Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]=[C:13]=[S:14]>C(O)C>[C:2]([NH:3][C:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[Cl:5])=[S:14])#[N:1]
Reactant: N#CN
Reactant: S=C=Nc1ccccc1Cl
Agent: [Na]
Solvent: CCO
Product: N#CNC(=S)Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
The suspension of monosodium cyanamide (1.9 g, 29.4 mmol) in absolute ethanol (50 mL) was slowly treated with 2-chlorophenylisothiocyanate (5.0 g, 29.4 mmol). The reaction was allowed to stir at room temperature for 1 hour and then heated at 75° C. for 4 hours. The reaction was cooled to room temperature and the colorless solid was filtered and washed with ethanol to give the title A compound (6.0 g), m.p. 253°-255° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C.CCOC(C)=O>[OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[O:11][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1ccc(NC(N)=O)cc1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1coc(Nc2ccc(C)c(O)c2)n1
Temperature: 60 °C
Yield: 50 %

Procedure:
A solution containing 1-(3-hydroxy-4-methylphenyl)urea (150 mg, 0.9 mmol) and ethyl 3-bromopyruvate (0.11 mL, 0.9 mmol) in dry DMF (3.611E) was heated at 60° C. for 6 h. The reaction mixture was diluted with EtOAc and washed with brine and saturated NaHCO3 solution and the combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography on silica gel (hexane:EtOAc 6/4) to give the product in 50% yield (119 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[CH:16]/I)[CH3:12].O>C(N(CC)CC)C.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>[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[CH:16]/[C:9]#[C:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([Cl:10])[CH:5]=1)[CH3:12]
Reactant: CCOC(=O)/C=C/I
Reactant: C#Cc1cc(Cl)cc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/C#Cc1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 1,3-dichloro-5-ethynyl-benzene (1.52 g, 8.9 mmol) in triethylamine (32.4 mL) was added PdC12(PPh3)2 (57.15 mg, 0.08 mmol), (E)-3-iodo-prop-2-enoic-acid ethyl ester (1.84 g, 8.1 mmol) and copper(l)iodide (7.7 mg, 0.04 mmol). The reaction mixture was stirred for 2 h at 50° C., whereafter the reaction mixture was cooled to room temperature, water (30 mL) added and the mixture extracted with diethyl ether (3×20 mL). The combined and dried organic phases were evaporated to give crude (E)-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid ethyl ester in 1.1 g yield.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][N:10]=[C:9]([NH:19][CH3:20])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([O:25][C:26](=[O:34])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32]Br)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26](=[O:34])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][N:19]([C:9]1[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][N:10]=1)[CH3:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)COCCCCBr
Reactant: CNc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Product: CN(CCCCOCC(=O)OC(C)(C)C)c1ncc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
In the same manner as in Example 22, except that 4,5-diphenyl-2-(methylamino)pyrimidine was used in place of 5,6-diphenyl-2-(methylamino)pyrazine and 2-(4-bromobutyloxy)acetic acid tert-butyl ester was used in place of 2-(4-bromobutyloxy)acetic acid methyl ester, the desired compound was prepared as a pale yellow oily substance.
Reaction SMILES: Cl.[O:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH2:18])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[C:19]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([S:27](Cl)(=[O:29])=[O:28])=[CH:25][CH:24]=1)(=[O:21])[CH3:20]>>[O:5]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][S:27]([C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:19](=[O:21])[CH3:20])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:8][CH2:7]2)[O:2][CH2:3][CH2:4]1
Reactant: Nc1ccccc1N1CCC2(CC1)OCCO2
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2N2CCC3(CC2)OCCO3)cc1

