Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[NH:2]=[C:1]([N:38]1[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 12 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2 equivalents of N-methyl-piperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[S:19][C:5]2[NH:6][C:7](=O)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].C(=O)(O)[O-].[Na+]>COCCOCCOC>[Cl:1][C:2]1[S:19][C:5]2[NH:6][C:7](=[S:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: O=C1CN=C(c2ccccc2F)c2cc(Cl)sc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOCCOC
Product: Fc1ccccc1C1=NCC(=S)Nc2sc(Cl)cc21

Procedure:
10 g of 7-chloro-5-(o-fluorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one are dissolved in 150 ml of diethyleneglycol dimethyl ether at 55° C. and stirred with a mixture of 15 g of finely triturated phosphorus pentasulphide and 10 g of sodium bicarbonate for 40 minutes. The solvent is distilled off and the residue washed with water, filtered under vacuum and dried. The 7-chloro-5-(o-fluorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione thus obtained is refluxed in 200 ml of methanol with 15 g of acetyl hydrazine for 30 minutes. On cooling, 2-(2-acetylhydrazino)-7-chloro-5-(o-fluorophenyl)-3H-thieno[2,3-e]-1,4-diazepine precipitates. The methanol is distilled off and the residue partitioned between methylene chloride and water. The solvent is evaporated under reduced pressure and the residue crystallized from methanol to yield a second crop of 2-(2-acetylhydrazino)-7-chloro-5-(o-fluorophenyl)-3H-thieno[2,3-e]-1,4-diazepine, melting point 207° -209° C.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])[CH:5]=[CH:4][N:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([CH:26]([NH2:28])[CH3:27])[O:23][N:22]=2)=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]=[C:24]([CH:26]([NH:28][C:2]3[N:7]=[C:6]([N:8]4[CH2:12][CH2:11][O:10][C:9]4=[O:13])[CH:5]=[CH:4][N:3]=3)[CH3:27])[O:23][N:22]=2)=[CH:19][CH:20]=1
Reactant: CC(N)c1nc(-c2ccc(Cl)cc2)no1
Reactant: O=C1OCCN1c1ccnc(F)n1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1nccc(N2CCOC2=O)n1)c1nc(-c2ccc(Cl)cc2)no1
Yield: 9.7 %

Procedure:
A solution of 3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (89.1 mg, 0.487 mmol), 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine (115.9 mg, 0.518 mmol, 1.06 equiv), and DIPEA (0.20 mL, 1.1 mmol, 2.4 equiv) in DMSO (1.5 mL) was heated at 110° C. for 100 min. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (MeOH in CH2Cl2 0 to 5%) provided 3-(2-(1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one (18.2 mg, white solid) in 10.3% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]([C:18]([OH:20])=[O:19])=[N:10]2)=[CH:5][CH:4]=1.[CH:21](N(C(C)C)CC)(C)[CH3:22].C(O)C>S(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc(C(=O)O)nn1-c1ccc(OC)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(C(=O)OC)n(-c2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.9 %

Procedure:
A solution of 1-[(4-methoxy)phenyl]-5-(methoxycarbonyl)pyrazole-3-carboxylic acid (7.50 g, 27.1 mmol) in 50 mL of thionyl chloride was stirred at 80° C. for 1 h. The volatiles were then removed and the residue was azeotroped with 20 mL of toluene and dried in vacuo. The residue was dissolved in 100 mL of tetrahydrofuran and then there was added diisopropylethylamine (11.8 mL, 67.9 mmol) and absolute ethanol (3.2 mL, 54.3 mmol). The reaction mixture was allowed to stir at ambient temperature for 24 h. The volatiles were removed and the residue was dissolved in ethyl acetate. This solution was filtered through a pad of silica gel and was concentrated in vacuo to afford 3.7 g (45%) of the title compound which was used without purification. LRMS (DCI): 305.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([OH:24])=O)=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:49][C:50]1[C:51]([CH3:56])=[CH:52][CH:53]=[CH:54][CH:55]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[CH3:56][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[NH:49][C:22](=[O:24])[CH2:21][O:20][C:19]1[CH:25]=[CH:26][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1
Reactant: COc1cc2nccc(Oc3ccc(OCC(=O)O)cc3)c2cc1OC
Reactant: Cc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(OCC(=O)Nc4ccccc4C)cc3)c2cc1OC
Yield: 55 %

