Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:10]([OH:12])=O)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[C:10]2=[O:12])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(CCc2cccc(OC)c2)C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C2CCc3cc(OC)ccc3C2=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.31 g (7.7 mmol) of 2-(4-methoxyphenyl)-4-(3-Methoxyphenyl)butyric acid was dissolved in 30 mL of CH2Cl2 and cooled to 0° C. To this solution was added 3.4 ml (23.1 mmol) of trifluoroacetic acid, the reaction was allowed to proceed for 30 minutes. The reaction was quenched by pouring into an aqueous solution of NaHCO3. The organic layer was separated, washed twice with NaHCO3 solution washed twice with brine, dried with Na2SO4, and evaporated to a solid. This yielded 1.5 g of the title compound as a tan amorphous solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[NH:24][C:25]([CH2:27][NH:28][C:29](=O)[CH2:30][CH3:31])=[N:26][C:22]=3[CH:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)([CH3:9])[CH3:8].O>C1COCC1>[CH:7]([C:10]1[CH:11]=[CH:12][C:13]([S:16]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[NH:24][C:25]([CH2:27][NH:28][CH2:29][CH2:30][CH3:31])=[N:26][C:22]=3[CH:21]=2)(=[O:17])=[O:18])=[CH:14][CH:15]=1)([CH3:8])[CH3:9]
Reactant: CCC(=O)NCc1nc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCNCc1nc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)ccc2[nH]1
Temperature: 25 °C
Yield: 3.2 %

Procedure:
To a suspension of lithium-aluminiumhydride (180 mg, 4.79 mmol) in THF (5 ml, dried Al2O3) at −5-0° C. a solution of N-[5-(4-isopropyl-benzenesulfonylamino)-1H-benzoimidazol-2-ylmethyl]-propionamide (320 mg, 0.80 mmol) in THF (5 ml) was added. After complete addition the mixture was allowed to warm to room temperature and was heated to reflux for 2 h. At 0° C. THF and then water were added. The mixture was dried with Na2SO4. The filtered solution was evaporated in vacuo and the residue was purified by preparative HPLC (water/5% acetonitrile/0.1% acetic acid) to give the product as a yellow oil (10 mg, 3%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][C:19](O)=[O:20])[CH2:11][CH2:10]2.C(N1C=CN=C1)([N:27]1C=CN=C1)=O.C([O-])(=O)C.[NH4+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][C:19]([NH2:27])=[O:20])[CH2:11][CH2:10]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CN1CCc2cc(OCc3cccc(F)c3)ccc2C1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CN1CCc2cc(OCc3cccc(F)c3)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of [6-(3-fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-acetic acid (0.245 mg, 0.744 mmol) and 1,1′-carbonyl-diimidazole (0.229 mg, 1.41 mmol) in N,N′-dimethylformamide (6 mL) was stirred at room temperature for 0.5 h. Ammonium acetate (0.917 g, 11 mol) was added and the mixture was stirred 2 h. Water was added and the mixture was extracted with ethyl acetate. Drying and evaporation of the solvent left a solid which was recrystallised with ethyl acetate and ether. MS: m/e=329.3 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=O)[CH2:19][C:20](=O)[C:21]([O:23][CH3:24])=[O:22])=[N:16][CH:17]=1.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[Cl:2])[N:10]=[C:20]([C:21]([O:23][CH3:24])=[O:22])[CH:19]=2)=[N:16][CH:17]=1
Reactant: COC(=O)C(=O)CC(=O)c1ccc(Br)cn1
Reactant: NNc1ccccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ccc(Br)cn2)n(-c2ccccc2Cl)n1
Temperature: 120 °C
Yield: 12.7 %

