Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:5]=[C:4]1[C:18](Cl)=[O:19])[CH3:2].Cl.[CH3:22][N:23](C)O.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:22][NH:23][C:18]([C:4]1[N:3]([CH2:1][CH3:2])[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:5]=1)=[O:19]
Reactant: CCn1cc(C#Cc2cccc(OC)c2)cc1C(=O)Cl
Reactant: CN(C)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1cc(C#Cc2cccc(OC)c2)cc1C(=O)NC
Reaction time: 4 h
Yield: 93.6 %

Procedure:
This intermediate (2.5 g, 9.28 mmol) was treated with oxalyl chloride (4.1 mL, 46.4 mmol), DMF (2 drops) in methylene chloride (70 mL) and stirred at room temperature for 2 hours to give 1-ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid chloride (2.7 g, 9.38 mmol) after a usual workup. 1-Ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid chloride (2.7 g, 9.38 mmol) was diluted with methylene chloride (35 mL) and added to a prepared solution of N,O, dimethyl-hydroxylamine hydrochloride (4.6 g, 46.4 mmol) and diisopropyl-ethyl amine (13 mL, 74.3 mmol) in methylene chloride (35 mL) over 5 minutes. The reaction was complete after 4 hours. Solvent was removed in vacuo and the residue was taken back in a mixture of saturated aqueous NH4Cl:H2O (1:1, 150 mL) solution and extracted with ether. Combined ether extracts were washed with brine dried (MgSO4) and filtered. Evaporation and purification by flash chromatography (hexane/ethyl acetate 9/1) gave the title compound as a light yellow oil (2.48 g g, 82% yield), 1H NMR (400 MHZ, CDCl3) □ 1.35-1.37 (t, 3H), 3.31 (s, 3H), 3.67 (s, 3H), 3.78 (s, 3H), 4.29-4.30 (q, 2H), 6.83 (m, 1H), 6.99 (m, 2H), 7.01 (m, 2H), 7.19 (m, 1H), MS m/e (M+H)+ 313.1.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([NH:13]C(=O)C(Cl)(Cl)[Cl:16])[CH:11]=[CH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O>[ClH:16].[CH2:1]([O:8][CH2:9][CH:10]([NH2:13])[CH:11]=[CH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(COCc1ccccc1)NC(=O)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CC(N)COCc1ccccc1
Product: Cl
Temperature: 80 °C

Procedure:
A mixture of N-[1-(benzyloxy)but-3-en-2-yl]-2,2,2-trichloroacetamide (7.5 g, 23 mmol) and sodium hydroxide (4.0 M in H2O, 40 mL, 160 mmol) was stirred and heated to 80° C. for 5 hours. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with ethyl acetate. The organic layer was separated and extracted with hydrochloric acid (2N). The aqueous layer was concentrated under reduced pressure to afford 1-(benzyloxy)but-3-en-2-amine hydrochloride. MS ESI calc'd. for C11H16NO [M+H]+ 178. found 178. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 2H), 7.37-7.28 (m, 5H), 5.89-5.80 (m, 1H), 5.44-5.32 (m, 2H), 4.57-4.50 (m, 2H), 3.99 (s, 1H), 3.62-3.55 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: Clc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCc2ccc(Cl)cc2)C1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of (R)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1.14 mmol, 1.0 eq) in THF (2.5 mL) was added to a suspension of sodium hydride (1.15 eq) in THF (2.5 mL) cooled at 0° C. and the resulting mixture was stirred for 45 min. A solution of 4-chlorobenzyl bromide (1.31 mmol, 1.15 eq) in THF (2.0 mL) was then added drop wise and reaction mixture was slowly warmed to room temperature and stirred for 18 h. The reaction mixture was quenched with water (1.0 ml) and diluted with ethyl acetate. The combined organics were dried over sodium sulfate. The crude product was purified on silica using gradient elution from hexane/ethyl acetate (10%) to hexane/ethyl acetate (30%). 1H-NMR (CDCL3) δ: 1.45 (9H, s), 1.80–2.05 (2H, m), 3.30–3.55 (4H, m), 4.05 (1H, m), 4.45 (2H, s), 7.15–7.30 (4H, m). ESI-MS m/z:311 (M+1), UV retention time: 2.94 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10](=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[C:11](=[O:13])[N:12]=2)[CH2:4][CH2:3]1.[NH2:28][CH2:29][C@H:30]([OH:40])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[OH:40][C@H:30]([CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[CH2:29][NH:28][CH:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:17]=[CH:16][C:15]([CH:14]=[C:10]3[S:9][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[N:12][C:11]3=[O:13])=[CH:20][CH:19]=2)[CH2:26][CH2:25]1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Reactant: CN1CCN(C2=NC(=O)C(=Cc3ccc(N4CCC(=O)CC4)cc3)S2)CC1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc(N4CCC(NC[C@H](O)COc5ccc(O)cc5)CC4)cc3)S2)CC1

