Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:15])[C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5](O)=[O:6].C([N:18](CC)CC)C.ClC(OCC)=O>C1COCC1.O>[C:5]([C:4]1[CH:3]=[C:2]([Cl:1])[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([Cl:15])[CH:8]=1)(=[O:6])[NH2:18]
Reactant: COC(=O)c1c(Cl)cc(C(=O)O)cc1Cl
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(Cl)cc(C(N)=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
To a solution of 3,5-dichloro-4-(methoxycarbonyl)benzoic acid (72 g, 289 mmol) and triethylamine (40 mL) in THF (240 mL) at room temperature was added ethyl chloroformate (40 mL). The reaction mixture was stirred for 20 min at room temperature and filtered. To the filtrate was added (NH4)2CO3 (28 g, 292 mmol) and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with petroleum-diethyl ether (5:1) to give methyl 4-carbamoyl-2,6-dichlorobenzoate (57 g, yield: 80%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 3.90 (s, 3H), 7.76 (s, 1H), 7.99 (s, 2H), 8.28 (s, 1H). LCMS (ESI) m/z: 248.0 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([O:9]CC)=O)=[N:4][N:3]=1.C(O)C.[CH3:15][NH2:16]>CO>[NH2:1][C:2]1[S:6][C:5]([C:7]([NH:16][CH3:15])=[O:9])=[N:4][N:3]=1
Reactant: CCOC(=O)c1nnc(N)s1
Reactant: CN
Solvent: CCO
Solvent: CO
Product: CNC(=O)c1nnc(N)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 102.3 %

Procedure:
To a suspension of ethyl 5-amino-1,3,4-thiadiazole-2-carboxylate (106 mg, 0.612 mmol) in methanol (1.5 mL) was added 33 wt % ethanol solution of methylamine (0.5 mL, 4.00 mmol). The mixture was stirred at room temperature for 6 h, heated to 70° C. and cooled. The mixture was concentrated, mixed with water and lyophilized to give 5-amino-N-methyl-1,3,4-thiadiazole-2-carboxamide as a white solid (99 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.69 (q, J=4.8 Hz, 1H), 7.70 (s, 2H) 2.73 (d, J=4.78 Hz, 3H); MS (ES+) m/z: 159 (M+H); LC retention time: 0.44 min (analytical HPLC Method A).
Reaction SMILES: [CH2:1]([C:3]1[C:14]([CH2:15][C:16]#[N:17])=[C:6]2[C:7]3[CH2:13][CH2:12][O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]>N.CO.[Co]>[CH2:1]([C:3]1[C:14]([CH2:15][CH2:16][NH2:17])=[C:6]2[C:7]3[CH2:13][CH2:12][O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2ccc3c(c2c1CC#N)CCO3
Agent: [Co]
Agent: N
Solvent: CO
Product: CCc1nn2ccc3c(c2c1CCN)CCO3
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.3 %

Procedure:
(2-Ethyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)acetonitrile (120 mg, 0.528 mmol) and Raney cobalt (1.2 g) were suspended in 2M ammonia/methanol solution (25 mL), and the suspension was stirred at room temperature for 12 hr under a hydrogen atmosphere. The catalyst was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (120 mg, yield 98%).
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:12]([S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[NH2:19][C:20]([NH2:22])=[S:21]>CO>[BrH:1].[NH2:22][C:20](=[NH:19])[S:21][CH2:2][C:3]1[C:12]([S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1CBr
Reactant: NC(N)=S
Solvent: CO
Product: Br
Product: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1CSC(=N)N

Procedure:
A solution of the crude reaction mixture from Example 11 and 4.5 g thiourea in 150 ml methanol was heated at reflux temperature for 1.5 hours. Removal of the methanol in vacuo left a viscous oil which afforded a white solid upon trituration with ethyl acetate and filtration. The yield of the title isothiouronium bromide salt, m.p. 157°-164°(dec.), was 22.2 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[C:9]([Cl:23])[CH:8]=1)[CH3:2].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]([C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[C:9]([Cl:23])[CH:8]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:2]
Reactant: CCOC(=O)CNc1cc(Cl)c(Oc2ccc(OC)cc2)c(Cl)c1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)CN(C(=O)OCC)c1cc(Cl)c(Oc2ccc(OC)cc2)c(Cl)c1
Yield: 61 %

