 150.45, 161.20, 163.67; LC-MS (ESI) 530.36 (M+H), retention time=4.11 min (10-90% MeOH in H2O with 0.1% TFA in a 4-min run).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][CH:3]=1.CO.[C:14](O)(=O)[CH:15]=[O:16]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[N:8]=[C:15]([OH:16])[CH:14]=[N:9]2
Reactant: O=CC(=O)O
Reactant: Nc1c(Cl)cccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CO
Product: Oc1cnc2cccc(Cl)c2n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 7.6 %

Procedure:
100 ml of triethylamine were added to the reduction product of 6-chloro-2-nitroaniline in methanol (assumed to be 8 mol), obtained as described under (a). The mixture was then heated to 50° C. 1,168 g (8 mol) of glyoxylic acid semiacetal ester were then added dropwise, over the course of 2 hours, to the mixture, thereby causing a slight exothermic reaction. The mixture was boiled for 2 hours under reflux, whereupon a solid product separated out. After 2 hours, the mixture was cooled to 0° C. and the precipitate was filtered off. 110 g (7.6% of theory) of 8-chloro-2-hydroxy-quinoxaline were obtained in the form of a light gray powder of melting point above 250° C. The mother liquor was concentrated, ether was added and the residue was filtered off. A further 583 g (40.6% of theory) were thus obtained. Accordingly, the total yield was 693 g (48% of theory). ##STR30##
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH2:32][CH2:33][O:34][CH3:35])=[N:29][N:28]=3)=[CH:25][C:8]([C:9](N3CCC(C4C=CC(C#N)=CC=4)CC3)=[O:10])=[C:7]([CH3:36])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[F:38][C:39]([F:53])([F:52])[C:40]1[CH:45]=[CH:44][C:43]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1.Cl.N1CCC(C2C=CC(C#N)=CC=2)CC1>>[CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH2:32][CH2:33][O:34][CH3:35])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:49]3[CH2:48][CH2:47][CH:46]([C:43]4[CH:42]=[CH:41][C:40]([C:39]([F:38])([F:52])[F:53])=[CH:45][CH:44]=4)[CH2:51][CH2:50]3)=[O:10])=[C:7]([CH3:36])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COCCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Reactant: FC(F)(F)c1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: N#Cc1ccc(C2CCNCC2)cc1
Product: COCCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C(F)(F)F)cc4)CC3)c(C)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(4-cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 153), using 4-(4-(trifluoromethyl)phenyl)piperidine hydrochloride salt instead of 4-(piperidin-4-yl)benzonitrile hydrochloride salt (compound 1.5). m/z (ES+) 527 (M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 11.30-11.10 (br, 1H), 7.60-7.47 (m, 3H), 7.35-7.28 (m, 3H), 5.10-4.93 (m, 1H), 4.24-4.13 (m, 1H), 3.78 (t, 2H), 3.70 (d, 1H), 3.45 (s, 3H), 3.12 t, 2H), 3.15-3.05 (m, 1H), 2.90-2.75 (m, 2H), 2.44 and 2.35 (2 singlets, amide rotamers, ArCH3, 3H), 2.25-2.13 (m, 2H), 2.13-1.85 (m, 4H), 1.87-1.66 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([OH:12])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].C[C:20]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1F)=[O:21]>C(#N)C>[F:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([O:12][C:8]2[CH:9]=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:22]=1[CH:20]=[O:21]
Reactant: Oc1cnc2c(F)cccc2c1
Reactant: CC(=O)c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1c(F)cccc1Oc1cnc2c(F)cccc2c1
Yield: 57.2 %

Procedure:
After 30 ml of acetonitrile was added to 3.0 g of 8-fluoro-3-hydroxyquinoline, 3.1 g of potassium carbonate and 3.5 g of 2,6-difluoroacetophenone were added. After the reaction solution was heated under reflux for 3 hours, the reaction solution was filtered with CELITE. After the filtrate was extracted with ethyl acetate, the organic layer was concentrated and purified by silica gel column chromatography to obtain 3.0 g of 2-fluoro-6-(8-fluoroquinolin-3-yloxy)-benzaldehyde (Compound Number 341).
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[C:22]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].[Mg].C(OCC)(=O)CC(OCC)=O>CCOCC>[CH2:27]([O:26][C:24](=[O:25])[CH:23]([C:14](=[O:15])[CH:13]([O:12][C:11]1[CH:18]=[CH:19][C:8]([O:7][C:6]2[CH:20]=[CH:21][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[CH3:17])[C:22]([O:30][CH2:31][CH3:32])=[O:29])[CH3:28]
Reactant: CC(Oc1ccc(Oc2ccc(C#N)cc2)cc1)C(=O)Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Mg]
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Oc1ccc(Oc2ccc(C#N)cc2)cc1
Yield: 72 %

