Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][SH:17]>>[C:1](=[O:12])([S:17][CH2:16][CH2:15][N:14]([CH3:18])[CH3:13])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CN(C)CCS
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)SCCN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 2-(dimethylamino)ethanethiol as starting materials to give the aimed compound.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:38]>C(OCC)(=O)C.C(O)C>[ClH:38].[F:1][C:2]1[C:3]([CH2:22][NH:23][CH3:24])=[CH:4][N:5]([S:14]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2nccs2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cn(S(=O)(=O)c2nccs2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
tert-Butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(1,3-thiazol-2-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (220 mg) was dissolved in ethyl acetate (2 mL) and ethanol (2 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (4 mL) was added. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol=1:2 to give the title compound as colorless crystals (yield 82.8 mg, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C#N)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
To a stirred solution of 2-chloro-4-cyanobenzoic acid, methyl ester (24.3 g) in methanol (150 ml) was added 2.5N sodium hydroxide (54.5 ml). After stirring at room temperature. for 45 minutes, the solvent was removed in vacuo. The residue was dissolved in water, cooled in an ice bath, and made acidic with 2N hydrochloric acid (14 ml). The resulting precipitate was filtered and dried in vacuo to yield the title compound as a solid (22.55 g) m.p. 154-158° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH:12]([CH2:14][O:15][CH3:16])[O:11][C:10]3[CH:17]=[C:18]([S:21]([N:24](CC4C=CC(OC)=CC=4)[C:25]4[S:26][CH:27]=[CH:28][N:29]=4)(=[O:23])=[O:22])[CH:19]=[CH:20][C:9]2=3)=[C:4]([C:39]#[N:40])[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH:12]([CH2:14][O:15][CH3:16])[O:11][C:10]3[CH:17]=[C:18]([S:21]([NH:24][C:25]4[S:26][CH:27]=[CH:28][N:29]=4)(=[O:22])=[O:23])[CH:19]=[CH:20][C:9]2=3)=[C:4]([C:39]#[N:40])[CH:3]=1
Reactant: COCC1CN(c2ccc(Cl)cc2C#N)c2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)cc2O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCC1CN(c2ccc(Cl)cc2C#N)c2ccc(S(=O)(=O)Nc3nccs3)cc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
To a solution of 4-(4-chloro-2-cyanophenyl)-N-(4-methoxybenzyl)-2-(methoxymethyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (170 mg, 0.28 mmol) in dichloromethane (10 mL) was added trifluroacetic acid (0.7 mL, Spectrochem) at 0° C. and the mixture was allowed to stir at room temperature for 4 h. The volatiles were removed under reduced pressure and the residue was basified (pH˜10) with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to get the crude material which was further purified by column chromatography (silica gel 100-200 mesh, 0-2% methanol in dichloromethane) to obtain 4-(4-chloro-2-cyanophenyl)-2-(methoxymethyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (70 mg, 51.5%) as an off white solid. m/z (ESI) 476.8 (M+H)+. 1H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 8.13 (d, J=2.5 Hz, 1H), 7.84 (dd, J=8.8, 2.5 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.35-7.04 (m, 3H), 6.80 (d, J=4.6 Hz, 1H), 6.57 (d, J=8.5 Hz, 1H), 4.46 (d, J=4.6 Hz, 1H), 3.80-3.76 (m, 1H), 3.65-3.57 (m, 3H), 3.29 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([Cl:17])[N:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1>C1COCC1.[Li+].[OH-].O>[Cl:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:18])=[O:2])=[CH:9][CH:8]=2)[CH:16]=1
Reactant: COC(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Nc2cc(Cl)ncn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(6-Chloro-pyrimidin-4-yl-amino)-benzoic acid methyl ester, (0.1 g, 0.38 mmol) in THF (3 mL), LiOH×H2O (0.017 g, 0.42 mmol) dissolved in H2O (1 mL) was added and the mixture stirred at room temperature for 18 h. The reaction mixture was then diluted with H2O (5 mL) and extracted with EtOAc (2×). The water layer was acidified (2.5M HCl) and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4) and the solvent evaporated under reduced pressure to afford 4-(6-Chloro-pyrimidin-4-yl-amino)-benzoic acid, as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[F:10]F.N#N.FF>FC(F)(F)C(O)=O>[F:10][C:2]1([CH3:1])[CH:7]=[N:6][C:5](=[O:8])[NH:4][C:3]1=[O:9]
Reactant: FF
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: N#N
Solvent: O=C(O)C(F)(F)F
Product: CC1(F)C=NC(=O)NC1=O
Temperature: 14 °C
Reaction time: 2 h