Procedure:
[3,5-Dichloro-4-(4-methoxy-phenoxy)-phenylamino]-acetic acid ethyl ester (10.0 g, 0.02 mol) was stirred with ethyl chloroformate (95 mL) at reflux temperature for 16 hrs. From the reaction mixture ethyl chloroformate was evaporated under reduced pressure and the residue was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give {[3,5-Dichloro-4-(4-methoxy-phenoxy)-phenyl]-ethoxycarbonyl-amino}-acetic acid ethyl ester (7.25 g, 61% Yield)
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[C:22]([Cl:23])=[C:21]([Cl:24])[C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:13]([CH3:14])[C:9]=2[CH:8]=1)C>C(O)C.[OH-].[Na+]>[Cl:23][C:22]1[C:7]([O:6][CH2:5][C:4]([OH:25])=[O:3])=[CH:8][C:9]2[C:13]([CH3:14])=[C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:11][C:10]=2[C:21]=1[Cl:24]
Reactant: CCOC(=O)COc1cc2c(C)c(-c3ccccc3)sc2c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(-c2ccccc2)sc2c(Cl)c(Cl)c(OCC(=O)O)cc12
Yield: 89 %

Procedure:
A mixture of 1.5 g ethyl[(6,7-dichloro-3-methyl-2-phenylbenzo[b]thien-5-yl)oxy]acetate in 50 ml of 95% ethanol and 50 ml of 15% aqueous sodium hydroxide is stirred under reflux for 1 hour. The mixture is concentrated under vacuum to dryness. The residue is triturated with water, cooled to 0° and acidified with conc hydrochloric acid. The solid product is extracted exhaustively with a mixture of ethyl ether-ethyl acetate (1:1) and the ether extracts are washed and dried over anhydrous magnesium sulfate. Removal of the solvents under reduced pressure leaves a tan-colored residue which is recrystallized from acetone to give 1.24 g of [(6,7-dichloro-3-methyl-2-phenylbenzo[b]thien-5-yl)oxy]acetic acid as shiny platelets, mp 232°-233° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.[OH-].[Li+]>O1CCCC1.CO.O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(-c2nccs2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2nccs2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 4-(1,3-thiazol-2-yl)benzoate (560 mg, 2.6 mmol) in a mixture of 2:1:1 tetrahydrofuran/methanol/water (20 mL) is added lithium hydroxide (322 mg, 3 mmol). The reaction mixture is stirred at room temperature for 2 h. The solvent is removed under reduced pressure and the residue is partitioned between diethyl ether and water. The aqueous layer is acidified to pH 1 with 1 N hydrochloric acid and a precipitate is observed. The solid is collected by filtration to afford the title compound. 1H NMR (300 MHz, CD3OD) δ 8.14-8.05 (m, 4H), 7.95-7.93 (m, 1H), 7.71-7.69 (m, 1H).
Reaction SMILES: [CH2:1]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:26][C:27]([O-:29])=[O:28])([C:16]2[C:24](O)=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)[C:8]1=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Li+]>C1COCC1.O>[CH2:1]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([C:16]3[CH:17]=[C:18]4[O:22][CH2:21][O:20][C:19]4=[CH:23][C:24]=3[O:29][C:27](=[O:28])[CH2:26]2)[C:8]1=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1C(=O)C(CC(=O)[O-])(c2cc3c(cc2O)OCO3)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCN1C(=O)C2(CC(=O)Oc3cc4c(cc32)OCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
To a solution of 2-(1-hexyl-3-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-2-oxoindolin-3-yl)acetate (0.19 g, 0.43 mmol) in THF:H2O (2:1) was added lithium hydroxide (0.04 g, 0.86 mmol). The mixture was stirred at ambient temperature for 4 hrs. The organic solvent was removed in vacuo and the pH of the aqueous residue was adjusted to 2 followd by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness and the residue was subjected to column chromatography eluting with 25% ethyl acetate/hexane to yield the title compound (0.09 g, 53%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.33 (dt, 1H), 7.14-7.03 (m, 2H), 6.93 (d, 1H), 6.66 (s, 1H), 6.06 (s, 1H), 5.88 (dd, 2H), 3.76-3.63 (m, 2H), 2.94 (q, 2H), 1.69-1.62 (m, 2H) 1.34-1.22 (m, 6H), 0.83 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 175.9, 165.8, 148.3, 147.2, 144.6, 142.6, 129.9, 129.6, 123.8, 123.4, 114.7, 109.2, 105.1, 101.9, 99.8, 49.6, 40.3, 37.2, 31.2, 27.2, 26.4, 22.4, 13.9; MS (ES+) m/z 394.5 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[N:7][CH:8]=1)[CH3:2].[OH:12]O>C(O)(=O)C>[CH3:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[N+:7]([O-:12])[CH:8]=1
Reactant: CCc1ccc(CCO)nc1
Reactant: OO
Solvent: CC(=O)O
Product: CCc1ccc(CCO)[n+]([O-])c1
Temperature: 100 °C
Yield: 81.8 %