Procedure:
A mixture of 30 g of 2-[-4'-(4"-cyano-phenoxy)-phenoxy]-propionyl chloride and 30 ml of ether is added dropwise to a 35% etheral solution of magnesium diethyl malonate prepared from 17.6 g of diethyl malonate. The addition of the acid chloride having been completed the reaction mixture is heated to boiling for an hour and worked up as described in Example 1. Thus 30 g of the desired compound are obtained in the form of a viscous oil which solidifies on standing and melts at 42°-46° C. Yield 72%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+].[CH3:12][OH:13]>>[CH3:9][O:10][C:2]1[CH:7]=[C:6]([O:13][CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: CO
Reactant: Clc1cc(Cl)ncn1
Reactant: C[O-]
Agent: [Na+]
Product: COc1cc(OC)ncn1
Temperature: 65 °C

Procedure:
To a suspension of 4,6-dichloropyrimidine (6.5 g, 43.9 mmol) in methanol (30 mL) at room temperature under argon was added NaOMe (7.1 g, 132 mmol) over 5 min. The resulting suspension was heated at 65° C. under argon for 24 h. Analysis by HPLC/MS indicated that the reaction was complete. Most of the solvent was removed under reduced pressure, then 1 M aqueous HCl (50 mL) and CH2Cl2 (50 mL) were added to the residue. The layers were separated and the organic phase was washed with saturated aqueous NaCl (30 mL), then dried (Na2SO4), filtered and evaporated. The crude product was purified by silica gel column chromatography eluted with ethyl acetate-hexanes to obtain the title compound (5.76 g) as a low melting solid. See also Synthesis 1998, page 36.
Reaction SMILES: [C:1]([O:4][O:5][CH:6]1[CH2:10][CH:9]([OH:11])[CH:8]=[CH:7]1)(=[O:3])[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])(=O)=O>C(Cl)Cl>[C:1]([O:4][O:5][CH:6]1[CH2:10][CH:9]([O:11][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH:8]=[CH:7]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)OOC1C=CC(O)C1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(=O)OOC1C=CC(O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To a stirred solution of 4-hydroxy-cyclopent-2-enyloxy acetate (4.1 g, 29 mmol) in CH2Cl2 (35 mL) and 2,6-lutidine (8.2 mL, 67 mmol) was added t-butyldimethylsilyl trifluoromethanesulfonate (10 mL, 44 mmol) at 0-5° C. The reaction mixture was stirred at r.t. for 1 hour. It was diluted with CH2Cl2, washed (brine), dried (Na2SO4), filtered and concentrated Column chromatography (silica gel, 5:1 hexanes:diethylether) gave desired product (5.1 g, 69%). 1H NMR (CDCl3, 400 MHz) δ; 5.88 (m, 1H); 5.84 (m, 1H); 5.42 (t, 1H); 4.64 (t, 1H); 2.80 (m, 1H); 2.02 (s, 3H); 1.59 (m, 1H); 0.83 (s, 9H); 0.04 (s, 6H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCOc1ccc(I)cc1
Yield: 90.2 %

