Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:5]([Cl:12])=[N:6][C:7]([Cl:11])=[N:8][C:9]=1Cl)[CH:2]=[CH2:3].[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([C:4]1[C:9]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([Cl:13])=[CH:15][CH:16]=2)=[N:8][C:7]([Cl:11])=[N:6][C:5]=1[Cl:12])[CH:2]=[CH2:3]
Reactant: Nc1ccc(Cl)cc1
Reactant: C=CCc1c(Cl)nc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=CCc1c(Cl)nc(Cl)nc1Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 5-allyl-2,4,6-trichloropyrimidine (7 g), 4-chloroaniline (4 g) and potassium carbonate (4.27 g) in ethanol (100 ml) was stirred at room temperature for 24 h. The mixture was partitioned between ethyl acetate and water, the organics dried (MgSO4), and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/diethylether (2:1). Yield 5 g
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([O:19][CH3:20])=[CH:9][CH:10]=[C:11]3[C:16]=2[O:15][C:14](=[O:17])[CH:13]=[C:12]3O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:41]>C(Cl)(Cl)Cl>[Cl:41][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]([O:19][CH3:20])=[CH:9][CH:10]=2)[O:15][C:14](=[O:17])[CH:13]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)cc(=O)oc2c1OC1CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(Cl)cc(=O)oc2c1OC1CCCC1
Temperature: 80 °C

Procedure:
A mixture of 8-(cyclopentyloxy)-4-hydroxy-7-methoxy-2H-chromen-2-one (415 mg, 1.5 mmol, Example 1, Step 2), triphenylphosphine (787 mg, 3.0 mmol), CCl4 (0.75 mL, 7.8 mmol), and chloroform (2 mL) was heated at 80° C. in a sealed vial for 4.5 h and then allowed to cool to rt. The reaction was concentrated and purified by silica gel chromatography (1:0→4:1; hexanes:ethyl acetate) to give 4-chloro-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one: MS (ESI): 294.8.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[OH:15].[C:16]1([CH3:25])[C:17]([N:22]=[C:23]=S)=[CH:18][CH:19]=[CH:20][CH:21]=1>C(O)C>[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[O:15][C:3]2[CH:4]=[C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Cc1ccccc1N=C=S
Reactant: CCOC(=O)CCc1ccc(N)c(O)c1
Solvent: CCO
Product: CCOC(=O)CCc1ccc2nc(Nc3ccccc3C)oc2c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
A solution of ethyl 3-(4-amino-3-hydroxyphenyl)-propionate (1.94 g) in ethanol (50 ml) was treated with o-tolyl isothiocyanate (1.66 g) and then heated at 40° C. for 2 hours. The mixture was evaporated then treated with ethanol (50 ml), then with diisopropylcarbodiimide (3 mL) and then stirred at 40° C. for 1 hour. The mixture was evaporated and the residue was treated with diethyl ether (50 ml) then filtered. The filtrate was evaporated to dryness and the residue subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (2:3, v/v) to give the title compound (1.6 g) as a colourless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([NH:10][CH2:11][C:12]1([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(=O)[CH3:8].O>O1CCCC1>[CH2:7]([NH:10][CH2:11][C:12]1([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH3:8]
Reactant: CC(=O)NCC1(N2CCN(C)CC2)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCNCC1(N2CCN(C)CC2)CCCCC1
Reaction time: 8 h