Procedure:
To a solution of 100 g (0.655 mol) 2-(5-ethyl-pyridin-2-yl)-ethanol in 500 mL acetic acid was added 118 g (1.049 mol) 30% hydrogen peroxide at 25-30° C. Reaction mixture was refluxed at 100° C. (tlc) for 14 hr. After completion of the reaction acetic acid was removed under vacuum, and the residual mass was poured in excess water and made alkaline by 10% Na2CO3 solution. Product was extracted with ethyl acetate and after concentrating ethyl acetate in vacuo, 89.58 g (81%) crystalline product was obtained.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1.C([O-])(O)=O.[Na+]>C1COCC1>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:10][C:22]([CH:19]2[CH2:21][CH2:20]2)=[O:23])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)C(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NC(=O)C(c1ccccc1)c1ccccc1)C1CC1
Yield: 20.2 %

Procedure:
To a stirred and cooled (0° C.) solution of 2,2-diphenylacetamide (500 mg, 2.36 mmol) in THF (20 ml) was added sodium hydride (95 mg, 2.36 mmol; 60%) and the mixture was stirred at RT for 0.5 h. Then cyclopropanecarboxylic acid chloride(247 mg, 2.36 mmol) dissolved in THF (5 ml) was added dropwise at RT and the solution was stirred at RT for 20 h. The reaction mixture was poured into sat. NaHCO3 solution (50 ml) and extracted with ethyl acetate (2×70 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by column chromatography (toluene/ethyl acetate 19:1) yielded the product which was recrystallized from ethyl acetate/hexane to give a white solid (133 mg, 20%), m.p. 178° C. and MS: m/e=279 (M+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=O)=[CH:35][CH:34]=1.[NH2:42][C@H:43]1[CH2:48][CH2:47][CH2:46][C@:45]([C:50]#[C:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([Cl:58])[CH:53]=2)([OH:49])[CH2:44]1>CC(N(C)C)=O>[Cl:58][C:54]1[CH:53]=[C:52]([C:51]#[C:50][C@:45]2([OH:49])[CH2:46][CH2:47][CH2:48][C@H:43]([NH:42][C:37](=[O:39])[C:36]3[CH:35]=[CH:34][C:33]([CH3:32])=[CH:41][CH:40]=3)[CH2:44]2)[CH:57]=[CH:56][CH:55]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: N[C@H]1CCC[C@@](O)(C#Cc2cccc(Cl)c2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N[C@H]2CCC[C@@](O)(C#Cc3cccc(Cl)c3)C2)cc1
Reaction time: 0.33 h
Yield: 80 %

Procedure:
A solution of TBTU (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate)(29.9 mg, 0.093 mmol) in DMA (0.23 ml) and DIPEA (36 μl, 0.213 mmol) was added to solid 4-methylbenzoic acid (11.6 mg, 0.085 mmol) under argon atmosphere at room temperature. After stirring for 20 min., a solution of (1S,3S)-3-amino-1-(3-chloro-phenylethynyl)-cyclohexanol (21.2 mg, 0.085 mmol) in DMA (0.43 ml) was added and the crude reaction mixture was purified without further treatment after stirring for 24 h on a preparative LC/MS system, yielding the title compound (25.1 mg, 0.068 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[C:18]1([C:24]#[C:25][CH2:26]O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C)C=[O:31]>O.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:1][C:2]1[CH:3]=[C:4]([C:26]#[C:25][CH:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[OH:31])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: OCC#Cc1ccccc1
Reactant: CN(C)C=O
Reactant: COc1ccc(I)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C#CC(O)c2ccccc2)cc1Cl
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a stirring mixture of 3-chloro-4-methoxyiodobenzene (0.3 g, 1.1 mmol), (PPh3)2PdCl2 (31 mg, 0.044 mmol), triethylamine (1.2 mL, 8.9 mmol) in dimethylformamide (3 mL) was added to phenylethynylcarbinol (0.29 g, 2.2 mmol) at temperature in the range of 20-40° C. under nitrogen atmosphere. The mixture was then stirred at 80° C. for 12 hours. After cooling the mixture to temperature in the range of 20-40° C. it was diluted with water (15 mL) and extracted with ethyl acetate (3×25 mL). The organic layers were collected, combined, washed with water (2×5 mL), dried over anhydrous sodium sulphate, and concentrated to give the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(-c3ccncc3)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc(-c3ccncc3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]=[C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:16]=3)[O:13][CH:14]=2)=[O:9])[C:4]([N:27]2[CH2:31][CH2:30][CH:29]([CH3:32])[C:28]2=[O:33])=[N:3]1>CCCCCC.C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]=[C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][C:23]([F:25])([F:26])[F:24])[CH:16]=3)[O:13][CH:14]=2)=[O:9])[C:4]([N:27]2[CH2:31][CH2:30][C@H:29]([CH3:32])[C:28]2=[O:33])=[N:3]1
Reactant: CC1CCN(c2nn(C)cc2NC(=O)c2coc(-c3ccnc(NCC(F)(F)F)c3)n2)C1=O
Solvent: CCCCCC
Solvent: CCO
Product: C[C@H]1CCN(c2nn(C)cc2NC(=O)c2coc(-c3ccnc(NCC(F)(F)F)c3)n2)C1=O
Yield: 46 %