Procedure:
The title compound was prepared from 2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamine hydrochloride (which was obtained in Example 220) and N-acetylsulfanilyl chloride according to the procedure of Example 215 as a crystalline solid; 1H NMR (300 MHz, DMSO-d6) δ 1.73 (t, J=5.4 Hz, 4H), 2.73 (t, J=5.4 Hz, 4H), 3.33 (s, 4H), 3.89 (s, 3H), 7.00-7.10 (m, 2H), 7.10-7.20 (m, 1H), 7.30-7.40 (m, 1H), 7.67 (d, J=9.3 Hz, 2H), 7.71 (d, J=9.3 Hz, 2H), 8.79 (s, 1H), 10.29 (s, 1H); MS (ES) m/z: 432.2 (MH+); HRMS Calcd. for C21H26N3O5S (MH+): 432.1593. Found: 432.1597. Anal. Calcd. for C21N25N3O5S: C, 58.45; H, 5.84; N, 9.74. Found: C, 58.41; H, 5.83; N, 9.72.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:16][CH3:17])(=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].Br[CH2:19][CH2:20][Cl:21]>C(C(C)=O)C>[CH3:17][O:16][C:7](=[O:15])[C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[O:10][CH2:19][CH2:20][Cl:21]
Reactant: COC(=O)c1ccccc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccccc1OCCCl

Procedure:
34 g (0.25 mol) of potassium carbonate were added to a solution of 25 g (0.16 mol) of methyl salicylate in 250 ml of methyl ethyl ketone. This mixture was refluxed for 1 h, then 27.3 ml (0.35 mol) of 1-bromo-2-chloro-ethane were added and the mixture was taken to reflux again. Four hours later, 34 g (0.25 mol) more of potassium carbonate and 16.3 ml (0.2 mol) more of 1-bromo-2-chloro-ethane were added. This operation was repeated until the reaction was completed. The inorganic salts were filtered off and the liquid phase was diluted with the same volume of hexane. This organic phase was washed twice with water and worked-up as usual. The yield in this step was quantitative and the product was pure enough for the next synthetic step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH:11]=[C:4]2[N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH:11]=[C:4]2[N:3]=1
Reactant: C1COCCN1
Reactant: Cc1ccccc1-c1cc2nc(Cl)cc(Cl)n2n1
Solvent: C1COCCO1
Product: Cc1ccccc1-c1cc2nc(Cl)cc(N3CCOCC3)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
There was dissolved, in 1,4-dioxane (2 mL), 5,7-dichloro-2-(2-methyl-phenyl)-pyrazolo[1,5-a]pyrimidine (74.4 mg, 0.267 mM), then morpholine (46.6 μL, 0.534 mM) was added to the solution and the mixture was stirred at room temperature for one hour. The solvent was distilled off from this reaction mixture, the resulting residue was diluted with water and then extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with methanol to give the title compound (75.3 mg, yield: 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[OH-:29].[Na+].CO>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:5]2[N:6]([C:8]([C:11]([NH2:12])=[O:29])=[CH:9][N:10]=2)[N:7]=1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C(N)=O)cnc23)cc1
Temperature: 100 °C

Procedure:
A mixture of 6-chloro-3-cyano-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (25 mgs) from Example XXXI(1) step 1b, 6N NaOH (0.1 mL), MeOH (0.1 mL) and dioxane (1 mL) in a vial was heated to 100° C. for 16 h. The mixture was cooled to room temperature and concentrated in vacuo. Upon addition of 1M HCl a precipitate forms. The precipitate was collected by filtration and dried to provide 35 mgs of crude 6-chloro-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH2:18]([O:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH2:10][CH3:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCc1cc(Br)cc(C)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc(Br)cc(C)c1OCc1ccccc1
Temperature: 25 °C

