Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:13])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][CH3:12])C.O.[NH2:15][NH2:16]>C(O)CCC>[CH2:11]([C:7]1[N:6]([CH2:5][C:4]([NH:15][NH2:16])=[O:13])[CH:10]=[CH:9][N:8]=1)[CH3:12]
Reactant: NN
Reactant: CCOC(=O)Cn1ccnc1CC
Solvent: CCCCO
Solvent: O
Product: CCc1nccn1CC(=O)NN
Yield: 94 %

Procedure:
As described for example 112a, (2-ethyl-imidazol-1-yl)-acetic acid ethyl ester in butanol was reacted with hydrazine hydrate (1.2 equivalents) at 100° C. for 6 h. Evaporation of all volatiles and crystallization from methanol/diisopropylether afforded the title compound as a white solid (yield: 94%). MS: m/e=169.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Br:7][CH2:8][CH2:9][CH2:10][O:11][CH3:12]>>[BrH:7].[CH3:12][O:11][CH2:10][CH2:9][CH2:8][N:6]1[CH:5]=[CH:4][S:3][C:2]1=[NH:1]
Reactant: Nc1nccs1
Reactant: COCCCBr
Product: Br
Product: COCCCn1ccsc1=N
Temperature: 85 °C
Yield: 47.4 %

Procedure:
A mixture of 2-aminothiazole (1.0 g, 10 mmol) and 1-bromo-3-methoxypropane (1.8 g, 12 mmol) were heated at 85° C. for 16 hours. The solid was cooled to ambient temperature, triturated with ethanol, and then collected by filtration to provide 1.2 g (48%) of the title compound. MS (DCI/NH3) m/z 173 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N[C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1N)[C:9]([OH:11])=[O:10].O.Cl>C(O)CCCC>[N:1]1[C:2](=[O:3])[N:4]=[C:13]2[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[CH:7]=[CH:6][C:14]=12
Reactant: NC(N)=O
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: Cl
Solvent: CCCCCO
Solvent: O
Product: O=C1N=c2ccc(C(=O)O)cc2=N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
Urea (1.20 g, 0.0200 mol) and 3,4-diaminobenzoic acid (3) (3.04 g, 0.0200 mol) in pentan-1-ol (10 mL) was vigorously stirred and heated to reflux under a nitrogen atmosphere. The heating was discontinued after 4 hours and on cooling to room temperature, water (30 mL) was added. The pH was adjusted to 1 with conc. HCl. The resultant dark solid was filtered off, washed with further water (2×20 mL) and dried to give 3.00 g (84% yield) of benzimidazol-2-one-5-carboxylic acid (4) as a black powder,
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[N:6][CH:7]=1.Cl.Cl[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)[CH2:23][CH2:24]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ncccc1NCC1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cn1)c1ncccc1NCC1CCN(c2ccncc2)CC1
Reaction time: 16 h
Yield: 16.3 %

Procedure:
A pressure tube (Aldrich) was charged with N-(5-chloropyridin-2-yl)-3-[(piperidin-4-ylmethyl)amino]pyridine-2-carboxamide (500 mg, 1.45 mmol), 4-chloropyridine hydrochloride (435 mg, 2.90 mmol), triethylamine (293 mg, 2.90 mmol) and EtOH (5 mL), sealed, and placed in a 110° C. bath. After 16 h, the mixture was cooled, concentrated, and the residue purified by column chromatography (SiO2: 5 to 7.5% methanol:methylene chloride) yielding 100 mg (16%) of the title compound.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)=O)=[CH:30][C:25]=2[O:24][CH2:23]1.O>C1COCC1>[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)=[CH:9][C:10]#[N:11])=[CH:30][C:25]=2[O:24][CH2:23]1
Reactant: COc1cccc(C(=O)c2ccc3c(c2)OCO3)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(=CC#N)c2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
To a solution of cyanomethylphosphonic acid diethyl ester (2.1 mL, 13.6 mmol) in anhydrous THF (15 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 13.6 mL, 13.6 mmol) at 0° C. and stirred for 30 min at room temperature followed by addition of benzo[1,3]dioxol-5-yl-(3-methoxy-phenyl)-methanone (1.74 g crude, 6.8 mmol) in THF (15 mL) and refluxed for one hour. The reaction mixture was poured into water (50 mL), extracted with CH2Cl2 (2×50 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4, and purified via flash column chromatography (EtOAc, Hexane) to give 3-benzo[1,3]dioxol-5-yl-3-(3-methoxy-phenyl)-acrylonitrile as an oil (0.87 g, 46% yield): 1H NMR (DMSO-d6) δ 3.77 and 3.78 (2s, 3H, OCH3), 6.10 and 6.13 (2s, 2H, CH2), 6.23 and 6.27 (2s, 1H, CH), 6.69-7.46 (m, 7H, Ar); 13C NMR (DMSO-d6) δ 55.2, 55.2, 94.4, 95.6, 101.6, 101.8, 107.4, 108.2, 108.3, 109.3, 113.7, 114.6, 115.0, 118.2, 120.9, 121.2, 123.7, 123.8, 129.7, 129.8, 130.6, 131.6, 138.6, 139.6, 147.3, 147.9, 148.5, 149.4, 159.1, 159.2, 160.9, 161.1. LC/MS showed desired peak at 280 for (M+1)+1 positive ion mass.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.[CH2:14]([O:21][CH2:22][C:23](O)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:23](=[O:24])[CH2:22][O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:7]=1
Reactant: O=C(O)COCc1ccccc1
Reactant: COC(=O)COc1ccc(N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)COc1ccc(NC(=O)COCc2ccccc2)cc1
Reaction time: 12 h
Yield: 68.7 %