Procedure:
Racemic N-(1-methyl-3-(3-methyl-2-oxopyrrolidin-1-yl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1,3-oxazole-4-carboxamide (399 mg) was resolved by HPLC (column: CHIRALPAK IA (trade name), 50 mmID×500 mL, manufactured by Daicel Chemical Industries, mobile phase: hexane/ethanol=500/500), and the compound (186.7 mg) having a shorter retention time was recrystallized from THF/diisopropyl ether to give the title compound (183.7 mg).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][C:3]=1[CH3:7].C(N(CC)CC)C.[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>COCCOC.C(OCC)(=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>[CH3:7][C:3]1[N:4]=[CH:5][S:6][C:2]=1[C:22]#[C:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C#Cc1ccccc1
Reactant: Cc1ncsc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ncsc1C#Cc1ccccc1
Reaction time: 16 h
Yield: 26 %

Procedure:
5-Bromo-4-methyl-1,3-thiazole (570 mg, 3.2 mmol) and CuI (120 mg, 0.63 mmol) were combined in DME (5 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (2.0 mL, 14 mmol) and PdCl2(PPh3)2 (220 mg, 0.32 mmol) were added, followed by the dropwise addition of phenylacetylene (1.0 mL, 9.5 mmol). After 16 h stirring at ambient temperature additional phenylacetylene (0.35 mL, 3.2 mmol), CuI, (61 mg, 0.32 mmol), and PdCl2(PPh3)2 (110 mg, 0.16 mmol) were added and the reaction mixture was stirred for a further 16 h. The reaction was then heated to reflux, and after 3 h the reaction mixture was cooled, diluted with ethyl acetate (20 mL), and filtered through Celite™. The filter pad was washed thoroughly with ethyl acetate and the combined filtrates were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 95:5 hexane:ethyl acetate to afford 4-methyl-5-(phenylethynyl)-1,3-thiazole (166 mg, 26% yield) as a red oil. 1H NMR (CDCl3, 300 MHz) δ 8.62 (s, 1H), 7.54–7.50 (m, 2H), 7.37–7.26 (m, 3H), 2.6 (s, 3H). MS (ESI) 200.1 (M++H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=3)[O:15][CH:10]2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][CH2:35][OH:36])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>ClCCl.B(F)(F)F.CCOCC>[OH:15][CH:10]([C:9]([O:36][CH2:35][CH2:34][C:28]1[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[CH:27]=1)([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)[C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COc1ccc(CCO)cc1OC
Reactant: CCc1ccc(C2(c3ccc(CC)cc3)OC2C(=O)OC)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCc1ccc(C(OCCc2ccc(OC)c(OC)c2)(c2ccc(CC)cc2)C(O)C(=O)OC)cc1
Reaction time: 1.5 h

Procedure:
6 g (19.3 mmol) of methyl 3,3-di(4-ethylphenyl)-2,3-epoxypropionate (crude) and 3.52 g (19.3 mmol) of 2-(3,4-dimethoxyphenyl)ethanol were dissolved in 20 ml of dichloromethane and, at room temperature, 5 drops of boron trifluoride etherate were added. The solution was stirred for 1.5 hours. The solvent was then distilled off, and the residue, a pale yellow oil (8.66 g, 91%), was immediately reacted further.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:9][NH:10][C:11](=[O:22])C1C=CC(C(F)(F)F)=CC=1)=O.ClC1C=CSC=1C(NN)=O.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:43]=[CH:42][C:38](C(Cl)=O)=[CH:37][CH:36]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:22][CH2:11][N:10]([C:38]2[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:44])[F:45])=[CH:43][CH:42]=2)[N:9]=1
Reactant: O=C(NNC(=O)c1sccc1Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: NNC(=O)c1sccc1Cl
Solvent: c1ccncc1
Solvent: O
Product: FC(F)(F)c1ccc(N2COC(c3sccc3Cl)=N2)cc1
Yield: 93 %