Procedure:
A mixture of 4-iodophenol (6.6 g), 1-bromopentane (4.5 g), anhydrous potassium carbonate (13.8 g) and acetone (100 ml) was stirred at reflux for 24 hours, with the additions of a further quantity of 1-bromopentane after 4 hours (4.5 g) and 8 hours (4.5 g). The acetone was removed by evaporation. The residue was triturated with water (50 ml) and extracted with ether (3×30 ml). The organic extracts were combined, dried (MgSO4) and evaporated. The residue, a colourless oil, was distilled at 160° C. and 0.05 mm pressure (using a Kugelrohr oven) to give 4-n-pentyloxyiodobenzene as a colourless oil (7.8 g); microanalysis, found C, 45.7; H, 5.4%; C11H15IO requires: C, 45.5; H, 5.2%; NMR(DMSO-d6): 0.84-0.95(3H,t), 1.25-1.48(4H,m), 1.62-1.77(2H,m), 3.88-3.97(2H,t), 6.72-6.8(2H,d), 7.52-7.6(2H,d); m/z 290 (M).
Reaction SMILES: CO[CH:3]=[C:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.Cl(O)(=O)(=O)=O.Cl.[CH2:18]([O:21][NH2:22])[C:19]#[CH:20]>>[CH2:18]([O:21][N:22]=[CH:3][CH:4]1[CH:9]2[CH2:8][CH2:7][N:6]([CH2:11][CH2:10]2)[CH2:5]1)[C:19]#[CH:20]
Reactant: C#CCON
Reactant: COC=C1CN2CCC1CC2
Agent: Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: C#CCON=CC1CN2CCC1CC2
Yield: 61.9 %

Procedure:
The operation is carried out as in Example 1 using 1.75 g of 3-methoxy methylidene quinuclidine, 3.8 cm3 of perchloric acid and 1.22 g of O-2-propynylhydroxylamine hydrochloride (U.S. Pat. No. 3,398,180 (1968)). After the ethyl ether has been evaporated off, the residue is chromatographed on silica (eluant: chloroform-methanol 7-3) then distilled at 190° C. under 0.05 mbar and 1.35 g of expected product is obtained.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[CH:8]1([NH:12][C:13]2[N:18]=[C:17]3[CH2:19][NH:20][CH2:21][CH2:22][C:16]3=[N:15][C:14]=2[N:23]2[CH2:28][CH2:27][CH:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=3[F:38])[CH2:25][CH2:24]2)[CH2:11][CH2:10][CH2:9]1.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42].C(N(CC)CC)C>C(Cl)Cl>[CH:8]1([NH:12][C:13]2[N:18]=[C:17]3[CH2:19][N:20]([C:41]([N:40]([CH3:44])[CH3:39])=[O:42])[CH2:21][CH2:22][C:16]3=[N:15][C:14]=2[N:23]2[CH2:28][CH2:27][CH:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=3[F:38])[CH2:25][CH2:24]2)[CH2:9][CH2:10][CH2:11]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CN(C)C(=O)Cl
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CNCC4)CC2)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CN(C(=O)N(C)C)CC4)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-cyclobutyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (9.1 mg, 0.017 mmol), dimethylcarbamic chloride (3.6 mg, 0.034 mmol) and triethylamine (5.1 mg, 0.050 mmol) in DCM (170 μL) was stirred at room temperature for 30 min. The mixture was purified by HPLC Method A to give the title compound as a TFA salt (6.0 mg, 58.3%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.74-1.84 (m, 2H), 1.89-2.04 (m, 4H), 2.06-2.15 (m, 2H), 2.36-2.46 (m, 2H), 2.79 (t, J=5.7 Hz, 2H), 2.90 (s, 6H), 2.94-3.02 (m, 2H), 3.34-3.43 (m, 2H), 3.51-3.56 (m, 2H), 3.76 (s, 3H), 4.26 (s, 2H), 4.43 (s, 2H), 6.64-6.69 (m, 1H), 6.74 (dd, J=12.9, 3.0 Hz, 1H), 7.08 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]+ 499.4.
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][C:3]=1[CH:18]=O.C([O-])([O-])=O.[Na+].[Na+].Cl.[NH:27]([CH2:29][C:30]([OH:32])=[O:31])[CH3:28].[C:33](O[K])(C)(C)[CH3:34]>CS(C)=O.CN(C=O)C>[CH3:28][N:27]1[C:2]2[CH2:7][CH2:6][N:5]([S:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)(=[O:9])=[O:10])[CH2:4][C:3]=2[CH:18]=[C:29]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CNCC(=O)O
Reactant: Cc1ccc(S(=O)(=O)N2CCC(Cl)=C(C=O)C2)cc1
Reactant: CC(C)(C)O[K]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(n1C)CCN(S(=O)(=O)c1ccc(C)cc1)C2
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-chloro-1-[(4-methylphenyl)sulfonyl]-1,2,5,6-tetrahydropyridine-3-carbaldehyde (1 eq) obtained in step II of example 200 in DMSO was added Na2CO3(4.0 eq) and sarcosine hydrochloride (2.0 eq) at room temp and the reaction mixture was stirred for 1.5 hr at 40° C. Reaction mass was then quenched with water and extracted with ethyl acetate. Organic layer was separated and dried over anhydrous Na2SO4, concentrated under reduced pressure to afford crude product, which, was dissolve in DMF and added to the mixture of tBuOK (1.0 eq) in DMF at 0° C. and stirred at room temperature for 2 h Reaction mass was quenched in water and extracted with ethyl acetate. Organic layer was separated dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded ethyl 1-methyl-5-[(4-methylphenyl)sulfonyl]-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][N:13]([CH2:20][CH2:21][OH:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:22][CH2:21][CH2:20][N:13]([CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CN(CCO)c1ccccn1
Product: CN(CCOc1ccc([N+](=O)[O-])cc1F)c1ccccn1