Procedure:
5-methyluracil (1.00 g) in trifluoroacetic acid (10 ml) was treated with gaseous fluorine-nitrogen mixture. The reaction began at an initial temperature of 0° C. and during the fluorination the reaction temperature was raised to 14° C. and the reaction continued until completion for 120 minutes. The mole ratio of fluorine to 5-methyl-uracil was 2.56. The solvent was evaporated at about 50° C. under reduced pressure leaving a brown solid, which upon extracting with acetone gave 5-fluoro-5-methyluracil (0.21g) whose structure was confirmed by NMR analysis.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][N:17]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([NH:15][CH2:14][C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]2)=[N:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CNc1ncnc2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(NC[C@@H]3CCCCN3)ncnc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-2-(Quinazolin-4-ylaminomethyl)-piperidine-1-carboxylic acid tert butyl ester (1.2 g) was dissolved in trifluoroacetic acid (60 ml) and stirred at room temperature for 2 hours. The solution was then evaporated and the residue chromatographed over silica gel, eluting with 0 to 10% (9:1 methanol-concentrated ammonia solution) in dichloromethane. The title compound was obtained as a white foam (0.84 g), MH+ 243.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C1(C)C=CC(S(O[CH2:19][C:20]([I:24])=[C:21]([I:23])[I:22])(=O)=O)=CC=1.C(N(CC)CC)C>CN(C=O)C>[I:24][C:20](=[C:21]([I:23])[I:22])[CH2:19][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)OCC(I)=C(I)I)cc1
Reactant: O=[N+]([O-])c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1nccn1CC(I)=C(I)I
Temperature: 60 °C

Procedure:
To a solution of 57 mg (0.5 mmoles) of 2-nitroimidazole and 300 mg (0.5 mmoles) of 3-p-toluenesulfonyloxy-1,1,2-triiodo-1-propene in 30 ml of dry DMF was added 0.07 ml (0.05 mmoles) of triethylamine and the resulting mixture was heated at 60° C. for one hour. After cooling, the reaction mixture was poured into 10 ml of ice-water, the brown crystalline substance thus separated was recovered by filtration, washed with water and then dried. Yield 246 mg (92%), mp 156°-158° C. (with decomposition).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]#[N:10])[CH2:3][CH2:2]1.C[O-].[Na+].[CH2:14]1[O:18][C:17]2[CH:19]=[C:20]([CH:23]=O)[CH:21]=[CH:22][C:16]=2[O:15]1>CS(C)=O>[O:1]1[CH2:6][CH2:5][N:4]([CH:7]=[C:8]([CH2:23][C:20]2[CH:21]=[CH:22][C:16]3[O:15][CH2:14][O:18][C:17]=3[CH:19]=2)[C:9]#[N:10])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: N#CCCN1CCOCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CC(=CN1CCOCC1)Cc1ccc2c(c1)OCO2

Procedure:
β-Morpholinopropionitrile (20 g.), dimethylsulphoxide (30 ml.), and sodium methoxide (1 g.) were heated together at 80° C and a solution of piperonaldehyde (19 g.) in dimethylsulphoxide was added. The mixture was reacted at 80° C for 15 min., and on work-up gave β-morpholino-α-piperonylacrylonitrile, Wt.=21 g. (61%) m.p. 85°-85.5° C (recrystallised from methanol).
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][C:5]([NH2:15])=[C:4]([N+:16]([O-])=O)[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH2:15])=[CH:6][C:7]=1[N:8]1[CH2:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: Nc1cc(N2CCCOCC2)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)c(N2CCCOCC2)cc1N
Yield: 48.6 %

Procedure:
7 g of 4-fluoro-2-nitro-5-perhydro-1,4-oxazepin-4-ylphenylamine in solution in 170 mL of methanol are hydrogenated under 1 bar of hydrogen pressure in the presence of 700 mg of palladium-on-charcoal at 22° C. for 10 hours. The reaction crude is filtered through celite and the filtrate is concentrated under vacuum in a rotary evaporator. After evaporation, the reaction crude is purified by flash chromatography (elution dichloromethane/methanol). 3 g of 4-fluoro-5-perhydro-1,4-oxazepin-4-ylbenzene-1,2-diamine are isolated. 1H NMR spectrum (400 MHz, DMSO-d6, δ in ppm): 1.88 (m, 2H); 3.11 (m, 4H); from 3.64 to 3.74 (m, 4H); 4.20 (broad s, 2H); 4.26 (broad s, 2H); from 6.25 to 6.31 (m, 2H).
Reaction SMILES: [Se](=O)=[O:2].[CH3:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6]>O1CCOCC1.O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]([CH:4]=[O:2])=[O:6])=[CH:8][CH:9]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: O=CC(=O)c1ccc(F)cc1
Reaction time: 12 h
Yield: 71.1 %