Procedure:
2-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenoxy}acetic acid (150 mg), WSC.HCl (122 mg), and HOBT.H2O (86 mg) were dissolved in chloroform (5 ml) to prepare a solution. o-Toluidine (0.055 ml) was then added to the solution, and the mixture was heated under reflux for 6 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (103 mg, yield 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:25]([F:28])([F:27])[F:26])[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[C:17]([CH3:24])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].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.[F:62][C:63]([F:73])([F:72])[CH2:64][CH2:65][N:66]1[C:70](=[O:71])[CH2:69][NH:68][CH2:67]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:25]([F:27])([F:28])[F:26])[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:68]4[CH2:69][C:70](=[O:71])[N:66]([CH2:65][CH2:64][C:63]([F:62])([F:72])[F:73])[CH2:67]4)=[O:20])=[C:17]([CH3:24])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=C1CNCN1CCC(F)(F)F
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N1CC(=O)N(CCC(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N,N-dimethylformamide (2 mL), 4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylbenzoic acid (50 mg, 0.11 mmol, 1.00 equiv), HATU (174 mg, 0.46 mmol, 4.00 equiv), DIEA (60 mg, 0.46 mmol, 4.00 equiv), 3-(3,3,3-trifluoropropyl)imidazolidin-4-one (25 g, 137.25 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at room temperature. The crude product was purified by Prep-HPLC. This resulted in 22.1 mg (32%) of 1-([4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl]carbonyl)-3-(3,3,3-trifluoropropyl)imidazolidin-4-one as a white solid. 641 [Ms+CH3CN+H]+; (300 MHz, CD3OD, ppm): δ7.77-7.64 (m, 4H), 7.45-7.28 (m, 1H), 5.12-4.69 (m, 1H), 4.32-4.22 (m, 1H), 4.08-4.01 (m, 1H), 3.87-3.54 (m, 2H), 3.14-2.87 (m, 3H), 2.70-2.31 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([F:14])[CH:3]=1.[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:15][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1ccc(Br)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1ccc(Br)cc1F
Temperature: 90 °C
Reaction time: 9 h
Yield: 96.1 %

Procedure:
To a stirring solution of ethyl 2-(4-bromo-2-fluorophenyl)acetate (3.92 g, 15.0 mmol) in carbon tetrachloride (50 mL) was slowly added N-bromosuccinimide (2.67 g, 15.0 mmol) and then azobisisobutyronitrile (0.37 g, 2.3 mmol). The reaction mixture was stirred for 9 h at 90° C. and then cooled to room temperature. The residue was purified by flash chromatography (0-100% ethyl acetate/hexanes) to provide the title product (4.9 g, 96% yield). MS(ES)+ m/e 340.9 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(F)ccc1Br
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1cc(F)ccc1Br
Temperature: 60 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a suspension of 2-bromo-5-fluorophenol (20.0 g, 104.7 mmol) and potassium carbonate (21.71 g, 157.1 mmol) in acetone (200 mL) was added dimethyl sulphate (10.90 mL, 115.2 mmol). The resulting suspension was allowed to stir at 60° C. for 2 h before being allowed to cool and then concentrated in vacuo. The residue was dissolved in ether (200 mL) and water (100 mL). The organic phase was washed with aqueous hydrochloric acid (2 N, 50 mL), saturated sodium bicarbonate solution (50 mL) with the resulting organic phase being dried (MgSO4) and the solvent evaporated in vacuo to give a pale yellow oil (21.46 g, 100%). δH (300 MHz, CDCl3) 7.45 (1H, dd, Ar), 6.70-6.55 (2H, m, Ar), 3.90 (3H, s, OCH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12]3=[N:16][N:17]=[C:18]([CH3:19])[N:11]3[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH:13]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:12]3=[N:16][N:17]=[C:18]([CH3:19])[N:11]3[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)=[CH:4][CH:3]=1
Reactant: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C2
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C2CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of 6-(4-chlorophenyl)-1-methyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one (200 mg, 0.62 mmol) in THF was added LiHMDS (0.9 mL, 0.9 mmol) at −78° C. The mixture was stirred at the same temperature for 1 h, and then tert-butyl 2-bromoacetate (180 mg, 0.92 mmol) was added, the mixture was warmed to room temperature and stirred overnight. NH4Cl aqueous (15 mL) was added, and then extracted with DCM (3×10 mL3). The combined organic layers were dried over Na2SO4, and the solvent was removed in vacuum. The residue was purified by column chromatography (silica-gel, DCM:MeOH=20:1) to give tert-butyl 2-(6-(4-chlorophenyl)-1-methyl-5-oxo-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-4-yl)acetate as a yellow solid (140 mg, 51.4%). LRMS (M+H)+: 324 m/z. 1H NMR (300 MHz, CD3OD): δ 1.46 (s, 9H), 2.72 (s, 3H), 3.08-3.15 (m, 1H), 3.31-3.39 (m, 1H), 4.10-4.15 (m, 1H), 7.15-7.23 (m, 3H), 7.40-7.43 (m, 2H), 7.50-7.54 (m, 2H), 7.74-7.79 (m, 1H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.C(N(C(C)C)CC)(C)C.[CH3:18][O:19][CH2:20]Cl.O>C(Cl)Cl>[CH3:18][O:19][CH2:20][O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1
Reactant: Cc1ccc(O)cc1
Reactant: COCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1ccc(C)cc1
Temperature: 25 °C

