Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])=[CH:12][C:11]=2[Cl:21])[CH:3]=1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH2:19][CH3:20])(=[O:17])=[O:18])=[CH:12][C:11]=2[Cl:21])[CH:3]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2N)c(Cl)c1
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc(S(=O)(=O)CC)cc1Cl

Procedure:
A mixture of the product from step (iii) (0.95 g), ethyl bromoacetate (0.145 ml) and sodium acetate (0.160 g) in dry ethanol (30 ml) was heated under reflux 24 h. A further 5 equivalents of ethyl bromoacetate were added and heated for a further 48 h. The mixture was partitioned between water/ethyl acetate, the organics separated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/diethylether 1:1, yield 0.44 g.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>ClCCl>[O:23]=[C:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H]1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCC1=O
Reaction time: 1.5 h
Yield: 67.7 %

Procedure:
Dess-Martin periodinane (2.72 g, 6.41 mmol) was added to a stirred solution of tert-butyl 2-hydroxycyclopentylcarbamate (1.23 g, 6.11 mmol, from Step 1) in dichloromethane (30 mL) while the reaction container was placed in a room temperature water bath. After 1.5 h at room temperature, the mixture was quenched with 1 M aqueous sodium thiosulfate. After shaking the mixture vigorously, the dichloromethane phase was separated and concentrated. Silica gel chromatography, eluting with 0 to 50% ethyl acetate in hexanes, gave tert-butyl 2-oxocyclopentylcarbamate as white crystalline solid (824.6 mg, 68% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 5.03 (1 H, br. s.), 3.90 (1 H, br. s.), 2.56 (1 H, br. s.), 2.38 (1 H, dd, J=19.15, 8.80 Hz), 2.08-2.22 (1 H, m), 1.96-2.08 (1 H, m), 1.73-1.89 (1 H, m), 1.52-1.69 (1 H, m), 1.42 (9 H, s).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH:12][CH2:13][CH:14](OC)OC.[S-:19][C:20]#[N:21].[K+]>Cl.C(O)C.O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[N:12]1[CH:13]=[CH:14][NH:21][C:20]1=[S:19]
Reactant: COC(CNC1CCc2c(F)cc(F)cc21)OC
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Fc1cc(F)c2c(c1)C(n1cc[nH]c1=S)CC2
Yield: 48.4 %

Procedure:
A mixture of (4,6-difluoroindan-1-yl)-(2,2-dimethoxyethyl)amine (11.68 g, 45.9 mmol), potassium thiocyanate (4.46 g, 45.9 mmol) in 21.6 mL of 12N hydrochloric acid, 86 mL of ethanol and 86 mL of water was heated at 80° to 85° C. for 15 hours. The mixture was cooled in an ice bath and diluted with water giving a crystalline material. The material was isolated by filtration and the filter residue was rinsed with cold ethanol (2×25 mL) and 50 mL of diethyl ether. Drying gave 1-(4,6-difluoroindan-1-yl)-1,3-dihydroimidazole-2-thione (5.65 g, 22.2 mmol), m.p. 205°-207° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:36]([OH:38])=O)[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][C:18]2[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:16])[CH:12]=[C:11]([O:24][C@@H:25]([CH3:35])[CH2:26][O:27][Si](C(C)(C)C)(C)C)[CH:10]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([CH:12]=[C:11]([O:24][C@@H:25]([CH3:35])[CH2:26][OH:27])[CH:10]=2)[C:15]([NH:17][C:18]2[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:16])=[N:6][CH:5]=[C:4]([C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:38])[CH:3]=1
Reactant: C1COCCN1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ncc(C(=O)O)cc2Cl)cc(C(=O)Nc2ccn(C)n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](CO)Oc1cc(Oc2ncc(C(=O)N3CCOCC3)cc2Cl)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 24.7 %

