Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22](I)[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22]([C:29]4[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=4)[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1F
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 4-(3,4-difluoro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.78) (0.45 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.26 g, 1.2 mmol) according to the general procedure VI. Obtained as a yellow solid (0.036 g, 9%). MS (ISP) 419.1 [(M+H)+]; mp 232° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:16]I.O>CN(C=O)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH3:16])[C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: CI
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)oc(=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1 g of 6-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (5.06 mmol) in DMF (20 ml) were carefully added 265 mg of sodium hydride (55% dispersion in oil, 6.07 mmol) at 0° C. and the mixture was stirred at RT for 30 min. Then 0.47 ml of methyl iodide (7.60 mmol) were added and stirring at RT was continued over night. Water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated and the remaining residue was purified by crystallization from heptane. This yielded 513 mg of 6-chloro-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (48%) as an off-white solid. 1HNMR (DMSO-d6, 300 MHz): δ 3.45 (s, 3H), 7.47 (d, J=8.9 Hz, 1H), 7.89 (dd, J=8.9 and 2.7 Hz, 1H), 7.95 (d, J=2.7 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([O:15][CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24].[H-].[Na+]>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:17][C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])(=[O:13])=[O:12])=[C:7]([O:15][CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C(C)(C)C)ccc1S(=O)(=O)Cl
Reactant: COC(=O)c1sccc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1OC
Yield: 29 %

Procedure:
To a solution of 31 (8.45 g; 32.16 mmol) and methyl 3-aminothiophene-2-carboxylate (5.60 g; 35.38 mmol) in tetrahydrofuran (160 mL) at room temperature was added sodium hydride (1.5 g; 38.59 mmol; 60% mineral oil). The reaction mixture was stirred at room temperature under nitrogen for 16 hours (an additional equivalent of sodium hydride was found to be necessary to drive reaction to an acceptable level of completion) and then quenched with water and aqueous hydrochloric acid (2N) and extracted with ethyl acetate. The combined organic phases were successively washed with water and aqueous saturated sodium chloride, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting crude residue was taken up in ethyl acetate. The resulting precipitate was filtered and triturated from diethyl ether to yield the title compound as a light brown solid (3.58 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[O:8][CH:9]([CH3:32])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:23]([C:28]([O:30]C)=[O:29])[C:24]([O:26]C)=[O:25])[C:20]#[C:21][CH3:22])=[CH:15][CH:14]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2].O.Cl>C(#N)C.[OH-].[Na+]>[C:1]([C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[O:8][CH:9]([CH3:32])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:23]([C:24]([OH:26])=[O:25])[C:28]([OH:30])=[O:29])[C:20]#[C:21][CH3:22])=[CH:15][CH:14]=1)=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC#CC(c1ccc(NC(=O)C(C)Oc2cccc(C(C)(C)C)c2)cc1)C(C(=O)OC)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC#CC(c1ccc(NC(=O)C(C)Oc2cccc(C(C)(C)C)c2)cc1)C(C(=O)O)C(=O)O

Procedure:
A solution of 323 mg (0.67 mmol) of dimethyl 2-(1-{4-[2-(3-tert-butylphenoxy)-propionylamino]phenyl}but-2-ynyl)malonate in 7 ml of acetonitrile and 6.7 ml of 1 N sodium hydroxide solution (aq) was stirred at room temperature for 18 h. The reaction mixture was admixed with water and adjusted to pH=1 with 1 N HCl (aq) and then extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under high vacuum. This gave 304 mg of 2-(1-{4-[2-(3-tert-butylphenoxy)propionylamino]phenyl}but-2-ynyl)malonic acid in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:14][Mg]Br.Cl>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:13])([CH3:14])[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Agent: Cl
Solvent: CCOCC
Product: CC(O)(c1ccc(Br)cc1)C(F)(F)F
Reaction time: 8 h

Procedure:
Commercial 1-(4-bromophenyl)-2,2,2-trifluoroethanone (1 g, 4 mmoles) in diethyl ether (8 mL) was cooled to −78° C. for the addition of commercial methylmagnesium bromide (2.65 mL, 7.9 mmoles, 3 M in diethyl ether). The cloudy reaction media was allowed to reach room temperature and stirred overnight. The reaction mixture was transferred to a separatory funnel containing 1.2 M hydrochloric acid (20 mL). This aqueous layer was extracted 3 times with ethyl acetate (30 mL). The combined organic layers were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The clear oil was pure enough to be used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([N+:14]([O-])=O)[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:14][C:12]1[CH:11]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cc(OC)cc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(N)cc(OC)c1
Yield: 96.7 %