Procedure:
To a mixture of 4-aminophenoxyacetic acid methyl ester 15 (20 g, 110.5 mmol) and benzyloxyacetic acid (20.4 g, 123 mmol) in anhydrous dichloromethane (200 ml) under nitrogen atm. was added dropwise a solution of 1,3-dicyclohexylcarbodiimide (63.2 g, 306 mmol) in anhydrous dichloromethane (80 ml). The reaction mixture was stirred at room temp. for 12 hrs. The solids were filtered off, the dichloromethane solution was washed with 5% sodium bicarbonate solution (100 ml), water (100 ml), dried over sodium sulphate, and distilled to get crude 66. The crude 66 was purified by column chromatography on silica gel using benzene as eluant to get pure 66 (25 g, 68.9%) as a white powder. M.p: 76-77.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:10]2[C:14](Cl)=[C:13]([S:16]([CH3:19])(=O)=O)[N:12]([CH3:20])[N:11]=2)[C:7]=1[CH:8]=[O:9])#[N:2].[OH:21][CH2:22][CH2:23]CO.[C:26]1(C)C=CC(S(O)(=O)=O)=C[CH:27]=1.O>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:10]2[CH:14]=[C:13]([S:16][CH3:19])[N:12]([CH3:20])[N:11]=2)[C:7]=1[CH:8]([O:21][CH2:22][CH3:23])[O:9][CH2:26][CH3:27])#[N:2]
Reactant: OCCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cn1nc(-n2ncc(C#N)c2C=O)c(Cl)c1S(C)(=O)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(OCC)c1c(C#N)cnn1-c1cc(SC)n(C)n1

Procedure:
1.0 g (3.2 mmol) of 4-cyano-5-formyl-1-(4-chloro-1-methyl-5-methylsulfonyl-3-pyrazolyl)pyrazole, 0.35 g (4.6 mmol) of 1,3-dihydroxypropane and 10 mg of p-toluenesulfonic acid in 40 ml of toluene are heated on a water separator for 3 hours. Work-up as in Example 1.3 gives the title compound in the form of colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[N:15][CH:14]=1)(=[O:10])=[O:9].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.C(OCC)(=O)C>[CH2:28]([N:11]([CH2:12][C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:19]=2)=[N:15][CH:14]=1)[S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:10])=[O:9])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)c1cccc(-c2ncc(CNS(=O)(=O)c3ccccc3Cl)s2)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cccc(-c2ncc(CN(Cc3ccccc3)S(=O)(=O)c3ccccc3Cl)s2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-chloro-N-[2-(3-methanesulfonyl-phenyl)-thiazol-5-ylmethyl]-benzenesulfonamide (30 mg) in N,N-dimethylacetamide (0.6 mL) were added benzyl bromide (13 mg) and cesium carbonate (26 mg). The mixture was stirred overnight at r.t. The mixture was diluted with ethyl acetate and washed with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:0 to 1:1) to give N-benzyl-2-chloro-N-[2-(3-methanesulfonyl-phenyl)-thiazol-5-ylmethyl]-benzenesulfonamide as a colorless solid. MS: 534.8 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[C:13](#N)CC>>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH2:11][CH3:13]
Reactant: CC(=O)c1cc(C)cc(C)c1N
Reactant: CCC#N
Product: CCC(=O)c1cc(C)cc(C)c1N