Procedure:
A solution 5-chloro-6-[(3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyridine-3-carboxylic acid (0.15 g, 0.267 mmol), morpholine (0.07 mL, 0.803 mmol), HATU (0.213 g, 0.560 mmol) and DIPEA (0.15 mL, 0.861 mmol) in DMF (7 mL) was stirred at RT for 2 days. Water (20 mL) was added and the solution extracted with ethyl acetate (50 mL). The ethyl acetate layer was separated, washed with brine and dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with 1% methanol in ethyl acetate. 3.5M Hydrochloric acid (0.5 mL) was added to a solution of the residual solid taken up in methanol (5 mL) and allowed to stir at RT for 20 minutes. The solution was neutralised with saturated sodium bicarbonate solution and the methanol removed in vaccuo and the residual solution partitioned between water (20 mL) and ethyl acetate. The ethyl acetate layer was separated and washed with brine, dried (MgSO4) and evaporated to give the desired product (34 mg). 1H NMR δ (d6-DMSO): 1.28 (d, 3H), 3.58 (m, 10H), 3.81 (s, 3H), 4.61 (sextet, 1H), 4.89 (t, 1H), 6.60 (d, 1H), 7.03 (t, 1H), 7.41 (s, 1H), 7.54 (s, 1H), 7.63 (d, 1H), 8.20 (q, 2H), 10.84 (s, 1H). m/z 516 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:29])[C:8]2[O:14][C:13]3[C:15]([Cl:25])=[CH:16][C:17]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:18][C:12]=3[CH2:11][S:10](=[O:27])(=[O:26])[C:9]=2[CH:28]=1)=[O:4].[Cl:30][C:31]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:32]=1[CH:33]=O.C([BH3-])#N.[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:29])[C:8]2[O:14][C:13]3[C:15]([Cl:25])=[CH:16][C:17]([N:19]4[CH2:20][CH2:21][N:22]([CH2:33][C:32]5[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:31]=5[Cl:30])[CH2:23][CH2:24]4)=[CH:18][C:12]=3[CH2:11][S:10](=[O:26])(=[O:27])[C:9]=2[CH:28]=1)=[O:4]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(Cc4ccc(Cl)cc4Cl)CC3)cc(Cl)c1O2

Procedure:
Titanium isopropoxide (0.25 mL, 0.82 mmol) was added to solution of Example 104k (0.3 g, 0.68 mmol) and 2,4-dichlorobenzaldehyde (0.120 g, 0.68 mmol) in dry methanol (10 mL). The reaction mixture was processed as described in the synthesis of Example 108k using sodium cyanoborohydride (0.041 g, 0.65 mmol) to obtain the title compound as a white solid. Yield: 0.285 g, (68.69%); 1H NMR (DMSO-d6): δ 2.60-2.80 (m, 7H, 2CH2, CH3), 3.20-3.35 (m, 4H, 2CH2), 3.95 (s, 3H, OCH3), 4.65 (s, 2H, CH2), 6.80 (d, 1H, Ar), 6.90 (d, 1H, Ar), 7.25-7.45 (m, 3H, Ar), 8.10 (s, 1H, Ar), 8.50 (s, 1H, Ar); MS: m/e (ES+) 596 (M+1).
Reaction SMILES: ClC(Cl)C.[Br:5][C:6]1[CH:15]=[N:14][C:13]2[NH:12][C:11](=O)[C:10]([CH3:18])([CH3:17])[O:9][C:8]=2[CH:7]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:25][NH2:26]>C(Cl)Cl>[Br:5][C:6]1[CH:15]=[N:14][C:13]2[NH:12]/[C:11](=[N:26]/[CH3:25])/[C:10]([CH3:18])([CH3:17])[O:9][C:8]=2[CH:7]=1
Reactant: CN
Reactant: CC1(C)Oc2cc(Br)cnc2NC1=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: C/N=C1/Nc2ncc(Br)cc2OC1(C)C
Temperature: -78 °C
Yield: 89 %