Procedure:
A mixture of (2-chlorophenyl)hydrazine hydrochloride (1.1 g, 6.1 mmol) and methyl 4-(5-bromopyridin-2-yl)-2,4-dioxobutanoate (1.7 g, 6.0 mmol) in MeOH (30 mL) was divided into two microwave reaction vessels. Each reaction vessel was then heated in the microwave at 120° C. for ten minutes. LC/MS analysis at this time showed the reaction to be essentially complete. The solutions were concentrated under reduced pressure to afford a dark brown semi-solid. This material was taken up in EtOAc and saturated aqueous NaHCO3. The layers were separated and the basic aqueous was extracted with EtOAc (3×). Combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford a dark oil. This crude product was purified by flash column chromatography eluting with a gradient from 0% to 100% EtOAc in hexane to afford methyl 5-(5-bromopyridin-2-yl)-1-(2-chlorophenyl)-1H-pyrazole-3-carboxylate (300 mg, 13% yield) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8])[CH3:2].Cl.[NH2:26]O>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:8][N:26]=1)=[O:24])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccc1OCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccccc2OCc2ccccc2)on1
Yield: 92.1 %

Procedure:
To a stirred solution of 4-(2-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester (3.75 g, 0.01149 mole) in acetic acid (20 mL) was added hydroxylamine hydrochloride (0.878 g, 0.0126 mole) and the resulting mixture was heated to reflux for 3 hours. Volatiles were removed and the resulting residue was diluted with water, basified with sodium bicarbonate solution and extracted with ethyl acetate, washed the ethyl acetate with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 3.42 g (92%) of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid ethyl ester. LCMS: 324.12 (M+1)+, 78.58%. To a stirred solution of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid ethyl ester (1.75 g, 0.00542 mol) in a mixture of THF (30 mL), methanol (15 mL) and H2O (15 mL) was added NaOH (0.651 g, 0.01628 mol) and the resulting mixture was stirred for 2 hours. The reaction mixture was then diluted with cold water. Volatiles were removed by evaporation and the residue was diluted with water acidified with concentrated HCl. The resulting precipitate was isolated by filtration and dried to afford 1.57 g (98%) of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid. LCMS: 296.08 (M+1)+, 84.73%
Reaction SMILES: [CH:1]([O:4][C:5]([NH:7][C@@H:8]([C:12]([OH:14])=O)[CH:9]([CH3:11])[CH3:10])=[O:6])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:41][C:42]1[CH:53]=[CH:52][C:45]2[N:46]=[C:47]([C@H:49]([NH2:51])[CH3:50])[S:48][C:44]=2[CH:43]=1>C1(C)C=CC=CC=1>[F:41][C:42]1[CH:53]=[CH:52][C:45]2[N:46]=[C:47]([C@H:49]([NH:51][C:12]([C@H:8]([NH:7][C:5](=[O:6])[O:4][CH:1]([CH3:2])[CH3:3])[CH:9]([CH3:10])[CH3:11])=[O:14])[CH3:50])[S:48][C:44]=2[CH:43]=1
Reactant: CC(C)OC(=O)N[C@@H](C(=O)O)C(C)C
Reactant: C[C@@H](N)c1nc2ccc(F)cc2s1
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CN1CCOCC1
Product: CC(C)OC(=O)N[C@@H](C(=O)N[C@H](C)c1nc2ccc(F)cc2s1)C(C)C
Yield: 60.8 %