Procedure:
2′-Amino-3′,5′-dimethylpropiophenone was synthesized in the same fashion as for 2′-amino-3′,5′-dimethylacetophenone (Example 39) except that propionitrile was used instead of acetonitrile.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH:7][C:8](=[O:14])[C:9]([O:11]CC)=[O:10])[CH:4]=[CH:3][C:2]=1[NH:15][C:16](=[O:22])[C:17]([O:19]CC)=[O:18].Cl>[OH-].[Na+].O>[N:1]1[CH:6]=[C:5]([NH:7][C:8](=[O:14])[C:9]([OH:11])=[O:10])[CH:4]=[CH:3][C:2]=1[NH:15][C:16](=[O:22])[C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)C(=O)Nc1ccc(NC(=O)C(=O)OCC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(=O)Nc1ccc(NC(=O)C(=O)O)nc1

Procedure:
Diethyl N,N'-2,5-pyridinediyldioxamate (1.0 g., 0.0032 mole) is stirred in 1.0 N sodium hydroxide (25 ml.) at 70°-85° until solution is complete. The reaction mixture is diluted with water (25 ml.) and acidified (pH=3) with concentrated hydrochloric acid. The desired product is collected by filtration (0.35 g., 43%, m.p. 290°-295° dec).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4][CH2:3]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:30][C:29]([CH:31]=O)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.NCCC(O)=O.CO.C(Cl)Cl>C(O)(=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:30][C:29]([CH:31]=[C:3]3[C:2](=[O:1])[N:6]([CH:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4]3)=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)s1
Reactant: O=C(O)C(Cc1ccccc1)N1C(=O)CNC1=S
Agent: NCCC(=O)O
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: O=C(O)C(Cc1ccccc1)N1C(=O)C(=Cc2ccc(-c3ccc(Cl)cc3)s2)NC1=S
Temperature: 170 °C

Procedure:
To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.080 g, 0.304 mmol) and 5-(4-chorophenyl)thiophene-2-carbaldehyde (0.068 g, 0.304 mmol) in acetic acid 5 mL is added β-alanine (2.7 mg, 0.030 mmol) and heat to 170° C. for 30 min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.110 g, 0.235 mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.66 (dd, J=8.7, 1.5 Hz, 2H), 7.50 (dm, J=12.6 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 7.18 (m, 5H), 6.69 (s, 1H), 5.65 (dd, J=12.0, 4.5 Hz, 1H), 3.68 (dd, J=13.8, 12.0 Hz, 1H), 3.51 (dd, J=14.4, 4.5 Hz, 1H). MS (ES+, m/z): 469.5 (M++1, 30.0).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5][OH:6])[CH3:2].[H-].[Na+].Cl[C:11]1[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][O:6][C:11]1[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)[CH3:2]
Reactant: Clc1nc2ccccc2o1
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1nc2ccccc2o1
Yield: 86.3 %

Procedure:
0.14 g (1.3 mmol) ethyl-hydroxyacetate is dissolved in 5 ml tetrahydrofurane and 0.06 g (1.6 mmol) 60% sodium hydride is added to it. After 20 minute stirring 0.16 g (1.1 mmol) 2-chloro-1,3-benzoxazole is added and the mixture is heated under reflux for 3 hours. The solvent is removed, the residue is dissolved in 15 ml water, extracted with 3×20 ml ethyl acetate. The united organic phase is dried over sodium sulfate and evaporated to obtain 0.21 g title compound as an oil. LC-MS[MH+]=222 (C11H11NO4 221.21)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH:10]2[NH:15][C:14](=O)[CH2:13][NH:12][C:11]2=O)=[CH:7][CH:6]=[CH:5][N:4]=1.CSC.B.[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[C:8]([CH2:9][CH:10]2[CH2:11][NH:12][CH2:13][CH2:14][NH:15]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CC1NC(=O)CNC1=O
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: COc1ncccc1CC1CNCCN1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a 100-mL round-bottomed flask was added 3-((2-methoxy-3-pyridinyl)methyl)-2,5-piperazinedione (398 mg, 1.69 mmol) and borane methyl sulfide, complex (0.64 mL, 6.77 mmol, Aldrich, St. Louis, Mo.) in THF (10 mL). The reaction mixture was stirred at 70° C. for 2 h. The mixture was cooled to room temperature, diluted with MeOH (1 mL), followed by 1N NaOH (12 mL), and extracted with DCM (2×50 mL). The organic extract was washed with saturated NaCl (20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude 2-((2-methoxy-3-pyridinyl)methyl)piperazine as colorless viscous oil, which was used without purification.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[S:10][C:11]([CH3:14])=[N:12][N:13]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(N(CC)CC)C>[C:15]([NH:8][C:9]1[S:10][C:11]([CH3:14])=[N:12][N:13]=1)(=[O:17])[CH3:16]
Reactant: Cc1nnc(N)s1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nnc(C)s1
Yield: 89.1 %