Procedure:
A suspension of 39.8 g (185 mmol) 4-bromo-2-ethyl-6-methyl-phenol, 63.9 g (0.46 mmol) K2CO3 and 22.0 mL (185 mmol) benzyl bromide in 450 mL acetonitrile was refluxed for 3 h, cooled to RT and concentrated by evaporation i. vac. The residue was combined with EtOAc, the organic phase was washed with water and saturated NaCl solution, dried on Na2SO4 and concentrated by evaporation i. vac.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[CH3:31][O-:32].[Na+].O>CO>[CH3:31][O:32][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
To a solution of 100 mg (0.225 mmol) of the oxadiazole from Example 23A in 8.0 ml of methanol were added 60.79 mg (1.124 mmol) of sodium methoxide, and then the reaction mixture was stirred under reflux for 18 h. The reaction mixture was admixed with water and extracted with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by means of preparative HPLC. Yield: 32.0 mg (31% of theory)
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:17])[N:3]=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[OH:27].CC(C)([O-])C.[K+]>C1COCC1>[CH2:13]([CH:12]([O:11][C:6]1[CH:5]=[C:4]([CH3:17])[N:3]=[C:2]([O:27][C:20]2[C:21]([CH3:26])=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=2[CH3:18])[C:7]=1[N+:8]([O-:10])=[O:9])[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)Oc1cc(C)nc(Cl)c1[N+](=O)[O-]
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a mixture of 2-chloro-4-(1-ethyl-propoxy)-6-methyl-3-nitro-pyridine (500 mg, 1.93 mmol) and 2,4,6-trimethylphenol (289 mg, 2.13 mmol) in dry THF was added potassium t-butoxide. The resulting mixture was stirred at rt. overnight. The mixture was quenched with water, brine and extracted 3 times with ethyl acetate. The organic layer was separated, dried (MgSO4) and concentrated to dryness. After silica gel column chromatography purification, the title compound was obtained as a light yellow crystal, mp 106–109° C. Anal. For C20H26N2O4 calc. C, 67.02; H, 7.31; N, 7.82; found, C, 67.34; H, 7.40; N, 7.42.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]([O:16]CC)=[O:15])=[CH:10][N:9]=[C:8]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Li+]>C(OCC)(=O)C>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]([OH:16])=[O:15])=[CH:10][N:9]=[C:8]2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnc(-c2ccccc2)n(C2CCCCC2)c1=O
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: O=C(O)c1cnc(-c2ccccc2)n(C2CCCCC2)c1=O
Yield: 45 %

Procedure:
Ethyl 1-cyclohexyl-1,6-dihydro-6-oxo-2-phenyl-5-pyrimidinecarboxyate (1.41 g, 4.32 mmol) (i.e. the product from Example 11, Step A) was dissolved in ethyl acetate and treated with lithium iodide (powder, 1.72 g, 12.8 mmol) and heated to reflux for 16 h. The crude reaction mixture was concentrated under reduced pressure and then aqueous sodium bicarbonate was added and the resulting solution was extracted with ethyl acetate which was then discarded. The aqueous layer was made acidic with hydrochloric acid (1 N) and then extracted with dichloromethane (2×40 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure resulting in 0.58 g of the title product as a solid.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:30])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[CH3:31][C:32]([CH3:43])([NH2:42])[CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>O1CCCC1>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:42][C:32]([CH3:43])([CH3:31])[CH2:33][CH2:34][CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: CC(C)(N)CCCc1cccnc1
Reactant: O=C(/C=C/C=C(c1ccc(F)cc1)c1ccc(F)cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CC(C)(CCCc1cccnc1)NC(=O)/C=C/C=C(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
As in Example 134, a solution of (E)-5,5-bis(4-fluorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.63 g) and alpha,alpha-dimethyl-3-pyridinebutanamine (0.9 mL) in tetrahydrofuran (20 mL) was stirred at reflux for 24 hours. The crude product, isolated in the usual manner, was crystallized from ethyl acetate to yield 1.6 g of (E)-5,5-bis(4-fluorophenyl)-N-[1,1-dimethyl-4-(3-pyridinyl)butyl]-2,4-pentadienamide, mp 163.5°-164.5° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[NH:27][N:26]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:17][C:11]1[C:10]([CH3:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:30]([C:28]3[NH:27][N:26]=[C:25]([C:21]4[O:20][CH:24]=[CH:23][CH:22]=4)[CH:29]=3)=[O:31])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1cc(-c2ccco2)n[nH]1
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3cc(-c4ccco4)n[nH]3)n2)ccc(C#N)c1Cl
Yield: 45.2 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.059 g, 0.331 mmol), 3-(furan-2-yl)-1H-pyrazole-5-carboxylic acid (0.091 g, 0.331 mmol), HOBt (0.068 g, 0.497 mmol), DIPEA (0.087 ml, 0.497 mmol) and EDCI (0.096 g, 0.497 mmol) using DCM as solvent using the method of Example 34(d) affording 0.065 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.16 (d, 3H), 2.53 (s, 3H), 4.28-4.38 (m, 2H), 4.43-4.51 (m, 1H), 6.60 (d, 2H), 6.81-6.91 (m, 2H), 7.66 (d, 1H), 7.77 (s, 1H), 7.82 (d, 1H), 7.85 (m, 1H), 8.31 (m, 1H), 13.69 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([OH:17])([CH3:16])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:3]=1.[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:21][C:20]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:19]=2[Cl:18])=[C:4]([C:9]([OH:17])([CH3:16])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:3]=1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CC(O)(Cn1ccnc1)c1cc(Cl)ccc1O
Product: CC(O)(Cn1ccnc1)c1cc(Cl)ccc1OCc1ccc(Cl)cc1Cl
Yield: 51.9 %