Procedure:
N-(3-Chloro-thiophene-2-carbonyl)-N′-(4-trifluoromethylbenzoyl)-hydrazine: A solution of 3-chloro-2-thiophenecarboxylic acid hydrazide (70.4 mg, 0.4 mmol), 4-trifluoromethylbenzoyl chloride (83.6 mg, 0.4 mmol) in pyridine (5 mL) was refluxed for 4 h and then cooled. The solution was diluted by water and the precipitate was collected by filtration, and then dried to yield 129 mg (93%) of the title compound.
Reaction SMILES: [F-].[K+].F[C:4]1[C:9](F)=[CH:8][C:7](F)=[C:6](F)[C:5]=1[OH:13].F[C:15]1[CH:20]=[C:19](F)[CH:18]=[C:17](F)[C:16]=1[OH:23].FC1C(F)=CC=C(F)[C:26]=1[OH:33].BrC(Br)=O>CO.C1COCC1.CN(C)C=O>[O:13]([C:26]([O:23][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:15]=1)=[O:33])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:4]=1
Reactant: Oc1c(F)ccc(F)c1F
Reactant: Oc1c(F)cc(F)cc1F
Reactant: Oc1c(F)c(F)cc(F)c1F
Agent: O=C(Br)Br
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
In scheme III above, the following abreviations are used: KF is potassium fluoride; DMF is N,N-dimethylformamide; ArOH is either 2,3,5,6-tetrafluorophenol, 2,4,6-trifluorophenol or 2,3,6-trifluorophenol; THF is tetahydrofuran; MeOH is methanol. Commercially available bromoketone D is reacted with the appropriatly substituted fluorophenol and potassium fluoride to give phenoxy ketone E. The ketone is then reduced with sodium borohydride to give the alcohol F, which is hydrogenated using palladium on carbon as catalyst to give the amino alcohol B (in formula I, Y=fluoro-substituted phenoxy).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([CH3:23])[CH:15]=3)=[N:11][C:10]=2[C:24]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:25])=[CH:5][CH:4]=1.[ClH:32].C(=O)([O-])O>C(O)C.O1CCOCC1.[Fe]>[ClH:32].[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[NH:13][C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[C:10]([C:24]([NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[O:25])[N:11]=2)=[CH:15][C:16]=1[CH3:23]
Reactant: COc1ccc(-c2[nH]c(-c3ccc([N+](=O)[O-])c(C)c3)nc2C(=O)Nc2nccs2)cc1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccc(-c2[nH]c(-c3ccc(N)c(C)c3)nc2C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(4-Methoxyphenyl)-2-(3-methyl-4-nitrophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (1.5 g) obtained in Example 84 was dissolved in 50% aqueous ethanol solution (60 ml) and dioxane (50 ml), and iron powder (0.6 g) was added. Conc. hydrochloric acid (0.06 ml) was added under refluxing and the mixture was refluxed for 1 hr. A saturated aqueous hydrogencarbonate solution was added and the mixture was neutralized. An insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After drying, the solvent was evaporated under reduced pressure. The obtained crystals (0.79 g) were dissolved in methanol (24 ml) and dioxane (35 ml) and 1 M hydrochloric acid—ether solution (5.85 ml) was added. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure and the obtained crystals were recrystallized from ethanol to give the objective 2-(4-amino-3-methylphenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide. Hydrochloride (0.43 g): melting point 250° C. or above
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][C:12]=1[NH2:23])([O-:10])=[O:9].[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27].O>CN(C=O)C>[CH3:24][N:25]([CH3:29])[C:26]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[C:12]([NH2:23])[CH:13]=2)[CH2:22][CH2:21]1)=[O:27]
Reactant: Nc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Reactant: CN(C)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Reaction time: 8 h
Yield: 92.4 %

Procedure:
Under a nitrogen atmosphere, triethylamine (0.546 g, 5.4 mmol) was added to 2-nitro-5-piperazin-1-yl-phenylamine (1.0 g, 4.5 mmol) in dry DMF (8 mL) and the mixture was cooled in an ice water bath. Dimethylcarbamyl chloride (0.581 g, 5.4 mmol) was added slowly to this reaction mixture via syringe and the mixture was brought up to room temperature and stirred overnight. After overnight stirring, the reaction mixture was slowly poured into cold water (100 mL) and stirred for 1 hour resulting in the solidification of the product. This was filtered, dried give the product, 4-(3-Amino-4-nitro-phenyl) -piperazine-1-carboxylic acid dimethylamide, as a yellow solid, 1.2 g (92.4% yield), which was used without any further purification.