Procedure:
The compound (5.1 g, 23.1 mmol) prepared in step 2 was dissolved in ethyl acetate (50.0 ml), added with 10%-palladium (Pd) (100 mg). The resulting mixture was then stirred at room temperature for 24 hours in presence of hydrogen gas. After completion, 10%-palladium (Pd) was removed by celite-filter and the filtrate concentrated to dryness. The residue was purified by flash column chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (4.36 g, yield: 96.8%, white solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([NH2:8])=[S:7].Cl[CH2:17][C:18](=O)[CH3:19]>C1C=CC=CC=1>[CH3:15][O:14][C:10]1[CH:9]=[C:5]([C:6]2[S:7][CH:17]=[C:18]([CH3:19])[N:8]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:11]=1[O:12][CH3:13]
Reactant: COc1cc(C(N)=S)cc(OC)c1OC
Reactant: CC(=O)CCl
Solvent: c1ccccc1
Product: COc1cc(-c2nc(C)cs2)cc(OC)c1OC
Temperature: 25 °C
Yield: 62 %

Procedure:
Into 200 ml of benzene, 22.7 g (0.1 mol) of 3,4,5-trimethoxythiobenzamide and 11.1 g (0.12 mol) of chloroacetone were dissolved, and the solution was heated under a reflux condenser for 5 hours. After cooling to room temperature, the crystals which separated out were collected by filtering and recrystallized from methanol. The product consisting of pale yellow needle-like crystals, and amounting to 16.5 g was thus obtained, melting at 105° to 106.5° C. The yield was 62%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:26][CH:27]([NH2:32])[C:28]([F:31])([F:30])[F:29].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:32][C@@H:27]([CH3:26])[C:28]([F:31])([F:30])[F:29])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Reactant: CC(N)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a solution of 6-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.28 mmol) and L-2,2,2-trifluoro-1-(methyl)ethylamine (32 mg, 0.28 mmol) in THF (10 mL) were added at 0° C., 1-hydroxybenzotriazole hydrate (43.3 mg, 0.28 mmol), N-ethyldiisopropylamine (121 μL, 0.69 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (54.2 mg, 0.28 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed by distillation. The remaining material was purified by chromatography (silica, ethyl acetate:heptane=2:8 to 1:0, then silica, dichloromethane:methanol=99:1 to 95:5) to afford the title compound (75 mg, 60%) as a white solid. MS: m/e=454.1 [M−H]−.
Reaction SMILES: [C:1]([SH:5])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Br.C1(C)C=CC=CC=1>CO.O>[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][S:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1Br
Reactant: CC(C)(C)S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)SCc1ccccc1Br
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
36.6 g (406 mmol) of tert-butylmercaptan were added to a mixed solution of 36.5 g (438 mmol) of 48% aqueous sodium hydroxide solution and 400 ml of methanol under a nitrogen atmosphere at room temperature. A solution of 99.5 g (398 mmol) of 2-bromobenzylbromide in 100 ml of methanol were dropped into this solution below 40° C. After stirring for 30 minutes at 40° C. 1000 ml of toluene and 500 ml of water were sequentially added to the reaction solution. The aqueous layer was separated, and the organic layer was sequentially washed with 500 ml of 5% aqueous sodium hydroxide solution and 500 ml of water. After drying the organic layer with magnesium sulfate, the solvent was distilled off to obtain 300 ml of residue, which was used in the next step.
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].O.[CH2:6]([CH:13]([C:19](=[O:21])[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO>[CH2:6]([CH:13]([CH:19]([OH:21])[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(=O)C(Cc1ccccc1)C(C)O
Yield: 85 %

Procedure:
0.05 Mol of NaBH4 and 0.4 g of NaOH were added into 25 ml of water. While cooling the reactor in ice bath, a mixture of 0.07 mol of ethyl 2-benzyl-3-oxo-butyrate and 30 ml of methanol was added dropwise with stirring, and the reaction was stirred at room temperature for 5 hours. After removing the solvent, the product was extracted with ethyl acetate, and the extract was dried over anhydrous Na2SO4. Removing the solvent gave a colorless liquid of 0.06 mol. Yield 85%.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:16])=[CH:11][CH:10]=2)[CH2:6][O:5][CH2:4]1.[BrH:23]>O>[Br:23][CH2:4][C:3]([CH2:6][OH:5])([CH2:2][OH:1])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:11][CH:10]=1
Reactant: O=C(c1ccccc1)c1ccc(OCC2(CO)COC2)cc1
Reactant: Br
Solvent: O
Product: O=C(c1ccccc1)c1ccc(OCC(CO)(CO)CBr)cc1