Procedure:
A dichloroethane (5 mL) solution of 7-bromo-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (520 mg, 2 mmol) and phosphorus pentachloride (840 mg, 4 mmol) was irradiated in a microwave oven for 10 min at 160° C. The solution was cooled to −78° C. and methylamine (2M in THF) was added it slowly until it became permanently basic. The mixture was diluted with CH2Cl2, washed with dilute solution of NaOH, dried and evaporated. Crystallization from CH2Cl2/hexane afforded 480 mg (89%) of the title compound. 1H NMR (300 MHz, CDCl3, 8) 8.07 (d, J=2.1 Hz, 1H), 7.21 (d, J=2.1 Hz, 1H), 4.9 (s, br, 1H), 3.06 (d, J=4.5 Hz, 3H), 1.46 (s, 6H). MS (ESI) m/e 270 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[C:17]2[S:22][CH2:21][S:20][CH2:19][S:18]2)[CH2:15][CH3:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH:17]2[S:18][CH2:19][S:20][CH2:21][S:22]2)[CH2:15][CH3:16])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=C1SCSCS1)c1ccc(Oc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(c1ccc(Oc2ccccc2)cc1)C1SCSCS1
Reaction time: 8 h
Yield: 90.5 %

Procedure:
In 10 ml of anhydrous dichloromethane were dissolved 1.0 g of 2-{1-(4-phenoxyphenyl)propan-1-ylidene}-1,3,5-trithiane and 0.67 g of triethylsilane, and a solution prepared by diluting 1 ml of trifluoroacetic acid with 5 ml of dichloromethane was added dropwise at room temperature. The resulting solution was stirred overnight. After sodium carbonate powder was added, the resulting mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation, and then the residue was purified by a silica gel column chromatography (chloroform:hexane=2:1) to give 0.91 g of the desired compound.
Reaction SMILES: Cl.C(OCC)(=O)C.[CH2:8]([O:10][C:11](=[O:33])[C@H:12]([NH:25]C(OC(C)(C)C)=O)[CH2:13][CH2:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)[CH3:9]>C(OCC)(=O)C>[CH2:8]([O:10][C:11]([C@H:12]1[CH2:13][CH2:14][C:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)=[N:25]1)=[O:33])[CH3:9]
Reactant: CCOC(=O)[C@@H](CCC(=O)c1ccc(F)c(F)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CCC(c2ccc(F)c(F)c2)=N1
Reaction time: 3 h
Yield: 84.3 %