Procedure:
In 500 ml of toluene, 10.2 g (0.05 mol) of N-isopropoxycarbonyl-D-valine was dissolved. Thereto were dropwise added, at −5° C., 12.4 g (0.0125 mol) of N-methylmorpholine and 6.8 g (0.05 mol) of isobutyl chlorocarbonate. Thereto was added, at −5° C., 18.3 g (0.05 mol) of (R)-1-(6-fluoro-2-benzothiazolyl)ethylamine p-toluenesulfonate. A reaction and a post-treatment were conducted in the same manner as in Reference Example 1, and the suspension of a solid in toluene was filtered to collect the solid. The solid was subjected to Soxhlet extraction for 1 week, and the extract was concentrated to obtain a solid. The solid was recrystallized from xylene to obtain 11.6 g (yield: 62.7%) of isopropyl {(R)-1-[(R)-1-(6-fluorobenzothiazol-2-yl)ethylcarbamoyl]-2-methylpropyl}carbamate. The compound obtained was confirmed for the structure by IR analysis and NMR analysis in comparison with its authentic material and identified.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:41][CH:40]=2)/[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1>C(Cl)Cl>[CH:28]1(/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:41][CH:40]=2)/[C:36]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
A solution of triphenylphosphine (8.79 g, 33.52 mmol) in methylene chloride (100 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (5.97 g, 33.52 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of (E)-3-cyclohexyl-2-(4-(methanesulfonyl)-phenyl)-acrylic acid (5.17 g, 16.76 mmol) in methylene chloride (20 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (5.04 g, 50.3 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (250 mL) and a 1N aqueous hydrochloric acid solution (150 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×100 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×250 mL), dried over anhydrous magnesium sulfate, filtered, and, concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 8.5/1.5 to 3/2 hexanes/ethyl acetate) afforded (E)-3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-acrylamide (2.8 g, 42%) as an amorphous solid: mp 167-1694° C.; EI-HRMS m/e calcd for C19H22O3S2 (M+) 390.1072, found 390.1073.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([C:19]([OH:21])=O)[CH:13]=[CH:12][C:11]=2[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:38]=[CH:37][C:27]([CH2:28][NH:29][CH2:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19](=[O:21])[N:29]([CH2:28][C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:38][CH:37]=3)[CH2:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2cc(C(=O)O)ccc2C1
Reactant: COc1ccc(CNCC2CCOCC2)cc1
Product: COc1ccc(CN(CC2CCOCC2)C(=O)c2ccc3c(c2)CC[C@H](NC(=O)OC(C)(C)C)C3)cc1

Procedure:
According to method G, (S)-6-tert-butoxycarbonylamino-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid was reacted with (4-methoxybenzyl)(tetrahydropyran-4-ylmethyl)amine. The crude product was purified by chromatography on silica gel (eluent: 30% n-heptane in ethyl acetate). The product was thus obtained with the molecular weight of 508.66 (C30H40N2O5); MS (ESI): 509 (M+H+).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:29](=[O:30])[C:28]([CH:31]([CH3:33])[CH3:32])=[C:21]2[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]2[C:19]1=[O:34].[I-].[Na+]>CN(C)C=O.O>[N:12]1[CH:11]=[CH:10][N:9]2[C:4]([S:3][CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:29](=[O:30])[C:28]([CH:31]([CH3:33])[CH3:32])=[C:21]4[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]4[C:19]3=[O:34])=[CH:5][CH:6]=[CH:7][C:8]=12
Reactant: CC(C)c1c2n(c(=O)n(CCCCCl)c1=O)CCCS2(=O)=O
Reactant: Sc1cccc2nccn12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1c2n(c(=O)n(CCCCSc3cccc4nccn34)c1=O)CCCS2(=O)=O
Reaction time: 0.5 h

Procedure:
To a suspension of 0.152 g (3.8 mmol) of 60% oily sodium hydride in 20 ml of N,N-dimethylformamide, 0.57 g (3.8 mmol) of 5-mercaptoimidazo[1,2-a]pyridine was added at room temperature, followed by stirring for 30 minutes. To this mixture, 1.22 g (3.5 mmol) of 7-(4-chlorobutyl)-9-isopropyl-1,1-dioxo-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione and 0.57 g (3.8 mmol) of sodium iodide were added, followed by stirring at 100° C. for 3 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate 3 times. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=25/1) to yield 1.11 g (68.6%, white powder) of the desired product.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)[CH3:4].O[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=2)[C:20](=[O:31])[N:19]1[CH2:32][C:33]([F:36])([F:35])[F:34]>CC(=O)OCC>[CH2:3]([O:5][C:6](=[O:16])[CH2:7][CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=2)[C:20](=[O:31])[N:19]1[CH2:32][C:33]([F:34])([F:35])[F:36])[CH3:4]
Reactant: O=C1c2ccc(C(F)(F)F)cc2C(O)N1CC(F)(F)F
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1c2cc(C(F)(F)F)ccc2C(=O)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.84 g of NaH were suspended using 60 ml of DME(anhydrous) and 4.5 ml of (diethoxy-phosphoryl)-acetic acid ethyl ester added at a temperature between 10° C. and 25° C. The mixture was stirred at ambient temperature for 30 minutes followed by addition of a solution of 4.2 g of 3-hydroxy-2-(2,2,2-trifluoro-ethyl)-5-trifluoromethyl-2,3-dihydro-isoindol-1-one in 20 ml DME(anhydrous). The reaction mixture was refluxed for 1 h, then cooled to ambient temperature. 100 ml of EA were then added and the mixture washed twice using 200 ml of a semisaturated aqueous NaHCO3-solution. The organic layer was dried over MgSO4 and the solvent was removed in vacuo. Chromatography was performed on Merck Lichrospher RP18, 10 μm, 50*250 mm. Conditions as follows:
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[OH:27][CH2:28][CH2:29][C:30]1[N:37]2[C:33]([S:34][CH:35]=[CH:36]2)=[CH:32][N:31]=1>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:31]3[CH:32]=[C:33]4[S:34][CH:35]=[CH:36][N+:37]4=[C:30]3[CH2:29][CH2:28][OH:27])[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: OCCc1ncc2sccn12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc[n+]4c3CCO)[C@H](C)[C@H]12
Yield: 6 %