Procedure:
4-Cresol (59 g) was dissolved in 500 ml of methylene chloride, followed by addition of 238 ml of diisopropylethylamine and 66 g of chloromethyl methyl ether, and stirred at room temperature for two nights. The reaction solution was poured into water, which was then extracted with methylene chloride. After washing in 2N hydrogen chloride and then washing in saturated aqueous sodium chloride, the extract was dried over anhydrous sodium sulfate to yield residue. The residue was subjected to chromatography which was eluted with chloroform, to obtain 4-tolyl methoxymethyl ether.
Reaction SMILES: N12CCCC1=NCCC2.Br[CH:11]([CH:22](Br)[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:12](=[O:21])[CH2:13][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>CS(C)=O>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]2[O:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][C:12](=[O:21])[CH:11]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(=O)CC(=O)C(Br)C(Br)c1ccc(OC)cc1
Agent: C1CN=C2CCCN2C1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(=O)cc(-c2ccc(OC)cc2)o1
Reaction time: 0.5 h

Procedure:
1,5-Diazabicyclo[4.3.0]non-5-ene (3.2 g) was added dropwise to a stirred solution of ethyl 5,6-dibromo-2,4-dioxo-6-(4-methoxyphenyl)hexanoate (5.6 g) in dimethylsulphoxide (30 ml) maintained at a temperature of 15°-20° C. After 30 minutes at room temperature, water (50 ml) and petroleum ether 40°-60° C. (20 ml) were added with cooling. The yellow solid which precipitated was filtered off and recrystallised from ethanol-water. A second recrystallisation from ethyl acetate-petroleum ether 60°-80° C. yielded the title product as yellow needles (mp 131°-133° C. with sublimation).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][NH:10][NH2:11]>C(OCC)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:10]([CH3:9])[NH2:11])=[N:3][CH:4]=1
Reactant: CNN
Reactant: Brc1ccc(Br)nc1
Solvent: CCOC(C)=O
Product: CN(N)c1ccc(Br)cn1
Temperature: 100 °C

Procedure:
A mixture of 2,5-dibromopyridine (500 mg) and methylhydrazine (1 mL) was heated at 100° C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with a saturated brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The resultant crude product was purified by column chromatography on silica gel (solvent; chloroform) and the eluted fraction was concentrated. The residue was dissolved in tert-butanol and lyophilized to give 5-bromo-2-(N-methylhydrazino)pyridine (460 mg) as an oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]3)[CH2:4][CH2:3]1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O>[C:19]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]3)[CH2:4][CH2:3]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1ccc2cc(N3CCC(O)CC3)ccc2[nH]1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: O=C(OC1CCN(c2ccc3[nH]c(=O)ccc3c2)CC1)c1ccccc1
Temperature: 100 °C
Yield: 50.5 %

Procedure:
A mixture of 6-(4-hydroxypiperidino)carbostyril (0.25 g), benzoyl chloride (0.17 g) and dry pyridine (2 mL) was heated for 3 hours at 100° C. The reaction mixture was cooled and water (about 25 mL) and sodium bicarbonate (1 g) were added. The mixture was chilled in ice and stirred. The resulting solid was removed by filtration, washed with water and dried to give crude 6-(4-benzoyloxypiperidino)-2(1H)-quinolinone (0.25 g). Recrystallization twice from ethyl acetate gave 6-(4-benzoyloxypiperidino)-2(1H)-quinolinone (0.18 g); m.p. 212°-215° C.
Reaction SMILES: I[C:2]1[C:3](=[O:15])[O:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[As](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>C1C=CC=CC=1.[OH-].[Na+].C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[C:16]1([C:2]2[C:3](=[O:15])[O:4][CH2:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CSc1ccc(C2=C(I)C(=O)OC2)cc1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: N#Cc1ccccc1
Solvent: c1ccccc1
Product: CSc1ccc(C2=C(c3ccccc3)C(=O)OC2)cc1

Procedure:
A mixture of 4 g of the product of Step 3, 3.7 g of PhB(OH)2, 0.4 g of Ph3As, 0.4 g of PdCl2(PhCN)2 in 100 ml of benzene and 15 ml of 2N NaOH is refluxed for 6 h. Ether(200 ml) is then added and the mixture is washed with 100 ml of saturated NaHCO3. The organic layer is dried over MgSO4 and concentrated. The residue is purified by flash chromatography on silica gel eluted with 4:1 hexane/EtOAc to give the tide compound.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5][CH2:4]2)[CH2:2]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:2]1[C:3]2([CH2:8][CH2:7][CH:6]([CH:9]=[O:10])[CH2:5][CH2:4]2)[CH2:1]1
Reactant: OCC1CCC2(CC1)CC2
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CC1CCC2(CC1)CC2
Temperature: 25 °C