Procedure:
The title compound was prepared from 1-{4-[2-(4-methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one (which was obtained in Intermediate 29) and (2S)-1-amino-3-(4-hydroxy-phenoxy)-propan-2-ol (which was obtained in Intermediate 5) according to the procedure of Example 1 as a yellowish solid; mp>210C (dec.); 1H NMR (300 MHz, DMSO-d6) δ1.20-1.40 (m, 2 H), 1.80-1.95 (m, 2 H), 2.24 (s, 3 H), 2.40-4.00 (m, 18 H), 6.64(d, J=8.9 Hz, 2 H), 6.73 (d, J=8.9 Hz, 2 H), 7.00(d, J=8.9 Hz, 2 H), 7.45(d, J=8.9 Hz, 2 H), 7.52 (s, 1 H), 8.89(brs, 1 H); MS (ES) m/z: 276.6 ((M+2H)2+, 100%); 552.0(MH+, 10%); HRMS Calcd. for C29H38N5O4S (MH+): 552.2645. Found: 552.2634.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:12]([OH:22])[C@@H:13]([C@@H:15]([C@H:17]([C@H:19]([CH3:21])[OH:20])[OH:18])[OH:16])[OH:14]>>[CH2:2]([OH:1])[C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].[OH:22][CH2:12][C:13]([C@@H:15]([C@H:17]([C@H:19]([CH3:21])[OH:20])[OH:18])[OH:16])=[O:14].[CH3:11][C:9]([C@@H:7]([C@H:5]([C@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])=[O:10]
Reactant: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O
Agent: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO
Product: CC(=O)[C@H](O)[C@@H](O)[C@@H](O)CO
Product: C[C@H](O)[C@H](O)[C@@H](O)C(=O)CO

Procedure:
6-Deoxy L-mannitol can readily be produced via chemical reduction of 6-deoxy L-mannose. At a productivity close to 99%, 6-deoxy L-mannose is completely converted to 6-deoxy L-mannitol. When the initial concentrations of 6-deoxy L-mannitol were 3%, 4% and 5%, almost 90%, 70% and 65%, respectively of 6-deoxy L-mannitol produced 6-deoxy L-fructose and 1-deoxy L-fructose, using the washed bacterial cell reaction.
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22](O)=[O:23])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1.C([N:37]([CH:41]([CH3:43])C)[CH:38]([CH3:40])C)C.N1CCCC1.F[P-](F)(F)(F)(F)F.C(C(=NO[C+](N(C)C)N1CCOCC1)C(OCC)=O)#N>CN(C=O)C.O>[F:2][C:3]([F:34])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22](=[O:23])[N:37]3[CH2:38][CH2:40][CH2:43][CH2:41]3)=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: CCOC(=O)C(C#N)=NO[C+](N(C)C)N1CCOCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1N=C(NCC(=O)N2CCCC2)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-2-oxo-2,5-dihydro-1,3-thiazol-4-yl]glycine hydrochloride (500 mg), N-ethyl-N-(1-methylethyl)propan-2-amine (0.49 mL) and pyrrolidine (0.24 mL) in DMF (5 mL) was added (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (403 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and the solid was recrystallized from ethyl acetate/heptane to give the title compound (90 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[CH3:6][C@@H:7]1[O:9][C@@:8]1([CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1>>[N:1]1[N:2]([C@H:7]([CH3:6])[C@:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=2)([OH:9])[CH2:21][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[N:3]=[CH:4][CH:5]=1.[N:1]1([C@H:7]([CH3:6])[C@:8]([C:10]2[CH:11]=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)([OH:9])[CH2:21][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: c1c[nH]nn1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(OC(F)(F)F)cc1
Product: C[C@@H](n1ccnn1)[C@](O)(Cn1cncn1)c1ccc(C(F)(F)F)cc1
Product: C[C@@H](n1nccn1)[C@](O)(Cn1cncn1)c1ccc(OC(F)(F)F)cc1