Procedure:
4 N hydrochloric acid/ethyl acetate (156 mL) was added to an ethyl acetate (30 mL) solution of (R)-2-t-butoxycarbonylamino-5-oxo-5-(3,4-difluorophenyl) valeric acid ethyl ester (21.2 g), and stirring was continued for 3 hours at room temperature. The solvent was removed under a vacuum, and ethyl acetate and sodium bicarbonate aqueous solution was added to the residue, and the organic layer was partitioned. After washing the organic layer with brine, the resultant was dried over anhydrous magnesium sulfate. The solvent was removed under a vacuum, and the title compound (12.19 g) was obtained. The physical property values were as follows.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[O:5][C:4](=O)[CH:3]=1.[NH4+:12].[OH-]>>[OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:12][C:4](=[O:5])[CH:3]=1
Reactant: [NH4+]
Reactant: CC(C)c1cc(O)cc(=O)o1
Agent: [OH-]
Product: CC(C)c1cc(O)cc(=O)[nH]1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 4-hydroxy-6-isopropyl-pyran-2-one (4.82 g, 31.3 mmol) in conc. NH4OH (15 mL) is stirred at 100° C. in a sealed tube for 4 h. The solution is then transferred to a recovery flask and concentrated in vacuo. Toluene is used to azeotropically remove any remaining water. 4-Hydroxy-6-isopropyl-1H-pyridin-2-one is obtained as a tan powder. 1H NMR (DMSO-d6, 300 MHz) δ 10.96 (br s, 1H), 10.36 (br s, 1H), 5.59 (d, J=2.1 Hz, 1H), 5.33 (d, J=2.1 Hz, 1H), 2.64 (sept, J=6.9 Hz, 1H), 1.11 (d, J=6.9 Hz, 6H) ppm.
Reaction SMILES: II.[Br:3][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[CH2:11])[CH:7]=[CH:8][CH:9]=1.N.[NH2:24][C:25]([NH2:27])=[O:26]>C(OCC)(=O)C.C(#N)C.[Ag]OC#N.ClCCl>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:20])([F:21])[F:22])=[CH:14][CH:13]=3)[CH2:11][O:26][C:25]([NH2:27])=[N:24]2)[CH:7]=[CH:8][CH:9]=1
Reactant: NC(N)=O
Reactant: C=C(c1ccc(OC(F)(F)F)cc1)c1cccc(Br)c1
Agent: N#CO[Ag]
Agent: II
Agent: N
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC1=NC(c2ccc(OC(F)(F)F)cc2)(c2cccc(Br)c2)CO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
A solution of iodine (2.92 g, 11.5 mmol) in ethyl acetate (50 mL) was added dropwise over 25 min to a mixture of 4-[1-(3-bromo-phenyl)-vinyl]-1-trifluoromethoxy-benzene (3.6 g, 10.5 mmol) and silver cyanate (1.88 g, 12.6 mmol) in acetonitrile (38 mL) and ethyl acetate (18 mL), cooled in an ice bath. After complete addition, the reaction suspension was stirred for another 15 min at room temperature when TLC indicated the complete conversion of starting material. The reaction mixture was filtered, and the filtrate concentrated to give a dark grey oil. 50 mL of aqueous ammonia (25%) was added to the oil, and the mixture was stirred and warmed to 60° C. for 4 hours. LC-MS at this point indicated complete conversion of the intermediate urea to the desired aminoxazoline. dichloromethane (40 mL) was added to the crude and the two phases were separated; organic layer was collected, dried over magnesium sulfate anhydrous, filtered and evaporated under reduced pressure. Crude was purified by silica gel chromatography eluting with dichloromethane to give 1.9 g of desired product as a colorless oil (45%)
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].[OH:9][C@H:10]([CH2:16][O:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][C:12](OC)=[O:13].[Li]CC(OC(C)(C)C)=O.[Cl-].[NH4+]>C(OCC)(=O)C.O1CCCC1>[OH:9][C@H:10]([CH2:16][O:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:11][C:12](=[O:13])[CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)C[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CC(=O)OC(C)(C)C
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)C[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -70 °C
Yield: 126.2 %

Procedure:
Under a nitrogen atmosphere and at 0° C., 87.78 ml. of 1.5M. n-butyllithium/hexane (132 mmoles) is added dropwise to 18.49 ml. (132 mmoles) of diisopropylamine in 150 ml. of dry tetrahydrofuran, and the mixture is stirred for 30 minutes to form a solution of lithium diisopropylamide. The obtained solution is cooled to -70° C., a solution of 17.76 ml. (132 mmoles) of t-butyl acetate in 25 ml. of dry tetrahydrofuran is added over a period of 1 hour with stirring at -65°--70° C., the reaction mixture is stirred for 1.5 hours at the same temperature, a solution of 11.28 g. (30 mmoles) of methyl (S)-3-hydroxy-4-(triphenylmethoxy)butanoate (obtainable by Step 3 of Example 1) in 75 ml. of dry tetrahydrofuran is added to the obtained solution of t-butyl lithioacetate at -65°--70° C., and the yellow solution is stirred at about - 70° C. for 0.5 hour, warmed to -10° C. and stirred at -10° C. for 1 hour (with thin layer chromatography (TLC) monitoring to indicate when the reaction is over), the reaction mixture being stirred under nitrogen throughout. 150 ml. of saturated aqueous ammonium chloride is added to quench the reaction at -60°--70° C., the mixture is warmed to 0° C., transferred to a separatory funnel and diluted with ethyl acetate, and the organic phase is separated. The aqueous layer is extracted with an additional 200 ml. of ethyl acetate, and the organic phases are combined, washed successively with 90 ml. of 1N. hydrochloric acid and 90 ml. of saturated aqueous sodium bicarbonate, dried and filtered. The organic solution is evaporated to yield the crude product (17.43 g.) (estimated to be about 80% pure by chromatography analysis).
Reaction SMILES: CC(C)[C@@H](N1CC2C(=CC=C(C3C=CC(NC(NC4C=CC=C(C(F)(F)F)C=4)=O)=CC=3)C=2)C1=O)C(O)=O.[O:38]=[C:39]1[C:47]2[C:42](=[CH:43][C:44]([C:48]3[CH:53]=[CH:52][C:51]([NH:54][C:55]([NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:66])[F:65])[CH:59]=4)=[O:56])=[CH:50][CH:49]=3)=[CH:45][CH:46]=2)[CH2:41][N:40]1[C:68]1([C:73]([O:75]C)=[O:74])[CH2:72][CH2:71][CH2:70][CH2:69]1>>[O:38]=[C:39]1[C:47]2[C:42](=[CH:43][C:44]([C:48]3[CH:49]=[CH:50][C:51]([NH:54][C:55]([NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:66])([F:65])[F:67])[CH:59]=4)=[O:56])=[CH:52][CH:53]=3)=[CH:45][CH:46]=2)[CH2:41][N:40]1[C:68]1([C:73]([OH:75])=[O:74])[CH2:72][CH2:71][CH2:70][CH2:69]1
Reactant: COC(=O)C1(N2Cc3cc(-c4ccc(NC(=O)Nc5cccc(C(F)(F)F)c5)cc4)ccc3C2=O)CCCC1
Agent: CC(C)[C@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Product: O=C(Nc1ccc(-c2ccc3c(c2)CN(C2(C(=O)O)CCCC2)C3=O)cc1)Nc1cccc(C(F)(F)F)c1
Yield: 83 %