Procedure:
To a mixture of toluene (20 ml) and triethylamine(2.63 g) was added 2-amino-5- methyl-1,3,4-thiadiazole (3.0 g) and acetic anhydride (3.2 g). The mixture was heated under reflux for 2.5 hours. After cooling, the precipitated solid was filtrated, washed with water and dried. The title compound(3.65 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[CH:18]1([C:23](=O)[CH2:24][C:25]#[N:26])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Cl:9][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[F:8])[N:1]=[C:23]([CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:24]([C:25]#[N:26])=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cc(F)c(Cl)cc1C(=O)c1ccccc1
Reactant: N#CCC(=O)C1CCCC1
Product: N#Cc1c(C2CCCC2)nc2cc(F)c(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-chloro-4-fluoro-phenyl)-phenyl-methanone and 3-cyclopentyl-3-oxo-propionitrile. Off-white solid. MS (ESI): 351.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O>C(COC)OC>[Cl:12][CH2:13][C:14]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]2[CH:16]=1
Reactant: O=C(CCl)CCl
Reactant: Nc1ccc(C(F)(F)F)cn1
Solvent: COCCOC
Product: FC(F)(F)c1ccc2nc(CCl)cn2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 72.1 %

Procedure:
A mixture of 2-amino-5-trifluoromethylpyridine (Fluorochem; 3.19 g), 1,3-dichloroacetone (Aldrich; 3.00 g), and dimethoxyethane (Aldrich; 15 mL) is stirred at room temperature for 4 days. The resulting solid is collected and washed with several milliliters of dimethoxyethane. The solid is then taken up in ethanol (30 mL) and the mixture is heated at 80° C. for 2.5 h, at which time diisopropylethylamine (Aldrich: 3.5 mL) is added. After stirring with heating an additional 3.5 h, the mixture is cooled and the solvent is removed under reduced pressure. The residue is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are filtered through sodium sulfate and concentrated; the residue is chromatographed on silica gel using methanol/dichloromethane (1/99) to give 3.33 g of 2-(chloromethyl)-6-(trifluoromethyl) imidazo[1,2-a]pyridine. 1H NMR (CDCl3) δ4.78, 7.36, 7.69, 7.73, 8.48.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH2:16]([NH:18][C:19]([NH:21][CH2:22][CH3:23])=[S:20])[CH3:17]>CO>[BrH:1].[CH2:22]([N:21]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=2)([OH:4])[CH2:2][S:20][C:19]1=[N:18][CH2:16][CH3:17])[CH3:23]
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Reactant: CCNC(=S)NCC
Solvent: CO
Product: Br
Product: CCN=C1SCC(O)(c2ccc(Cl)c(S(N)(=O)=O)c2)N1CC
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To 6.2 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone 2.2 g of ground 1,3-diethyl-thiourea were added in 40 ml of methanol, the mixture was stirred for 10 minutes at 40° C. and for 3 hours at room temperature and the salt was precipitated by adding diethyl ether. After decanting the solvent, the oily product was crystallized with diisopropyl ether heated to 30°-40° C. Colorless crystals melting at 203° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1([CH3:32])[CH2:18][CH2:17][N:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([N:16]1[CH2:17][CH2:18][C:13]([CH3:32])([CH3:12])[CH2:14][CH2:15]1)[C:22]1[CH:23]=[N:24][C:25]([C:28]([F:30])([F:31])[F:29])=[N:26][CH:27]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: CC1(C)CCN(C(CN)c2cnc(C(F)(F)F)nc2)CC1
Product: CC1(C)CCN(C(CNC(=O)c2cccc(Cl)c2Cl)c2cnc(C(F)(F)F)nc2)CC1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4,4-dimethylpiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[CH:10]=[C:9]([NH:11][C:12]([CH:14]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[N:8]=[C:7]1CCCCCC)C.[OH-:34].[K+].CO.O>C(OCC)(=O)C>[CH2:21]([CH:5]([N:6]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2([OH:34])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:21]3[C:26]2=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:13])[N:8]=[CH:7]1)[C:4]([OH:3])=[O:33])[CH2:26][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCc1nc(NC(=O)C2c3ccccc3-c3ccccc32)cn1CC(=O)OCC
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCC(C(=O)O)n1cnc(NC(=O)C2(O)c3ccccc3-c3ccccc32)c1