Procedure:
To a stirred solution of lithium aluminium hydride (3 g.,) in dry tetrahydrofuran (40 ml) was added a solution of 1-[1-(Acetamidomethyl)cyclohexyl]-4-methyl piperazine (3 g.,) in dry tetrahydrofuran (40 ml) dropwise. The stirring was continued overnight, the suspension was heated under reflux for a further 6 hrs. and the excess LiAlH4 neutralised with water. The mixture was filtered and the filtrate was dried (anhyd. Na2SO4) and evaporated to an oil, which was micro distilled to give 1-[1-(Ethylaminomethyl)cyclohexyl]-4-methyl piperazine as a colourless oil. b.p. 35mm 105°-109° (1.96 g., 69%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:12](=[CH:13][CH:14]=1)[S:9](=[O:11])(=[O:10])[N:8]([CH:15]([S:22][C:23]1[NH:27][N:26]=[N:25][N:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]2=[O:28])([O-])=O>[Ni].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:12](=[CH:13][CH:14]=1)[S:9](=[O:11])(=[O:10])[N:8]([CH:15]([S:22][C:23]1[NH:27][N:26]=[N:25][N:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:7]2=[O:28]
Reactant: O=C1c2cc([N+](=O)[O-])ccc2S(=O)(=O)N1C(Sc1nnn[nH]1)c1ccccc1
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc2c(c1)C(=O)N(C(Sc1nnn[nH]1)c1ccccc1)S2(=O)=O
Yield: 42.9 %

Procedure:
5-Nitro-2-(1-phenyl-1H-tetrazol-5-ylthiomethyl)saccharin (1 g, 0.0024 mol) was reduced over 3 spatulas of Rainey nickel (washed with THF prior to use) in 150 ml of THF under 50 psi hydrogen pressure. When reduction was complete (in about 5 hours) the reaction mixture was filtered, the filter pad washed with THF, and the filtrate evaporated to dryness to give a pale yellow, cloudy oil which was taken into hot ethanol and filtered. On cooling, the product separated and was collected to give 0.4 g (43%) of 5-amino-2-(1-phenyl-1H-tetrazol-5-ylthiomethyl)saccharin as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[CH:11][N:10]=[C:9]2[CH:15]([NH:17][CH3:18])[CH3:16])=[CH:4][CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[CH:11][N:10]=[C:9]2[CH:15]([N:17]([CH3:18])[C:28]([NH:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:30])([F:31])[F:19])[CH:22]=2)=[O:29])[CH3:16])=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CNC(C)c1nccc(=O)n1-c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: CC(c1nccc(=O)n1-c1ccc(F)cc1)N(C)C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
The amine (26) (12 mg, 0.05 mmol) and 3-trifluoromethylphenyl isocyanate (7.5 L, 0.05 mmol) were dissolved in chloroform (0.2 mL) and stirred at ambient temperature. After complete conversion of the starting material by TLC analysis, the solvent was removed and the resulting residue was subjected to silica-gel column chromatography [eluent: Dichloromethane] to give the title urea (27) (14 mg, quant.) as a solid:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([S:18][N:19]([CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=3)=[CH:30][CH:29]=2)[C:20](=[O:24])[O:21][CH2:22][CH3:23])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[C:12]1([S:18]([N:19]([CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=3)=[CH:30][CH:29]=2)[C:20](=[O:24])[O:21][CH2:22][CH3:23])=[O:9])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)N(CCOc1ccc(Oc2cc(F)cc(F)c2)cc1)Sc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)N(CCOc1ccc(Oc2cc(F)cc(F)c2)cc1)S(=O)c1ccccc1