Procedure:
The compound of example 370 was prepared analogous to the compound of example 361 by hydrolysis of the compound of example 369.
Reaction SMILES: Cl[CH2:2][CH:3]([O:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4]Cl.[CH2:20]([NH2:22])[CH3:21]>>[CH2:20]([N:22]1[CH2:4][CH:3]([O:6][CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2]1)[CH3:21]
Reactant: CCN
Reactant: ClCC(CCl)OC(c1ccccc1)c1ccccc1
Product: CCN1CC(OC(c2ccccc2)c2ccccc2)C1
Yield: 47.5 %

Procedure:
Following the procedure of Preparation 13, the title compound was prepared from 1,3-dichloro-2-diphenylmethoxypropane (44.0 g, 0.15 mol) and ethylamine (100 ml) in 47.5% yield; bp 135°-142° C./0.10 mm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[Cl:20].C(=O)([O-])[O-].[Cs+].[Cs+].O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:20][C:13]1[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COc1ccc(Cl)c(Br)c1
Reactant: OB(O)c1ccccc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cl)c(-c2ccccc2F)c1
Temperature: 80 °C
Yield: 88.6 %

Procedure:
Tetrakistriphenylphosphinepalladium (0) (229 mg, 0.20 mmol) was added to a degassed mixture of 2-fluorophenylboronic acid (556 mg, 3.97 mmol), 2-bromo-1-chloro-4-methoxybenzene (0.49 mL, 3.57 mmol), caesium carbonate (3.87 g, 11.9 mmol), water (5.0 mL) and dioxane (26.0 mL). The reaction was heated at 80° C. for 18 hours, cooled to room temperature and then partitioned between ethyl acetate (30.0 mL) and sat. aq. ammonium chloride (10.0 mL). The aqueous phase was separated and extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with brine (5.0 mL), dried over MgSO4, filtered and evaporated to give a pale yellow oil. Column chromatography purification on silica, eluting with heptanes gave the title compound (749 mg, 88%) as a colourless oil.
Reaction SMILES: CC1(C)O[C@@H](CO)CO1.CC(C)(C)[Si](C1C=CC=CC=1)(C1C=CC=CC=1)OC[C@@H](O)CO.[N+:33]([O:36][C@@H:37]([CH2:40][O:41][N+:42]([O-:44])=[O:43])[CH2:38][OH:39])([O-:35])=[O:34]>>[N+:33]([O:36][C@H:37]([CH2:40][O:41][N+:42]([O-:44])=[O:43])[CH2:38][OH:39])([O-:35])=[O:34]
Reactant: O=[N+]([O-])OC[C@@H](CO)O[N+](=O)[O-]
Agent: CC(C)(C)[Si](OC[C@@H](O)CO)(c1ccccc1)c1ccccc1
Agent: CC1(C)OC[C@H](CO)O1
Product: O=[N+]([O-])OC[C@H](CO)O[N+](=O)[O-]