Procedure:
Using 1H-1,2,3-triazole and (2R,3S)-3-methyl-2-[(1H-1,2,4-triazol-1-yl) methyl]-2-(4-trifluoromethoxylphenyl)oxirane, substantially the same reaction as in Example 30 was conducted to give Compound 40 as colorless prisms and Compound 41 as colorless needles.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH:21][CH:20]=1>>[N:19]1([C:2]2[N:7]=[C:6]([NH:8][C@H:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH3:10])[CH:5]=[N:4][CH:3]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[CH:20]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: COc1ccc([C@H](C)Nc2cncc(Cl)n2)cc1
Product: COc1ccc([C@H](C)Nc2cncc(-n3cnc4ccccc43)n2)cc1
Yield: 41.3 %

Procedure:
In a procedure analogous to example 25, reaction of 6-chloro-N-[(1S)-1-(4-methoxyphenyl)ethyl]pyrazin-2-amine (105 mg, 0.40 mmol) and benzimidazole (52 mg, 0.44 mmol) furnished the product (57 mg, 41%).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Triethylamine (1.52 ml) and ethyl chlorooxoacetate (1.11 ml) were successively added to a solution of 4-chloroaniline (1.16 g) in methylene chloride (26 ml), and the mixture was stirred at room temperature for 14 hours. After a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture to conduct liquid separation, the resultant organic layer was successively washed with a 10% aqueous solution of citric acid and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After the solvent was concentrated under reduced pressure, hexane was added to the residue to deposit crystals, and the crystals were collected by filtration and dried to obtain the title compound (1.89 g).
Reaction SMILES: [CH:1]([C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1)=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O-:25])=[O:24])C=CC=CC=1.[Na+].O.S(=O)(=O)(O)O>CS(C)=O>[C:23]([CH2:22][CH2:21][CH2:20][CH:19]=[CH:1][C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1)([OH:25])=[O:24]
Reactant: O=Cc1cccc2cncn12
Reactant: O=C([O-])CCCC[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CCCC=Cc1cccc2cncn12

Procedure:
A solution of 5-formylimidazo[1,5-a]pyridine (1.46 g) in 15 ml of dry dimethylsulfoxide is added to a solution of sodium 5-(triphenylphosphoranyl)valerate (4.4 g) in 50 ml of dry dimethylsulfoxide at room temperature (Helv. Chem. Acta 63 1430 (1980)). The reaction is stirred for 3 hours, hydrolyzed with water and neutralized with dilute sulfuric acid. Extraction with ethyl acetate and chromatography or silica gel yields 5-(5-carboxypent-1-enyl)-imidazo[1,5-a]pyridine.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O-:13])(O)=[O:11].[Na+].[C:15](#[N:17])C>>[C:1]1([CH2:7][CH2:8][NH:17][CH2:15][C:10]([O:13][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC#N
Reactant: O=C([O-])O
Reactant: BrCCc1ccccc1
Agent: [Na+]
Product: O=C(CNCCc1ccccc1)OCc1ccccc1
Yield: 38 %