Procedure:
Spiro[2.5]oct-6-yl-methanol (2.57 g, 18.3 mmol, 1.0 eq.) was dissolved in CH2Cl2 (30 mL) and placed in a ice-water bath at 0° C. Pyridinium dichromate (PCC) (7.9 g, 36.6 mmol, 2.0 eq.) was added and the reaction warmed to room temperature for 4 hours with stirring. The crude reaction was filteredd through a Celite pad and washed with CH2Cl2 and evaporated. The crude material was dissolved in diethyl ether and filtered through Celite, washing with diethyl ether several times. Evaporated solvent to provide Spiro[2.5]octane-6-carbaldehyde as a brown oil (2.98 g, quantitative) that was used directly. 1H NMR (CHCl3, 400 MHz) δ 0.17-0.27 (m, 4H), 0.88-0.91 (m, 2H), 1.09-1.25 (m, 2H), 1.52-1.54 (m, 2H), 1.69-1.75 (m, 3H), 9.44 (d, 1H, J=1.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:16][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]3[N:4]([CH3:7])[N:5]=[CH:6][C:2]=3[F:1])[CH:9]=2)=[O:26])=[CH:20][C:19]=1[C:27]([F:28])([F:29])[F:30]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Product: COc1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1-c1c(F)cnn1C
Yield: 29 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4-chloro-3-trifluoromethylphenylisocyanate, in a similar manner as described in Example 1.68, providing 15 mg (29% yield) of Compound 84: LCMS m/z (%)=445 (M+H37Cl, 34), 443 (M+H35Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.69 (s, 1H), 8.39 (s, 1H), 8.15 (d, J=2.4 Hz, 1H), 7.74 (dd, J1=8.6 Hz, J2=2.2 Hz 1H), 7.65 (dd, J1=9.0 Hz, J2=2.6 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.49 (d, J=2.4 Hz, 1H), 7.38 (d, JH,F=4.4 Hz, 1H), 7.14 (d, J=9.2 Hz, 1H) 3.83 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −63.75 (s, 3F), −177.40 (d, JH,F=5.3 Hz, 1F).
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH2:8][O:9][CH3:10])[CH:5]=[N:4][C:3]=1[C:11]1[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][N:12]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:29]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:6]([CH2:7][CH2:8][O:9][CH3:10])[CH:5]=[N:4][C:3]=2[C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][N:12]=2)=[CH:22][C:21]=1[F:29]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: COCCn1cnc(-c2cc(C#N)ccn2)c1Br
Product: COCCn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(Cl)c(F)c1

Procedure:
The title compound was prepared from 2-[5-bromo-1-(2-methoxyethyl)-1H-imidazol-4-yl]pyridine-4-carbonitrile and 4-chloro-3-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C18H14ClFN4O, 358. Found, 357, 359.
Reaction SMILES: [C:1]1([C@@H:7]([NH:14][C:15]([C@H:17]2[N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19][S:18]2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[C:29]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:34]=[CH:33][C:32]([S:35]([N:21]2[CH2:20][CH2:19][S:18][C@H:17]2[C:15]([NH:14][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:16])(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCS[C@H]1C(=O)N[C@H](c1ccccc1)c1ccccn1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: O=C(N[C@H](c1ccccc1)c1ccccn1)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general strategies and protocols outlined in Example 1, starting from tert-butyl (2S)-2-({[(R)-phenyl(pyridin-2-yl)methyl]amino}-carbonyl)-1,3-thiazolidine-3-carboxylate (Intermediate 6) and [1,1′-biphenyl]-4-sulfonyl chloride, the title compound was obtained in 99% purity by HPLC.
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:14][OH:15].C(N(CC)CC)C>CO>[OH:15]/[N:14]=[C:7](\[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)/[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)/C(=N/O)c1ccccc1
Temperature: 60 °C
Reaction time: 17 h
Yield: 12.9 %

Procedure:
A mixture of methyl phenylglyoxylate (25.5 g), hydroxylamine hydrochloride (11.3 g), triethylamine (22.8 ml) and methanol (300 ml) was stirred for 17 hours at 60° C. The reaction mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, (MgSO4), and then concentrated. The residual crystals were recrystallized from ethyl acetatehexane to obtain methyl E-2-hydroxyimino-2-phenylacetate (3.58 g, yield 13%) as colorless crystals. m.p. 151-153° C.