Procedure:
The general procedure of Example 6 was repeated using 4-chloro-2-(1-hydroxy-2-(1H-1-imidazolyl)-1-methylethyl)phenol [compound (2-1)] and 2,4-dichlorobenzyl chloride, to thereby yield 2-(5-chloro-2-((2,4-dichlorobenzyl)oxy)phenyl)-1-(1H-1-imidazolyl)-2-propanol as colorless crystals (yield: 51.9%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16](=[O:32])[C:17]3[CH:22]=[C:21]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:20]=[CH:19][C:18]=3[N+:29]([O-])=O)=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]>CO.[Pd]>[NH2:29][C:18]1[CH:19]=[CH:20][C:21]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:22][C:17]=1[C:16]([NH:15][C:12]1[N:13]=[CH:14][C:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)=[CH:10][N:11]=1)=[O:32]
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3[N+](=O)[O-])nc2)cc1C
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3N)nc2)cc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of N-(5-(3,4-dimethylphenyl)pyrimidin-2-yl)-2-nitro-5-(piperidin-1-yl)benzamide (550 mg, 1.27 mmol, 1.00 equiv) in methanol (80 mL). The mixture was treated with Pd/C (550 mg) and stirred under a hydrogen atmosphere for ca. 4 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield in 420 mg (82%) of 2-amino-N-(5-(3,4-dimethylphenyl)pyrimidin-2-yl)-5-(piperidin-1-yl)benzamide as a brown syrup
Reaction SMILES: C(O[C@@:5]([CH3:21])([C:19]#[CH:20])[CH2:6][CH2:7][C:8]1[C:9](=[O:18])[C:10]([CH3:17])=[C:11]([CH3:16])[C:12](=[O:15])[C:13]=1[CH3:14])(=O)C.C(O)(=O)C>C(Cl)Cl.[Zn]>[C:19]([C@:5]1([CH3:21])[CH2:6][CH2:7][C:8]2[C:13]([CH3:14])=[C:12]([OH:15])[C:11]([CH3:16])=[C:10]([CH3:17])[C:9]=2[O:18]1)#[CH:20]
Reactant: C#C[C@@](C)(CCC1=C(C)C(=O)C(C)=C(C)C1=O)OC(C)=O
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C#C[C@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Temperature: 4 °C
Reaction time: 0.83 h
Yield: 25 %