Procedure:
A solution of 8.1 g of 55% 3-chloroperbenzoic acid in 50 ml of dichloromethane is added dropwise at 0° to +5° C. in the course of 20 minutes to a solution of 11.5 g of ethyl N-phenylthio-2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate in 80 ml of dichloromethane, with stirring. After the reaction mixture has been stirred for 2 hours at +20° to +22° C., it is extracted twice with a 10% sodium carbonate solution and washed to neutrality with water. The dichloromethane phase is dried over sodium sulfate, and the solvent is distilled off in vacuo. The residue is purified by chromatography on silica gel (eluent: n-hexane/diethyl ether, 3:1), which process gives ethyl N-phenylsulfinyl-2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate, colourless viscous oil nD20 :1.5645.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][CH:16]=[C:17]([CH2:20][C:21]#[N:22])[C:18]#[N:19])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[O-]CC.[K+].O>O1CCCC1.C(O)C>[NH2:22][C:21]1[N:15]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=[C:17]([C:18]#[N:19])[CH:20]=1
Reactant: N#CCC(C#N)=CNC(c1ccccc1)c1ccc(F)cc1
Agent: CC[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1cc(N)n(C(c2ccccc2)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-({[(4-fluorophenyl)(phenyl)methyl]amino}methylene)butanedinitrile (13.9 g, 47.7 mmol) in tetrahydrofuran (50 ml) and ethanol (50 ml) was slowly added potassium ethoxide (7.05 g, 83.8 mmol), the mixture was stirred at room temperature for 1 hour and poured into iced water. The product was extracted with ethyl acetate, the extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give the objective product as oily matter.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:12]([N:17]([CH3:25])[C:18](=[O:24])[C@H:19]([CH:21]([CH3:23])[CH3:22])[NH2:20])[C@@H:13]([CH3:16])[CH2:14][CH3:15])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH:26]1[C:38]2[CH:37]([CH2:39][O:40][C:41]([NH:43][C:44]3([C:49](O)=[O:50])[CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:42])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]=2[CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.C(OCC)(=O)C>[CH:26]1[C:38]2[CH:37]([CH2:39][O:40][C:41]([NH:43][C:44]3([C:49]([NH:20][C@H:19]([C:18]([N:17]([CH3:25])[C@@H:12]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])=[O:24])[CH:21]([CH3:23])[CH3:22])=[O:50])[CH2:45][CH2:46][CH2:47][CH2:48]3)=[O:42])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: O=C(NC1(C(=O)O)CCCC1)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)C1(NC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1)C(C)C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
To #6 (287 mg, 0.801 mmol, 1 eq.) in dichloromethane (4 mL, 0.2 M) were added 1-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}cyclopentanecarboxylic acid (309 mg, 0.879 mmol, 1.1 eq.), diisopropylethylamine (281 μL, 1.60 mmol, 2 eq.) and HATU (376 mg, 0.960 mmol, 1.2 eq.). The mixture was stirred for 18 hours and diluted with ethyl acetate (15 mL). The reaction mixture was washed with 1 M aqueous hydrochloric acid solution (2×5 mL) and with brine (5 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (Gradient: 0% to 60% ethyl acetate in heptane) to provide #27 (502 mg, 91%) as a white foam. LC-MS: m/z 692.3 [M+H+], 714.3 [M+Na+], 636.3 [(M−2-methylprop-1-ene)+H+], retention time=1.13 minutes; 1H NMR (400 MHz, DMSO-d6), characteristic signals: δ 7.89 (br d, J=7.4 Hz, 2H), 7.67-7.75 (m, 2H), 7.60 (br s, 1H), 7.38-7.44 (m, 2H), 7.30-7.36 (m, 2H), 7.21 (br d, J=8.8 Hz, 1H), 4.44-4.59 (m, 2H), 4.17-4.27 (m, 3H), 3.68-3.78 (br m, 1H), 3.21 (s, 3H), 2.88 (br s, 3H), 2.09-2.20 (m, 2H), 1.39 (s, 9H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([C:8]#[N:9])=[CH:5][CH2:4][CH2:3]1.[C:10](OC=C)(=[O:13])[CH2:11][CH3:12]>CC(OC)(C)C>[C:10]([O:1][CH:2]1[CH2:3][CH2:4][CH:5]=[C:6]([C:8]#[N:9])[CH2:7]1)(=[O:13])[CH2:11][CH3:12]
Reactant: C=COC(=O)CC
Reactant: N#CC1=CCCC(O)C1
Solvent: COC(C)(C)C
Product: CCC(=O)OC1CCC=C(C#N)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a 2 L flask containing racemic 5-hydroxycyclohex-1-ene-1-carbonitrile (151 g, 1.22 mol), vinyl propionate (147 g, 1.47 mol), and MTBE (1.5 L) was added the enzyme AMANO Lipase PS from Burlholderiacepacia (20 g, Sigma-Aldrich). The mixture was stirred at ambient temperature for 48 hours. The mixture was filtered through celite and rinsed with MTBE. The filtrate was concentrated in vacuo to remove both solvent and unreacted vinyl propionate. The residue was diluted with brine (1.5 L) and extracted with hexanes (1000 mL+600 mL×3 respectively). The combined organics was washed with H2O (400 mL×5), then dried over anhydrous Na2SO4, and concentrated in vacuo to afford the title compound, which was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[S:5]1(=[O:21])=[O:20].[CH3:22][N:23]([CH2:31][CH2:32][NH:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([CH2:3][CH2:2][N:33]([CH3:34])[CH2:32][CH2:31][N:23]([CH3:22])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[S:5]1(=[O:21])=[O:20]
Reactant: O=S1(=O)N(CCBr)c2ccccc2N1c1ccccc1F
Reactant: CNCCN(C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCN(C)C(=O)OC(C)(C)C)CCN1c2ccccc2N(c2ccccc2F)S1(=O)=O
Temperature: 125 °C