Procedure:
Selenium dioxide (6.70 g, 61.0 mmol) was added to a solution of 4-fluoroacetophenone (8.43 g, 61.0 mmol) in dioxane (100 mL) and water (3 mL), and the resulting mixture was heated at 55° C. until complete dissolution of selenium dioxide had occurred. The reaction mass was then refluxed for 5-6 hrs. After completion of the reaction (TLC), the mixture was filtered and the filtrate was concentrated in vacuo affording a viscous oil. Water (50 mL) was added and the resulting mixture was stirred for 12 hrs, after which time the solid was collected on a filter, washed with water (25 mL) and dried in vacuo, affording 4-fluorophenylglyoxal (6.60 g, 85%).
Reaction SMILES: [NH2:1][CH2:2][S:3]([OH:6])(=[O:5])=[O:4].C([O-])(=O)C.[K+:11].[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>C(O)(=O)C>[K+:11].[C:12]1(=[O:17])[N:1]([CH2:2][S:3]([O-:6])(=[O:5])=[O:4])[C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CS(=O)(=O)[O-]

Procedure:
A suspension of 15.1 g. (0.136 mol.) of aminomethanesulfonic acid and 14.2 g. (0.145 mol.) of anhydrous potassium acetate in 48 ml. of acetic acid is refluxed for ten minutes. Phthalic anhydride (21.4 g., 0.145 mol.) is then added and the resulting mixture is refluxed for 2.5 hours. The product is collected by filtration and washed with acetic acid and ethanol to give phthalimidomethanesulfonic acid potassium salt.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4](Cl)=[O:5].[CH3:15][OH:16]>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]([O:16][CH3:15])=[O:5]
Reactant: O=C(Cl)c1c(F)cccc1C(F)(F)F
Reactant: CO
Product: COC(=O)c1c(F)cccc1C(F)(F)F
Reaction time: 18 h

Procedure:
2-Fluoro-6-(trifluoromethyl)benzoyl chloride (Sigma-Aldrich; 950 mg, 4.19 mmol) was added drop-wise to dry methanol (5 mL) under nitrogen. After 18 hours LCMS indicated that no starting material remained. The reaction solution was partitioned between DCM (˜50 mL) and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with further DCM and the combined DCM extracts were dried (sodium sulfate) and evaporated to give the title product as a colourless liquid (786 mg). This material was used in the next step without further purification. LCMS (System 3): tRET=1.05 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[N:39])[CH:33]=4)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:41][OH:42].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([C:38](=[N:41][OH:42])[NH2:39])[CH:35]=[CH:36][CH:37]=4)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Temperature: 80 °C
Yield: 47.7 %