Procedure:
Suspend (4-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}phenyl)(phenyl)methanone in a mixture of 48% aq. HBr and water and heat the mixture to reflux for 1 hour. Extract the product into dichloromethane, and evaporate the solvent, the solid residue may be recrystallised from ethanol to provide {4-[3-bromo-2,2-bis(hydroxymethyl)propoxy]phenyl}(phenyl)methanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[CH:6]=[C:5]2[C:19]([OH:21])=O.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[CH:6]=[C:5]2[C:19]([Cl:24])=[O:21]
Reactant: Cc1ccc(-c2cc(C(=O)O)c3cc(Cl)ccc3n2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(C(=O)Cl)c3cc(Cl)ccc3n2)cc1

Procedure:
A mixture of 28.4 g of 6-chloro-2-(4-methylphenyl)-4-quinolinecarboxylic acid, 100 ml of thionyl chloride, and 200 ml of toluene was stirred and heated under reflux for 1.5 hr. The reaction mixture was then concentrated in vacuo, the residue was treated with more toluene, and the mixture again concentrated in vacuo. The residue was recrystallized from 300 ml of heptane to give 17.7 g of the above-named compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[CH:5]=[CH:4][N:3]=1.[CH3:20][N:21]([CH3:30])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O.C([O-])(=O)C.[NH4+]>C(O)C>[CH3:20][N:21]([CH3:30])[C:22]1[CH:23]=[C:24]([C:25]2[NH:1][C:2]3=[N:3][CH:4]=[CH:5][C:6]([NH:9][C@@H:10]4[C@@H:15]5[CH2:16][C@@H:12]([CH:13]=[CH:14]5)[C@@H:11]4[C:17]([NH2:19])=[O:18])=[C:7]3[N:8]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2ccnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: CN(C)c1cccc(C=O)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN(C)c1cccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)ccnc3[nH]2)c1
Yield: 37.3 %

Procedure:
(1S,2S,3R,4R)-3-(2,3-Diamino-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.0 mg, 0.193 mmol) and 3-dimethylamino-benzaldehyde (31.6 mg, 0.212 mmol) were combined with ammonium acetate (29.7 mg, 0.386 mmol) and heated in ethanol (2.5 mL) at 70° C. for 18 h. The reaction mixture was concentrated and chromatographed by reverse phase preparative HPLC. The desired fractions were neutralized with bicarb solution and extracted into EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. This residue was triturated in ethyl ether and filtered to yield 28 mg (37%) of the title compound. mp: 200-204° C., 1H NMR (300 MHz, DMSO-d6): 13.02 (s, 1H), 7.90 (d, 1H), 7.66 (s, 1H), 7.50 (s, 1H), 7.47 (d, J=8 Hz, 1H), 7.30 (t, J=8 Hz, 1H), 7.15 (s, 1H), 6.86 (m, 1H), 6.81 (d, J=8 Hz, 1H), 6.40 (d, J=5 Hz, 1H), 6.33 (s, 2H), 2.98 (s, 6H), 2.87 (s, 1H), 2.77 (s, 1H), 2.60 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.42 (d, J=8 Hz, 1H). HPLC: 1.63 min (G method), MS: 389 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:9]([Br:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+:18].[K+].Br[CH:21](C(OCC)=O)[C:22]([O:24]CC)=[O:23]>CC(=O)CC>[N+:11]([C:7]1[CH:8]=[C:9]([Br:10])[C:2]2[O:1][C:21]([C:22]([O-:24])=[O:23])=[CH:4][C:3]=2[CH:6]=1)([O-:13])=[O:12].[K+:18]
Reactant: O=Cc1cc([N+](=O)[O-])cc(Br)c1O
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C([O-])c1cc2cc([N+](=O)[O-])cc(Br)c2o1
Temperature: 25 °C
Yield: 108.1 %