Procedure:
A solution of 285 mg (0.99 mmol) of (R)-2-[3-(acetyloxy)-3-methyl-4-pentynyl]-3,5,6-trimethyl-2,5-cyclohexadiene-1,4-dione in 4 mL of CH2Cl2 was stirred with 250 mg of Zn dust, and 250 mg of glacial acetic acid. The reaction mixture was stirred at 4° C. under argon for 50 min, then filtered. It was worked up with CH2Cl2 as described above. The crude hydroquinone acetate was taken into 6 mL of CH2Cl2 and treated with 20 mg of AgClO4.H2O as described above to give 124 mg of crude product after workup, and purification by flash chromatography. Crystallization of this material from toluene-hexane (1:1) at -15° C. gave 57 mg of (S)-2-ethynyl-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol: [α]D25 +20.20°, (c 1.3, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][C:6]1[S:10][C:9]([CH:11]=O)=[CH:8][CH:7]=1.C(OCC)(=O)C.CO.[NH3:24].CO>[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][C:6]1[S:10][C:9]([CH2:11][NH2:24])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Cc2cccc(Cl)c2)s1
Reactant: N
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CO
Product: NCc1ccc(Cc2cccc(Cl)c2)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 61.4 %

Procedure:
To a solution of 5-(3-chloro-benzyl)thiophene-2-carbaldehyde described in Preparation Example 44 (1.2 g, 5.08 mmol) in 7N ammonia/methanol (40 mL) was added Raney nickel (2 g), and the solution was stirred at room temperature for 17 hours under hydrogen atmosphere. The reaction solution was filtered through Celite pad, the catalyst was removed, then, this filtrate was evaporated in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate, then ethyl acetate:methanol=5:1), and the title compound (740 mg, 3.12 mmol, 61.4%) was obtained as a brown oil.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C@@H:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][C:18]2=C)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=O.[O:39]=[O+][O-].O=[O+][O-].CSC>CO>[C:8]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C@H:21]3[S:20][CH2:19][C:18]2=[O:39])=[O:16])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=C1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=[O+][O-]
Agent: O=O
Solvent: CO
Solvent: CSC
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(=O)CS[C@H]12
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of 0.50 g of 3-methylene-7β-phenylacetylamino-cepham-4α-carboxylic acid diphenylmethyl ester in 100 ml of methanol is treated for 6.5 minutes at -70° C. with an oxygen-ozone stream containing 0.175 mmol of ozone/minute. The reaction mixture is mixed with 0.5 ml of dimethyl sulphide and stirred for one hour at -70° C., then for 2 hours at room temperature and evaporated to dryness. The residue, in methylene chloride is chromatographed on 15 g of silica gel. Elution with methylene chloride yields amorphous 7β-phenylacetylaminocepham-3-one-4ξ-carboxylic acid diphenylmethyl ester, thin layer chromatography (silica gel): Rf~0.47 (system: toluene/acetone/methanol/acetic acid, 80:10:5:5); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95μ, 5.61μ, 5.77μ, 5.85μ, 5.95μ, 6.21μ and 6.87μ; the compound shows a positive reaction with iron-III chloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[CH:13]1([C:16]([NH2:18])=[O:17])[CH2:15][CH2:14]1>>[CH:13]1([C:16]([NH:18][C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=2)=[O:17])[CH2:15][CH2:14]1
Reactant: NC(=O)C1CC1
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Product: COC(=O)c1cc(C)nc(NC(=O)C2CC2)n1
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (2.70 g, brown oil) from methyl 2-chloro-6-methylpyrimidine-4-carboxylate (3.00 g, 16.1 mmol) and cyclopropanecarboxamide by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8])=[CH:4]1.C(N(CC)CC)C.[F:26][C:27]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:28]=1[CH:29]=[CH:30][C:31](O)=[O:32].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:26][C:27]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:28]=1[CH:29]=[CH:30][C:31]([NH:8][C@H:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][C:5]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]([CH3:2])[CH:4]=1)=[O:32]
Reactant: COC(=O)[C@@H](N)Cc1cn(C)c2ccccc12
Reactant: O=C(O)C=Cc1c(F)cccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1c(F)cccc1F
Yield: 53 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 20 (1.4 g), triethylamine (0,72 mL), 2,6-difluorocinnamic acid (1.0 g), WSC.HCl (1.0 g), and methylene chloride (50 mL), to give the captioned compound (1.1 g, 51%) as an oily product.