Procedure:
When 2.1 g of -hexyl-4-[(9H-fluoren-9-yl-carbonyl)amino]-1H-imidazole-1-acetic acid ethyl ester was heated with 3.0 g of potassium hydroxide, 30 ml of methanol, and 15 ml of water at reflux for one hour, upon adjustment of pH to 3.8, a thick oil formed. The oil was dissolved in ethyl acetate and separated from the aqueous layer. The organic layer was dried and concentrated in vacuo. The oil was taken up in ethanol and saturated with hydrogen chloride gas. The resulting product was purified by high pressure liquid chromatography to provide 0.370 g of the titled product, m.p. 128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[CH:7][C:3]=1[C:4]([OH:6])=O.[S:25](Cl)(Cl)=O.[CH:29]1[CH:34]=CC=C[CH:30]=1>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[N:14]([CH3:23])[C:13]2=[O:24])=[CH:7][C:3]=1[C:4]([S:25][CH:29]([CH3:34])[CH3:30])=[O:6]
Reactant: c1ccccc1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)O)c(Cl)cc2F)c1=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)SC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2.5 g of 2-chloro-5[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4fluorobenzoic acid are heated at reflux temperature for 3 hours in 20 ml of benzene and 2.4 ml of thionyl chloride together with one drop of dimethylformamide. Subsequently, the reaction mixture is evaporated to dryness and dissolved in 15 ml of dioxan. This solution, which consists mainly of the acid chloride of the above-mentioned benzoic acid and the solvent, is added dropwise at room temperature to a solution of 0.7 g of isopropyl mercaptan and 0.8 g of pyridine in 10 ml of dioxan. The reaction mixture is then stirred at room temperature for 2.5 hours, treated with 300 ml of water and extracted twice with 300 ml of ethyl acetate each time. The combined organic phases are washed twice with 150 ml of lN hydrochloric acid each time and once with 150 ml of saturated sodium chloride solution, dried over anhydrous sodium sulphate and evaporated. The residue is purified by chromatography on silica gel with ethyl acetate/n-hexane (2:3). In this manner there is obtained S-isopropyl 2-chloro-5-[3,6-dihydro-2 6-dioxo-3-methyl-4 -trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorothiobenzoate as a viscous oil.
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[NH2:17])=[O:5])C.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=O)[C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:4](=[O:5])[C:6]3[O:10][N:9]=[C:8]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:7]=3[N:17]=[C:26]2[C:27]2[CH:28]=[CH:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=2)=[CH:23][CH:24]=1
Reactant: CC(C)c1ccc(C(=O)Nc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)c1onc(-c2ccccc2)c1N
Product: CC(C)c1ccc(-c2nc3c(-c4ccccc4)noc3c(=O)n2-c2ccc(Cl)cc2)cc1

Procedure:
6-(4-Chloro-phenyl)-5-(4-isopropyl-phenyl)-3-phenyl-6H-isoxazolo[4,5-d]pyrimidin-7-one is prepared as described in Example 2, using 4-amino-3-phenyl-isoxazole-5-carboxylic acid ethyl ester from step C instead of ethyl 5-amino-1-phenyl-4-pyrazole-carboxylate, and N-(4-chloro-phenyl)-4-isopropyl-benzamide instead of N-(4 bromo-phenyl)-4-methyl-benzamide; 1H NMR (CDCl3, 400 MHz) δ 8.42 (dd, 2H), 7.53 (m, 3H), 7.34 (d, 2H), 7.25 (d, 2H), 7.12 (m, 4H), 2.87 (m, 1H), 1.22 (s, 3H), 1.20 (s, 3H); HPLC-MS calculated for C26H20ClN3O2 (M+H+) 442.1. Found 442.1.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](N)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:19][C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][OH:37])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:37][CH2:36][C@H:33]1[CH2:32][CH2:31][C@H:30]([N:29]2[C:21]3=[C:22]4[S:28][CH:27]=[CH:26][C:23]4=[N:24][CH:25]=[C:20]3[N:19]=[C:3]2[C@H:2]([OH:1])[CH3:6])[CH2:35][CH2:34]1
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CO)CC1
Reactant: C[C@@H](O)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (42 mg, 0.48 mmol) and triethyloxonium tetrafluoroborate (85 mg, 0.45 mmol) in tetrahydrofuran (0.65 mL) was stirred at room temperature for 2 h. The solvent was removed, and the residue dissolved in ethanol (0.27 mL) and added to a suspension of {trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methanol (41 mg, 0.15 mmol) in ethanol (0.99 mL). The resulting mixture was stirred at 85° C. for 1 h. The solvent was removed and the residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (2.3 mg, 4.7%). LCMS calculated for C17H22N3O2S (M+H)+: m/z=332.1. Found: 332.1.