Procedure:
In substantially the same manner as in Reference Example 54, 3,4-difluoronitrobenzene was reacted with 2-[N-methyl-N-(2-pyridyl)amino]ethanol to yield 3-fluoro-4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]nitrobenzene. The product was recrystallized from ethyl acetate-hexane to give yellow prisms, m.p.95-96° C.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17]C)(=[O:5])[CH2:2][CH2:3][CH3:4].[B].C(C1C=NC2C(C=1Cl)=CC=CC=2O)(=O)CCC.[F:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[C:40]([CH3:45])[CH:39]=1>ClCCl.O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:42][C:41]1[CH:43]=[CH:44][C:38]([F:37])=[CH:39][C:40]=1[CH3:45])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Cc1cc(F)ccc1N
Agent: CCCC(=O)c1cnc2c(O)cccc2c1Cl
Agent: [B]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
A solution of 3-butyryl-4-chloro-8-methoxyquinoline (131.9 g, 0.5 mol) in dichloromethane (1 liter), was cooled to -78° C., then boron tribomide (142 ml, 1.5 mol) added slowly over 10 minutes. The mixture was warmed slowly to 0°, stirred 2 hours, then allowed to warm to room temperature overnight. After recooling in ice the reaction was quenched cautiously with water, then the resulting solid filtered off and dried. This was heavily contaminated with boron-containing impurities, but was used without purification. Crude 3-butyryl-4-chloro-8-hydroxyquinoline (64 g) and 4-fluoro-2-methylaniline (16.7 ml, 0.15 mol) were dissolved in dioxan (300 ml), heated on a steam bath for 2 hours, then left to stand overnight. The dioxan was evaporated, dichloromethane and aqueous sodium bicarbonate added, the mixture stirred until all the solid had dissolved, then the organic layer dried and evaporated. Recrystallization from methanol gave 3-butyryl-4-(4-fluoro-2-methylphenylamino)-8-hydroxyquinoline (37 g) m.p. 121°-122°.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:19]=[C:20]([C:23]#[N:24])[S:21][CH:22]=1>O>[CH3:1][C:2]1([CH3:16])[O:3][C:4](=[O:15])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:18]3[CH:19]=[C:20]([C:23]#[N:24])[S:21][CH:22]=3)=[CH:8][C:7]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: N#Cc1cc(Br)cs1
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3csc(C#N)c3)cc21

Procedure:
Prepared from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 4-bromo-2-thiophenecarbonitrile according to Procedure B. Yellowish solid: mp 230-231° C. (decomposed); 1H-NMR (CDCl3) δ 8.32 (s, 1H, D2O exchangeable), 7.83 (d, 1H, J=1.5 Hz), 7.61 (d, 1H, J=1.4 Hz), 7.43 (dd, 1H, J=8.2, 1.9 Hz), 7.29 (d, 1H, J=1.8 Hz), 6.85 (d, 1H, J=8.2 Hz), 1.78 (s, 6H); MS (EI) m/z 283(M−H, 100%). Anal. Calc. For C15H12N2O2S.0.2 H2O: C, 62.57; H, 4.34, N, 9.73. Found: C, 62.48; H, 4.31; N, 9.64.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.C[O-].[Na+].[NH2:26][NH:27][C:28](=O)[CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(O)C.CO>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[N:6]=[C:28]([CH2:29][N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[NH:27][N:26]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: NNC(=O)CN1CCOCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: Fc1ccc(-c2n[nH]c3ccc(-c4n[nH]c(CN5CCOCC5)n4)cc23)cc1
Temperature: 0 °C
Yield: 5 %