Procedure:
A mixture of 11.0 gm (44.7 mMol) 2-hydroxy-3-bromo-5-nitrobenzaldehyde, 5.56 gm (40.24 mMol) potassium carbonate, and 8.0 mL (46.95 mMol) diethyl bromomalonate in 55 mL 2-butanone was heated at reflux for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between 450 mL diethyl ether and 250 mL water and the aqueous phase was adjusted to pH of about 1 by the addition of dilute sulfuric acid. The phases were separated and the aqueous phase was extracted with two 150 mL portions of diethyl ether. The organic phases were combined, washed with 50 mL saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residual solid was dissolved in 200 mL ethanol to which were added 4.8 gm (85.5 mMoL) potassium hydroxide. The resulting suspension was warmed on a steam bath for 1 hour. The suspension was then cooled to room temperature. After about 18 hours the mixture was filtered and dried under reduced pressure to provide 14.1 gm (98%) of the desired compound as an orange solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[N:6][N:7]2[C:12]([N:13]([CH3:20])C3C=CC=CC=3)=[N:11][C:10]([S:21][CH3:22])=[N:9][C:8]=12)([CH3:3])[CH3:2].[S:23]1[CH:27]=[CH:26][C:25]([C:28]2[CH:35]=[CH:34][C:31](CN)=[CH:30][CH:29]=2)=[CH:24]1>CCO>[CH:1]([C:4]1[CH:5]=[N:6][N:7]2[C:12]([NH:13][CH2:20][C:31]3[CH:30]=[CH:29][C:28]([C:25]4[CH:26]=[CH:27][S:23][CH:24]=4)=[CH:35][CH:34]=3)=[N:11][C:10]([S:21][CH3:22])=[N:9][C:8]=12)([CH3:2])[CH3:3]
Reactant: NCc1ccc(-c2ccsc2)cc1
Reactant: CSc1nc(N(C)c2ccccc2)n2ncc(C(C)C)c2n1
Solvent: CCO
Product: CSc1nc(NCc2ccc(-c3ccsc3)cc2)n2ncc(C(C)C)c2n1
Yield: 74 %

Procedure:
According to the same conditions resulting in the preparation of the compound IIa.1, the compound IIa.3 is prepared from 8-isopropyl-4-(N-methyl-N-phenylamino)-2-(methylsulfanyl)pyrazolo[1,5-a]-1,3,5-triazine and from 4-(thiophen-3-yl)benzylamine. Yield=74%. Mp=141-143° C. (EtOH). 1H NMR (300 MHz, CDCl3): δ 7.73 (s, 1H, Harom), 7.57 (d, 2H, J=8.3 Hz, Harom), 7.45-7.36 (m, 5H, Harom), 6.78 (bs, 1H, NH), 4.81 (d, 2H, J=6.0 Hz, CH2), 3.16 (hept, 1H, J=7.0 Hz, CH), 2.58 (s, 3H, CH3), 1.33 (d, 6H, J=7.0 Hz, 2 CH3). MS (ESI): m/z 396 (MH+).
Reaction SMILES: [F:1][C:2]1[N:3]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1.C([Li])(C)(C)C.[CH3:31][S:32]SC.CCOCC>CCCCC.C1COCC1>[F:1][C:2]1[N:3]([C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:4]=[C:5]([S:32][CH3:31])[N:6]=1
Reactant: CSSC
Reactant: Fc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CCOCC
Product: CSc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reaction time: 0.5 h