Procedure:
To a suspension of N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-cyano-phenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine (0.050 g, 0.086 mmol) in 80% ethanol-water (2.5 mL) was added an aqueous solution (0.50 mL) containing 6.65 mg of hydroxylamine hydrochloride (1.1 equivalents) and 4.61 mg of sodium carbonate (0.5 equivalents). The resulting solution was heated at 80° C. for 20 hours. Solid was collected by filtration and treated with hot (80° C.) 80% ethanol-water (2 mL×5). Solid was collected and dried under vacuum at 45° C. overnight to afford 25 mg (48%) of the title compound as a yellow solid. M.p.=272-273° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 9.52 (s, 1H), 8.70 (bs, 1H), 8.11 (d, J=5.2 Hz, 1H), 7.93 (s, 1H), 7.77-7.73 (m, 3H), 7.67-7.66 (m, 2H), 7.59 (d, J=6.8 Hz, 1H), 7.47-7.40 (m, 2H), 7.11 (d, J=7.6 Hz, 1H), 6.38 (d, J=4.4 Hz, 1H), 5.68 (s, 2H), 3.94 (br. s, 1H), 3.73 (d, J=8.4 Hz, 1H), 3.48 (d, J=10.8 Hz, 1H), 2.49-2.48 (m, 1H), 2.35 (t, J=8.8 Hz, 1H), 1.95-1.84 (m, 2H), 1.60-1.5 (m, 1H), 1.46-1.30 (m, 1H). LCMS: 610 [M+H].
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[N:13]=1.[CH3:14][C:15]([OH:32])([CH3:31])[CH2:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O>[CH3:14][C:15]([OH:32])([CH3:31])[CH2:16][N:17]1[CH:21]=[C:20]([C:2]2[CH:3]=[CH:4][C:5]3[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=3[N:13]=2)[CH:19]=[N:18]1
Reactant: CSc1ncc2ccc(Cl)nc2n1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CSc1ncc2ccc(-c3cnn(CC(C)(C)O)c3)nc2n1
Temperature: 140 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
A suspension of 7-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine (Preparation 57, 50.6 mg, 0.239 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (Preparation 124, 63.6 mg, 0.239 mmol), Pd(dppf)C2•DCM (20.2 mg, 0.024 mmol), Na2CO3 (2M, 0.24 mL, 0.48 mmol) in DME (4 mL) was stirred at 140° C. under microwave irradiation for 60 minutes. The reaction mixture was diluted with EtOAc and dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified using Biotage silica gel column chromatography eluting with 25-80% EtOAc/cyclohexane to give the title compound as orange semi-solid (21 mg, 28%).
Reaction SMILES: [C:1]([N:6]([CH2:14][C:15]1[S:19][C:18]([Cl:20])=[N:17][CH:16]=1)[C:7](=[N:10][N+:11]([O-:13])=[O:12])SC)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:21][NH2:22].CO.Cl>ClCCl>[C:1]([N:6]([CH2:14][C:15]1[S:19][C:18]([Cl:20])=[N:17][CH:16]=1)[C:7]([NH:22][CH3:21])=[N:10][N+:11]([O-:13])=[O:12])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CSC(=N[N+](=O)[O-])N(Cc1cnc(Cl)s1)C(=O)C(C)C
Reactant: CN
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CNC(=N[N+](=O)[O-])N(Cc1cnc(Cl)s1)C(=O)C(C)C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To a solution of N-iso-butyroyl-N-(2-chloro-5- thiazolylmethyl)-S-methyl-N'-nitroisothiourea (560 mg) in dichloromethane (5 ml) was added 40% methylamine-methanol solution (129 mg) dropwise below -11° C. and the mixture was stirred at the same temperature for 1 hour. To the mixture was added 40% methylamine-methanol solution (64 mg) dropwise below -11° C. and the mixture was stirred at the same temperature for 5.5 hours. After addition of 2N hydrochloric acid (10 ml) under ice-cooling, the mixture was extracted with toluene (5 ml). The organic layer was washed with an aqueous saturated sodium bicarbonate solution, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in toluene. Crystallization by addition of n-hexane gave 190 mg of 1-iso-butyroyl-1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitroguanidine (Compound No. 34) as a white crystal, m.p. 101°-104° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O[NH:35][C:36](=[NH:44])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:44]=[C:36]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[N:35]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Reactant: N=C(Cc1ccccn1)NO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2ccccn2)no1
Temperature: 25 °C
Reaction time: 17 h
Yield: 25.9 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (300 mg, 1.00 mmol) in dichloromethane (15 ml) was treated sequentially with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (192 mg, 1.00 mmol), 4-(dimethylamino)pyridine (125 mg, 1.02 mmol) and N-hydroxy-2-(2-pyridinyl)ethanimidamide (Chem.Pharm.Bull.; 21; 10; 1973; 2146-2160) (152 mg, 1.00 mmol). The resulting mixture was stirred at room temperature for 17 hours. The solvent was removed under reduced pressure and the residue was heated neat at 120° C. under a nitrogen atmosphere for 2 hours. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1). The residue was further purified by column chromatography on silica gel eluting with ethyl acetate: pentane (30:70) to afford the title compound as an oil (107 mg).
Reaction SMILES: [NH2:1][C@H:2]([CH3:5])[CH2:3][OH:4].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])(O)=O.[Na+].[BH4-].[Na+]>CO>[CH2:6]([NH:1][C@H:2]([CH3:5])[CH2:3][OH:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@@H](N)CO
Reactant: O=Cc1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](CO)NCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of (2R)-2-amino propanol (1.2 equivalents), benzaldehyde (1 equivalent), NaHCO3 (1.5 equivalents), and MeOH, (˜1 M) was heated at reflux for 4 hours and then cooled to 0° C. Sodium borohydride (4.8 equivalents) was added portionwise to the stirred reaction mixture during a period of 2 hours at ca. 10° C. The whole was stirred at room temperature for 4 hours. The insoluble materials were filtered off and then the filtrate was concentrated to dryness. The residue was dissolved in CH2Cl2, and the solution was washed successively with water (2×) and brine (1×). The organic extracts were collected and dried (Na2SO4). The solvent was evaporated to give the desired product as a colorless oil, which solidified on standing and was used in the next step without further purification. GC/MS: 134 (100%, M+-CH2OH), Rt 11.57 minutes.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[OH:13].[Cl:14][CH2:15][CH:16]=O.Cl.O>CC(O)=O>[Cl:14][CH2:15][CH:16]1[O:13][C:4]2[CH:5]=[C:6]([C:9]([F:11])([F:12])[F:10])[CH:7]=[CH:8][C:3]=2[CH2:2][O:1]1
Reactant: O=CCCl
Reactant: OCc1ccc(C(F)(F)F)cc1O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc2c(c1)OC(CCl)OC2
Reaction time: 24 h
Yield: 6.1 %