Procedure:
A suspension of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (0.300 g, 0.94 mmol) in 4 mL of anhydrous ethanol was prepared and cooled to 0° C. An excess of a freshly prepared solution of sodium methoxide in methanol (1.41 mL, 2.0 M)) was added followed by 3 equivalents of N-amino-2-morpholin-4-ylacetamide (0.449 g, 2.82 mmol) as a solid. The reaction mixture was heated to reflux temperature in a sealed tube for 2 days. The reaction was then quenched with water, the pH adjusted to neutral and he crude product extracted with ethyl acetate. The components of the crude mixture were separated by preparative HPLC (title compound: 0.017 g, 5% yield): 1H NMR (CD3OD) δ 8.71 (d, 1H), 8.08–8.03 (m, 3H), 7.68 (d, 1H), 7.3 (t, 2H), 3.73 (m, 6H), 2.59 (m, 4H); ES-MS (m/z) 379 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=1)[C:10]([O-:12])=[O:11].[H-].[Na+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.[CH3:27]N(C)C=O>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:6]2[CH2:5][CH2:4][N:3]([C:7]3[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=3)[C:10]([O:12][CH3:27])=[O:11])[C:2]2=[O:1])=[CH:21][CH:22]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C([O-])c1ccnc(N2CCNC2=O)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 2-(2-oxoimidazolidin-1-yl)isonicotinate (10.00 g, 45.20 mmol) in N,N-dimethylformamide (300 mL) was added sodium hydride (60% dispersion in mineral oil, 1.90 g, 45.20 mmol) at 0° C. The resulting solution was stirred for 30 minutes at 0° C., followed by the addition of 1-(bromomethyl)-4-fluorobenzene (8.54 g, 45.20 mmol). The reaction mixture was warmed to ambient temperature, stirred for 17 hours and concentrated in vacuo to dryness. The residue was purified by column chromatography eluted with dichloromethane and ethyl acetate to give methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate as a colorless solid (10.03 g, 67%): mp 119-121° C.; 1H NMR (300 MHz, CDCl3) δ 8.87 (d, J=0.6 Hz, 1H), 8.35 (d, J=5.4 Hz, 1H), 7.45-7.43 (m, 1H), 7.29-7.25 (m, 2H), 7.04-6.98 (m, 2H), 4.44 (s, 2H), 4.20 (t, J=7.8 Hz, 2H), 3.91 (s, 3H), 3.35 (t, J=7.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 165.9, 164.0, 160.7, 156.8, 153.4, 148.0, 138.7, 132.3, 130.0, 116.7, 115.8, 115.5, 112.5, 52.6, 47.8, 41.3, 41.0; MS (ES+) m/z 330.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:17]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:17])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)ccc1O
Yield: 94.8 %

Procedure:
A mixture of 5-chloro-2-hydroxybenzoic acid (100 g, 0.57 mol), 20 ml of conc. H2SO4 and 200 ml of dry methanol was heated under reflux for 22 hours. An additional 5 ml of conc. H2SO4 was then added and the solution heated for an additional 24 hours. The solvent was evaporated under reduced pressure and the resulting residue poured into aqueous saturated Na2CO3 and then extracted with CH2Cl2 (2×400 ml). The organic layers were combined, dried over anhydrous Na2SO4, and evaporated to give the desired compound as a white solid (100.5 g, 94.8% yield), mp 44°-46° C. IR (nujol) 1680 (ester) cm-1. NMR (CDCl3) δ10.60 (s, 1H, OH), 7.73 (d, 1H, JBC =3 Hz HC), 7.33 (d of d, 1H, JAB =9 Hz, HB), 6.87 (d, 1H, HA), and 3.92 (s, 3H, CH3).