Procedure:
The title compound was prepared in four steps from ((4S)-2,2-dimethyl-1,3-dioxolan-4-yl)methan-1-ol following the procedures for Examples 5a, 5b, 5c, and 5d.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)(C1C=CC(C)=CC=1)(=O)=O.[Cl:24][C:25]1[CH:34]=[CH:33][C:28]2[N:29]=[C:30]([SH:32])[NH:31][C:27]=2[CH:26]=1.C(N(CC)CC)C.O>C(#N)C>[Cl:24][C:25]1[CH:34]=[CH:33][C:28]2[N:29]=[C:30]([S:32][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[NH:31][C:27]=2[CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCOc2ccccn2)cc1
Reactant: Sc1nc2ccc(Cl)cc2[nH]1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: Clc1ccc2nc(SCCCCCOc3ccccn3)[nH]c2c1
Temperature: 25 °C
Yield: 36 %

Procedure:
0.67 g of the compound obtained in Example 3b and 0.37 g of 5-chloro-2-mercaptobenzimidazole were refluxed for 5 hours in 15 ml of acetonitrile containing 0.25 g of triethylamine. The reaction mixture was cooled to room temperature, then added with water and extracted with ethyl acetate. The extract was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 0.25 g of the title compound (yield: 42%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].[Li]CCCC.[N:21]1[C:30]2[C:25](=[CH:26][C:27]([CH:31]=[O:32])=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1>C1COCC1>[F:1][C:2]1[C:7]([CH:31]([OH:32])[C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[N:21]=[CH:22][CH:23]=[N:24]3)=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: O=Cc1ccc2nccnc2c1
Reactant: CC(C)(C)C(=O)Nc1ccc(F)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(F)c(C(O)c2ccc3nccnc3c2)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To a solution of N-(2,4-difluorophenyl)pivalamide (740 mg, 3.46 mmol, 1.2 eq.) in THF (10 mL) cooled at −78° C. was added n-BuLi (2.76 mL, 6.9 mmol, 2.4 eq.) dropwise. The resulting mixture was stirred at −78° C. for 1 h, then a solution of quinoxaline-6-carbaldehyde (450 mg, 2.88 mmol, 1.0 eq.) in THF (20 mL) was added dropwise. The mixture was stirred at −78° C. for 1 h, then quenched by the addition of NH4Cl solution. The mixture was extracted with EA (20 mL×3) and the combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was purified via flash column chromatography (PE/EA=2/1, v/v) to afford N-(2,4-difluoro-3-(hydroxy(quinoxalin-6-yl)methyl)phenyl)pivalamide as a yellow foam (541 mg, 50.7%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:27])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14]3)[CH:11]=2)[C:6](=[O:28])[C:5]([C:29]([OH:31])=[O:30])=[CH:4]1)[CH3:2].[CH2:32]=O>C(O)=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:27])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:32])[CH:15]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14]3)[CH:11]=2)[C:6](=[O:28])[C:5]([C:29]([OH:31])=[O:30])=[CH:4]1)[CH3:2]
Reactant: CCCCCCOCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CCN1
Reactant: C=O
Solvent: O=CO
Product: CCCCCCOCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CCN1C

Procedure:
A 400 mg portion of 1-ethyl-6-fluoro-7-[3[(hexyloxy)methyl]-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added to a mixture of 1.2 ml of 37% formaldehyde and 1.5 ml of 90% formic acid. The mixture was heated on a steam bath for one hour, evaporated to an oil, diluted with 5 ml of water and neutralized with 1N sodium hydroxide. The solid was collected and dried, giving 360 mg of the desired product, mp 172°-174° C.