Procedure:
A mixture of 2-fluoro-1-triphenylmethylimidazole (0.328 g.) and t-butyl lithium (1.0 ml. of a 2M solution in pentane) in THF (3 ml.) was stirred at -78° for 2 hours. Dimethyl disulphide (0.18 ml.) was added and the mixture was stirred for 0.5 hours at -78° then at -15° for 1 hour. Ether was added and the organic layer washed to neutrality with water and finally with brine. The solution was dried and the solvent evaporated to give 2-fluoro-4-methylthio-1-triphenylmethylimidazole (0.368 g.), m.p. 142°-143°.
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:10]3[CH2:27][S:26](=[O:29])(=[O:28])[C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:11]=3[N:12]([CH:14]3[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]3)[N:13]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[O:39]1[CH:43]=[CH:42][C:41]([C:44](Cl)=[O:45])=[CH:40]1>C(Cl)Cl>[O:39]1[CH:43]=[CH:42][C:41]([C:44]([N:16]2[CH2:17][CH2:18][CH2:19][CH:14]([N:12]3[C:11]4[C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=5[S:26](=[O:29])(=[O:28])[CH2:27][C:10]=4[C:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])=[N:13]3)[CH2:15]2)=[O:45])=[CH:40]1
Reactant: O=C(Cl)c1ccoc1
Reactant: O=C(c1nn(C2CCCNC2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccoc1)N1CCCC(n2nc(C(=O)N3CCOCC3)c3c2-c2ccccc2S(=O)(=O)C3)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of Enantiomer B of 3-(morpholin-4-ylcarbonyl)-1-[piperidin-3-yl]-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (30 mg; 0.07 mmol; 1 eq.) in DCM (0.45 mL) is added N,N-diisopropylethylamine (25 μl; 0.14 mmol; 2 eq.) followed by 3-furoyl chloride (14 mg; 0.11 mmol; 1.5 eq.) and the reaction mixture is stirred at rt overnight. The solvent is concentrated and the residue is purified by flash chromatography (eluent MeOH/EtOAc 0 to 10%) to afford 20 mg (54%) of the title compound as a white foam. 1H NMR (DMSO-d6): δ 8.04 (d, J=7.7 Hz, 2H), 7.86 (s, 1H), 7.75 (d, J=7.8 Hz, 2H), 6.67 (s, 1H), 4.85 (s, 1H), 4.79 (s, 2H), 3.91 (s, 2H), 3.64 (d, J=9.7 Hz, 5H), 2.26 (s, 2H), 1.95-1.61 (m, 2H). HPLC (max plot) 99.4%; Rt 3.02 min. MS (ESI+): 511.30.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH2:12]([C:18]1[CH:19]=[CH:20][C:21]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:22][CH:23]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCc1ccccc1
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: CCCCCCc1ccc(C(O)C(=O)c2ccccc2)cc1

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and n-hexylbenzene (0.76 ml, 4 mM) were dissolved in dichloroethane (3 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 1 hour. Using the same procedure as in Example 1, 4'-n-hexylbenzoin was obtained as crystal (352.8 mg, 59.4% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][C:18]1=[O:23]>CN(C)C=O.C(Cl)(Cl)Cl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:20]2[CH2:21][CH2:22][NH:17][C:18](=[O:23])[CH2:19]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C1CN(c2ccc([N+](=O)[O-])cc2)CCN1
Temperature: 140 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 1.275 g (9.04 mmol) of 4-fluoronitrobenzene in 30 mL of N,N-dimethylformamide were added 1.879 (13.56 mmol) of potassium carbonate and 905 mg (9.04 mmol) of piperazine-2-one, and the mixture was stirred for 1 hour at 130° C. and for 1 hour at 140° C. The reaction mixture was cooled to room temperature and diluted with chloroform, then, insoluble substances were removed off by filtration. The filtrate was condensed under reduced pressure and the resulting solid was washed with ethanol to give 859 mg (43%) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Cl:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[CH:28])=[CH:21][CH:20]=1.C(N(CC)CC)C.CCOC(C)=O>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[C:28][C:2]2[C:3]([NH:10][CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)=[CH:21][CH:20]=1
Reactant: C#CCOc1ccc(CCl)cc1
Reactant: N#Cc1ncc(Br)c(NC2CCCCC2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ncc(C#CCOc2ccc(CCl)cc2)c(NC2CCCCC2)n1
Temperature: 65 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
5-Bromo-4-cyclohexylamino-pyrimidine-2-carbonitrile (0.19 mmol) and chloromethyl-4-prop-2-ynyloxy-benzene (0.22 mmol) in DMF (5 ml) are treated with triethylamine (0.56 mmol), copper (I) iodide (0.019 mmol), and dichlorobis(triphenylphosphine)palladium(II) (0.0093 mmol) at room temperature. The mixture is stirred for 2 h at 65° C., poured into an ice water, extracted with AcOEt. The organic layer is washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give the product in 21% yield. Rf=0.75 (n-hexanes:AcOEt=1:2). 1H-NMR (400 MHz, CDCl3) δ 1.02-1.48 (m, 5H), 1.57-1.78 (m, 3H), 1.80-1.98 (m. 2H), 3.94-4.04 (m, 1H), 4.61 (s, 2H), 5.03 (s, 2H), 5.38 (d, 1H), 7.04 (d, 2H), 7.41 (d, 2H), 8.21 (s, 1H).