Procedure:
A mixture of benzyl glycinate, p-toluenesulfonic acid salt (2.68 g, 7.94 mmol), (2-phenyl)bromoethane (0.98 g, 5.29 mmol), and solid NaHCO3 (1.56 g, 18.5 mmol) in acetonitrile (25 mL) were heated at reflux for 18 hour. The reaction was concentrated and diluted with EtOAc (25 mL). The organic solution was washed with H2O (25 mL) and brine (25 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by elution through a pad of silica gel with a gradient mixture of hexane:EtOAc. The intermediate benzyl N-[(2-phenyl)ethyl]-glycinate (0.82 g) was obtained in 38% yield. Low Res MS: (M+H)+ =270.
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].BrC1C=CC=CC=1.[C:19]1([CH3:38])[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[B:27]([C:29]1[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=1[CH3:37])F>O1CCCC1.O>[C:19]1([CH3:38])[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[B:27]([C:29]1[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=1[CH3:37])[C:8]1[CH:7]=[CH:6][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cc(C)c(B(F)c2c(C)cc(C)cc2C)c(C)c1
Reactant: CCCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Brc1ccccc1
Solvent: O
Product: Cc1cc(C)c(B(c2ccccc2)c2c(C)cc(C)cc2C)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.1 equivalents of 1.6 M butyllithium in hexane (37.5 ml, 0.066 mol) are added over the course of 15 minutes at -78° C. to a solution of 9.42 g (0.06 mol) of bromobenzene in 80 ml of tetrahydrofuran (THF). The reaction mixture is stirred at this temperature for 3 h. Then 16.1 g (0.06 mol) of solid dimesitylfluoroborane are added, and the mixture is allowed to warm to room temperature and stirred for a further hour. The mixture is poured into 500 ml of water and the resulting suspension is filtered. The product is purified by trituration with boiling methanol, to give 16.9 g (86% of theory) of the product as a white solid with a melting range of 185-187° C. The shifts δ in the 1H NMR, measured in CDCl3 are 7.50 ppm (d,2,J=7 Hz), 7.46 ppm (t,1,J=10 Hz), 7.50 ppm (br t, 2, J=7 Hz), 6.82 ppm (s, 4), 2.30 ppm (s,6) and 2.00 ppm (s,12).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[C:13](SC)=[CH:12][N:11]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([CH:23]=3)[C:21]#[N:22])[N:10]=2)=[C:5]([CH3:24])[N:4]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[C:3]1=[O:35].OO.[S:38]([O-:42])([O-])(=[O:40])=S.[Na+].[Na+].[C:45](O)(=O)C>C(OCC)(=O)C.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[C:13]([S:38]([CH3:45])(=[O:42])=[O:40])=[CH:12][N:11]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([CH:23]=3)[C:21]#[N:22])[N:10]=2)=[C:5]([CH3:24])[N:4]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=2)[C:3]1=[O:35]
Reactant: O=S([O-])([O-])=S
Reactant: CSc1cn(-c2cccc(C#N)c2)nc1-c1c(C)n(-c2cccc(C(F)(F)F)c2)c(=O)n(C)c1=O
Reactant: CC(=O)O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1c(-c2nn(-c3cccc(C#N)c3)cc2S(C)(=O)=O)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylthio)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 269) (57.4 mg) in acetic acid (1.0 ml) were added aqueous hydrogen peroxide solution (63.4 μl) and sodium tungstate (3.8 mg) and the resulting mixture was stirred at room temperature for four hours. To the reaction mixture was added 10% aqueous sodium thiosulfate solution (1 ml) and the resulting mixture was stirred at room temperature for one hour. The reaction mixture was diluted with ethyl acetate (50 ml) and then washed with saturated saline (20 ml) and the organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylsulfonyl)-1H-pyrazol-1-yl)benzonitrile (29.4 mg).
Reaction SMILES: ClC1C=CC=C(Cl)C=1C(Cl)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=1[C:42]([N:44]=[C:45]=[S:46])=[O:43]>C1(C)C=CC=CC=1.C(O)C>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=1[C:42]([N:44]=[C:45]=[S:46])=[O:43].[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=1[C:42]([NH:44][C:45]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][C:17]2[C:16]3[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=3)[N:20]=[CH:19][CH:18]=2)=[CH:28][CH:29]=1)=[S:46])=[O:43]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1c(Cl)cccc1Cl
Agent: O=C(N=C=S)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4c(Cl)cccc4Cl)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
2,6-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,6-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,6-dichloro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (57 mg, yield 64%).
Reaction SMILES: [C:1]([C:4]1([O:9]/[N:10]=[C:11](/[C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)\[C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5]1)([OH:3])=O.[CH3:21][O:22][NH2:23].C(Br)(Br)Br>CS(C)=O>[CH3:21][O:22][NH:23][C:1]([C:4]1([O:9][N:10]=[C:11]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3]
Reactant: COC(=O)/C(=N\OC1(C(=O)O)CCCC1)c1ccco1
Reactant: CON
Solvent: CS(C)=O
Solvent: BrC(Br)Br
Product: CONC(=O)C1(ON=C(C(=O)OC)c2ccco2)CCCC1
Yield: 75 %