Procedure:
2-(hydroxymethyl)-5-(trifluoromethyl)phenol (1.0 g, 5.2 mmol) was dissolved in AcOH (4 ml) and cooled on ice-bath. Chloroacetaldehyde (0.93 ml, 7.3 mmol) and concentrated HCl (1.0 ml) were consecutively added drop wise. After 24 h, further addition of chloroacetaldehyde (0.50 ml, 3.9 mmol) and concentrated HCl (1.0 ml) were done and the reaction mixture was allowed to stir another 24 h. Water was added and the aqueous phase was extracted with EtOAc. The combined organic phases were dried (Na2SO4) and evaporated under reduced pressure to give an oil. Twice purification by flash column chromatography (isooctane/EtOAc 4:1) gave the pure title compound (0.08 g, 6%). MS m/z (rel. intensity, 70 eV) 252 (M+, 10), 174 (76), 146 (bp), 145 (47), 127 (44).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:14]N1C(=O)C2=CC=CC=C2C1=O.O=O>C(O)(=O)C>[C:1]1(=[O:14])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: O=O
Solvent: CC(=O)O
Product: O=C1C=CC=C2C1=Cc1ccccc12
Yield: 48 %

Procedure:
A mixture of 10 millimoles of fluorene, 1 millimole of N-hydroxyphthalimide, 0.05 millimole of acetylacetonatovanadium V(AA)3 and 25 milliliters of acetic acid was stirred, in an oxygen atmosphere, at a temperature of 90° C. for 6 hours. In analyzing a product in the reaction mixture by gas chromatography, fluorene was transformed into fluorenone (yield 48%) with a transformation rate of 54 percent.
Reaction SMILES: [CH:1]([N:4]([C:20](=[O:39])/[CH:21]=[CH:22]/[C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:24]=1)[NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]([O:17]C)=[O:16])[CH:8]=1)([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:35]([O:34][C:32]([N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](/[CH:22]=[CH:21]/[C:20]([N:4]([CH:1]([CH3:3])[CH3:2])[NH:5][C:6]([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[O:13][CH2:14][C:15]([OH:17])=[O:16])=[O:19])=[O:39])=[CH:24]1)=[O:33])([CH3:37])([CH3:38])[CH3:36]
Reactant: COC(=O)COc1cccc(C(=O)NN(C(=O)/C=C/c2cn(C(=O)OC(C)(C)C)c3ccccc23)C(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(NC(=O)c1cccc(OCC(=O)O)c1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Reaction time: 0.33 h

Procedure:
(E)-tert-butyl 3-(3-(1-isopropyl-2-(3-(2-methoxy-2-oxoethoxy)benzoyl)hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate (70 mg, 0.13 mmol) was dissolved in THF/H2O (2 ml/1 ml), stirred for 20 min, lithiumhydroxide (10.96 mg, 0.26 mmol) was slowly drop-wise added, and stirred at room temperature for 12 hr. THF was concentrated under reduced pressure, and after titration with 6N HCl at pH=2, the reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4 filtered, and concentrated under reduced pressure so that while solid form of (E)-2-(3-(2-(3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acryloyl)-2-isopropylhydrazinecarbonyl)phenoxy)acetic acid was obtained (68.1 mg, 99%).