Procedure:
A mixture of 1-(2-bromoethyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (171 mg, 0.461 mmol), tert-butyl methyl[2-(methylamino)ethyl]carbamate (695 mg, 3.69 mmol, 8 equiv.), sodium carbonate (489 mg, 4.61 mmol, 10 equiv.) and N,N-dimethylformamide (5 mL) was sealed and heated at 125° C. for 5 h. After cooling, the reaction mixture was partitioned between ethyl acetate (40 mL) and water (40 mL). The organic layer was washed with brine, dried (anhydrous sodium sulfate), and concentrated. The crude liquid was pre-adsorbed onto Florisil and purified via Isco flash column chromatography (12-g redisep silica gel column, 15-70% ethyl acetate/hexane) to give tert-butyl {2-[{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}(methyl)amino]ethyl}methylcarbamate as a viscous, colorless liquid. Yield: 142 mg (64%). MS (ESI) m/z 479.0 ([M+H]+). HRMS: calcd for C23H31FN4O4S+H+, 479.2123; found (ESI, [M+H]+), 479.2129. HPLC purity 96.6% at 210-370 nm, 9.0 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][N:19]=[C:18](F)[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:23])[C:8](=[O:24])[C@H:7]2[CH2:25][CH3:26])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][NH2:28]>CCN(CC)CC>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:28][CH3:27])[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:23])[C:8](=[O:24])[C@H:7]2[CH2:25][CH3:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccnc(F)c3)nc2N1C1CCCC1
Solvent: CCN(CC)CC
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccnc(NC)c3)nc2N1C1CCCC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a solution of (R)-8-cyclopentyl-7-ethyl-2-(2-fluoropyridin-4-yl)-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 16, 200 mg, 0.56 mmol) in methylamine (5 mL of 2M in CH3OH), 1 mL of Et3N was added. The mixture was stirred at 110° C. in a sealed tube for 18 h, and then concentrated under reduced pressure, quenched with water and extracted with EtOAc. The combined organic phase was dried with Na2SO4, concentrated under reduced pressure, and chromatographed (CH2Cl2:CH3OH=10:1) to give the title compound as a white solid (150 mg, 70% yield). 1H NMR (CDCl3) δ: 9.76 (broad, 1H), 8.08 (s, 1H) 7.85 (d, 1H), 7.74 (s, 1H), 7.58 (d, 1H), 4.40 (m, 2H), 3.43 (s, 3H), 3.1 (s, 3H), 2.2-1.7 (m, 10H) and 0.89 ppm (t, 3H); LCMS: 367.2 m/z (M+H)+; ret. Time: 1.44 min (Analytical Method E).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:21]#[N:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:21]([NH:24][OH:25])=[NH:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: Cc1ccc2nc(C#N)c(OCc3ccccc3)c(=O)n2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2nc(C(=N)NO)c(OCc3ccccc3)c(=O)n2c1
Temperature: 70 °C
Yield: 80 %