Procedure:
This compound was prepared from methyl Z-2-(carboxycyclopent-1-yloxyimino)-2-(fur-2-yl)acetate and methoxyamine as described in Preparation 7(c) νmax (CHBr3) 3400, 3350 (--NH--), 1740 (--CO2R), 1686 cm-1 (--CONH--), τ(DMSO d6), 6.4 (--OMe), --0.88 (--CONHO), 7.7-8.7 (cylopentyl), 2.1, 3.1, 3.3 (furyl), 6.1 (--CO2Me). Yield 75%
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:14]([N:17]1[C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:20][C:19]([C:29]([NH2:31])=O)=[N:18]1)[CH2:15][CH3:16].C(N(CC)CC)C>ClCCl>[CH2:14]([N:17]1[C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:20][C:19]([C:29]#[N:31])=[N:18]1)[CH2:15][CH3:16]
Reactant: CCCn1nc(C(N)=O)cc1CC1CCOCC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1nc(C#N)cc1CC1CCOCC1
Reaction time: 3 h
Yield: 106 %

Procedure:
A solution of trifluoroacetic anhydride (2.50 mL, 17.7 mmol) in dichloromethane (32 mL) was added over a period of ten minutes to a 0° C. solution of 1-propyl-5-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole-3-carboxamide (4.05 g, 16.1 mmol) and triethylamine (4.89 g, 48.3 mmol) in dichloromethane (32 mL). After the addition was complete, the cooling bath was removed and the solution was stirred for three hours. The solution was washed with 2 M aqueous sodium carbonate. The aqueous layer was extracted three times with tert-butyl methyl ether. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by automated flash chromatography (eluting with 40% to 70% ethyl acetate in hexane) to provide 3.98 g of 1-propyl-5-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole-3-carbonitrile as a pale yellow oil.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9]>C(O)(=O)C.O>[Br:1][C:11]1[CH:12]=[C:13]([CH3:14])[C:5]([O:4][CH3:3])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: BrBr
Reactant: COc1cc(C(=O)O)ccc1C
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)c(Br)cc1C
Temperature: 60 °C

Procedure:
Br2 (0.74 mL, 14.4 mmol) was added to a RT suspension of 3-methoxy-4-methylbenzoic acid (2.0 g, 12 mmol) in acetic acid (15 mL) and water (15 mL) and the resulting mixture was heated to 60° C. for 2 h. The reaction mixture was cooled to RT and filtered rinsing with cold water (40 mL) to yield 2-bromo-5-methoxy-4-methylbenzoic acid as a white solid that was used further without purification. LC-MS A: tR=0.76 min, [M+H]+=No ionisation. 1H NMR (DMSO) δH: 7.49 (s, 1H), 7.29 (s, 1H), 3.82 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH2:27][CH3:28])=[N:7][N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH:13]=2)[C:9]=1[CH2:10][CH3:11])=[O:4].[OH-].[Li+]>C1COCC1.CO>[Cl:26][C:23]1[CH:24]=[CH:25][C:20](/[CH:19]=[CH:18]/[C:14]2[CH:13]=[C:12]([N:8]3[C:9]([CH2:10][CH3:11])=[C:5]([C:3]([OH:4])=[O:2])[C:6]([CH2:27][CH3:28])=[N:7]3)[CH:17]=[CH:16][CH:15]=2)=[CH:21][CH:22]=1
Reactant: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)O
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A solution of 1.78 g (4.5 mmol) of 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-diethyl-1H-pyrazole-4-carboxylic acid methyl ester in 100 ml of THF/MeOH (1:1) was treated with 11.3 ml of lithium hydroxide solution (1 M in water) at RT and then stirred at reflux (boiling temperature=80° C.) for 60 hours. The reaction mixture was then cooled to RT and evaporated. The residue was partitioned between water and CH2Cl2, acidified with HCl (2N) to pH 1-2 and extracted twice with CH2Cl2. The organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated to give 1.69 g of crude title compound as light yellow solid. MS: 379.2 ([M−H]−, 1 Cl).
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[O:17][CH:16]=1>[Cu]I>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[O:17][CH:16]=[C:15]([N:3]3[CH2:4][C@:5]4([CH:10]5[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]5)[CH2:6]4)[O:1][C:2]3=[O:13])[CH:19]=2)[CH:21]=1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Reactant: Brc1coc(-c2cccnc2)c1
Agent: [Cu]I
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1coc(-c2cccnc2)c1

Procedure:
The title compound was prepared by a method analog to that described in Preparation 3 from (S)-spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 3-bromo-5-(3-pyridyl)-furan with 3 equivalents of copper (I) iodide. The title compound (119 mg) was obtained as a pale yellow solid, m/z 342 (MH+).