Procedure:
The product from Example 11.2 (530 mg, 1.82 mmol) and hydroxylamine hydrochloride (0.549 g, 7.9 mmol) were mixed with ethanol (50 mL). To this stirred solution was added sodium bicarbonate (663 mg, 7.9 mmol) and the mixture was heated at 70° C. for 3 h. The solvent was removed in vacuo and the residue dissolved in a mixed solvent (dichloromethane/ethanol 200 mL:10 mL), washed with water, dried (Na2SO4) and concentrated in vacuo to give the desired compound (472 mg, 80%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]1[C:14]([NH2:18])=[N:15][NH:16][CH:17]=1.[C:19](OC)(=[O:25])[CH2:20][C:21](OC)=[O:22].C[O-].[Na+]>CO>[CH3:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]1[CH:17]=[N:16][N:15]2[C:21](=[O:22])[CH2:20][C:19](=[O:25])[NH:18][C:14]=12
Reactant: COC(=O)CC(=O)OC
Reactant: Cc1c(Cc2c[nH]nc2N)cccc1C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(Cc2cnn3c2NC(=O)CC3=O)cccc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
To a solution of 4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-amine (1.71 g, 6.7 mmol) in methanol (10 mL) was added dimethyl malonate (0.93 g, 7.0 mmol), followed by adding a 25% sodium methoxide solution (2.95 g, 13.40 mmol). The reaction vessel was sealed and irradiated (microwave) to 125° C. for 45 minutes. After the reaction mixture was cooled, precipitate was collected by filtration. The solid was washed with cooled methanol (5 mL×2). Product was dried under air. The product was then suspended with 1 N HCl (30 mL), stirred for 10 minutes. Product was obtained by filtration. It was dried under vacuum oven and was used in next step. (2.13 g, 98%). LC/MS: MS (ES+) m/e 324 (MH+)
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([CH3:11])[O:10][C:6]=2[C:5]([NH:12][NH:13][C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[CH:4][C:3]=1[CH3:20].C1C=C(Cl)C=C(C(OO)=O)C=1.CC1CC2C=CC=C(NNC(N(OC)C)=O)C=2O1>>[Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([CH3:11])[O:10][C:6]=2[C:5]([N:12]=[N:13][C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[CH:4][C:3]=1[CH3:20]
Reactant: CON(C)C(=O)NNc1cc(C)c(Cl)c2c1OC(C)C2
Agent: CON(C)C(=O)NNc1cccc2c1OC(C)C2
Agent: O=C(OO)c1cccc(Cl)c1
Product: CON(C)C(=O)N=Nc1cc(C)c(Cl)c2c1OC(C)C2

Procedure:
2 was prepared, as a yellow solid, by treating 2E with MCPBA according to the procedure and conditions described in Example 1 for preparing 1 from 1E.
Reaction SMILES: [ClH:1].[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:4]=[CH:3]1.Cl.[CH3:12]O>>[ClH:1].[CH3:12][O:9][C:8](=[O:10])[CH2:7][C:5]1[N:4]=[CH:3][NH:2][CH:6]=1
Reactant: CO
Reactant: O=C(O)Cc1c[nH]cn1
Agent: Cl
Product: COC(=O)Cc1c[nH]cn1

Procedure:
A solution of 1H-imidazole-4-acetic acid hydrochloride (4.00 g, 24.6 mmol) in methanol (100 ml) was saturated with gaseous hydrogen chloride. The resulting solution was allowed to stand at room temperature (RT) for 18 hr. The solvent was evaporated in vacuo to afford the title compound as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:15]=[CH:14][N:13]=2)=[CH:6][CH:5]=1.O[Li].O.Cl>C1COCC1.CO.O>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([S:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:26])=[O:2])=[CH:5][CH:6]=3)[N:17]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(CSc2nccc(-c3ccc(OC)cc3)n2)cc1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2ccnc(SCc3ccc(C(=O)O)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.6 %

Procedure:
To a stirred solution of 226a (4.58 mmol) in THF (20 ml) and MeOH (20 ml) at room temperature was added a solution of LiOH—H2O (960 mg, 22.9 mmol) in water (50 ml). The reaction mixture was stirred 18 h at room temperature, diluted in water and acidified with 1N HCl (pH 5-6) to form a precipitate which was collected by filtration, washed with water and dried to afford the title compound 227a (1.64 g, 99% yield). LRMS (calc.): 352.4, (found): 353.4.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH3:20])[CH2:5][C@H:6]1[CH2:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:7]1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>CCO>[OH:2][CH2:3][CH:4]([CH3:20])[CH2:5][C@@H:6]1[CH2:7][N:8]([C@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[C:9](=[O:11])[CH2:10]1
Reactant: COC(=O)C(C)C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(CO)C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Temperature: 0 °C
Yield: 58.5 %

Procedure:
To the ester 93 (4.82 g, 0.017 mol) in EtOH (100 mL) was added NaBH4 (3.7 g, 0.10 mol) and the mixture heated to reflux for 2.5 hours. The solution was cooled to 0° C. and 1 M citric acid carefully added followed by water. The solution was concentrated to half volume added and extracted with ether. The combined organic extracts were dried (MgSO4) and concentrated. Flash chromatography (1:1 hexane/acetone) of the residue gave the product as an oil (2.6 g, 59%). MS m/z 262 (M+H, 100%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[CH3:10]I>O1CCCC1>[CH3:10][C:4]1([C:7]([OH:9])=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: CI
Reactant: O=C(O)C1CCOCC1
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCOCC1
Temperature: 25 °C
Reaction time: 84 h

Procedure:
nButyllithium (21.1 ml, 33.8 mmol, 1.6 M in hexanes) was added dropwise over 10 minutes to a stirred solution of duisopropylamine (4.7 ml, 33.8 mmol) in anhydrous tetrahydrofuran (40 ml) under an atmosphere of nitrogen at <10° C. Upon addition, tetrahydropyran-4-carboxylic acid (J. Am. Chem. Soc., 1993, 115, 8407) was added in anhydrous tetrahydrofuran (20 ml) under nitrogen at <5° C. The mixture was stirred at room temperature for one hour after which methyl iodide (2.4 ml, 38.4 mmol) was added dropwise at <5° C. The resultant solution was stirred at <5° C. for 30 minutes, allowed to warm to room temperature and stirred for a further 3.5 days. The solvent was removed by evaporation and the residue dissolved in dichloromethane (100 ml) and 2N hydrochloric acid (100 ml) added. The aqueous layer was extracted with dichloromethane (3×100 ml) and the combined organic layers were washed with water (100 ml), brine (100 ml), dried (MgSO4), filtered and evaporated to yield the title product (1.4 g) which was used in the next step without purification. Data for the title compound: 1H NMR (250 MHz, CDCl3) δ 1.00 (3H, s), 1.47-1.58 (2H, m), 2.06-2.11 (2H, m), 3.49-3.60 (2H, m), 3.78-3.86 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([Br:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:17]O>>[NH2:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([Br:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:17])=[O:8]
Reactant: Cc1cc(Br)c(C(=O)O)cc1N
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(N)c(C)cc1Br
Yield: 99 %

Procedure:
To a cooled solution (5° C.) of 5-amino-2-bromo-4-methylbenzoic acid (100.0 g, 0.434 mmol) in anhydrous methanol (1.6 L) was added dropwise thionyl chloride (112.4 g). The reaction mixture was refluxed and monitored by TLC. After refluxing for 6 h, the reaction was complete. The reaction solution was concentrated under reduced pressure. The residue was diluted with ice water (1.2 L) and neutralized with 5% of NaHCO3 to pH 7.5. The aqueous layer was extracted with ethyl acetate (3×600 mL), and the combined organic layers were washed with brine (2×500 mL), and dried over anhydrous Na2SO4. Concentration under reduced pressure provided the title compound as a pale solid. Yield: 99%. 1H NMR (DMSO-d6, 300 MHz): δ 7.25 (s, 1H), 7.14 (s, 1H), 3.30 (s, 3H), 2.15 (s, 3H); MS ESI (m/z) 244 [M+1]+, calc. 243.