Procedure:
The same procedure as in Example 1 was repeated except that 134 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 185 mg of 5-(2-hydroxyethyl)imidazo[5,1-b]thiazole were used, thereby obtaining 8.6 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][O:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][N:8]=[CH:7][N:6]=1.[OH-].[NH4+]>C(O)C.C(OCC)(=O)C.[Ni]>[F:14][C:2]([F:1])([CH3:13])[CH2:3][O:4][C:5]1[C:10]([CH2:11][NH2:12])=[CH:9][N:8]=[CH:7][N:6]=1
Reactant: CC(F)(F)COc1ncncc1C#N
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(F)(F)COc1ncncc1CN
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
4-(2,2-difluoropropoxyl)pyrimidine-5-carbonitrile (1.0 equiv.) was dissolved in a 1:1 mixture of ethanol and ethyl acetate (0.2 M). Sponge nickel catalyst (50% aqueous slurry) (19 equiv.) and ammonium hydroxide (12 equiv.) were added to the reaction vessel, which was purged thoroughly with hydrogen gas and allowed to stir at room temperature for 16 h. The reaction mixture was filtered through a microfiber filter containing celite, washed with ethanol, and volatile solvents were removed under reduced pressure. The residue was purified using silica gel chromatography (60-100% ethyl acetate in hexanes followed by 1-20% MeOH in ethyl acetate). The desired fractions were combined and volatile solvents were removed under reduced pressure to afford (4-(2,2-difluoropropoxyl)pyrimidin-5-yl)methanamine (82% yield). MS(ESI) m/z 204.1 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](OC)=[O:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[N:5]=[C:4]([Cl:16])[CH:3]=1.O.[NH2:18][NH2:19]>CN(C=O)C>[Cl:16][C:4]1[N:5]=[C:6]([C:12]([F:15])([F:14])[F:13])[C:7]2[C:8](=[O:9])[NH:18][NH:19][C:2]=2[CH:3]=1
Reactant: COC(=O)c1c(Cl)cc(Cl)nc1C(F)(F)F
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH][nH]c2cc(Cl)nc(C(F)(F)F)c12
Temperature: 150 °C

Procedure:
A solution of methyl 4,6-dichloro-2-(trifluoromethyl)nicotinate (535.9 mg, 1.956 mmol) in DMF (2 ml) was charged with hydrazine hydrate (190 μL, 3.92 mmol) and heated to 150° C. for 30 min under microwave irradiation. Concentrated in vacuo and washed residue with DCM. Purified via flash chromatography (0-20% MeOH/DCM) to provide 6-chloro-4-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-3(2H)-one MS: [M+H]+ m/z 238.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1I.[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[C:17]([O:24][CH3:25])[CH:16]=1>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][C:17]=1[O:24][CH3:25]
Reactant: COc1cc(F)ccc1B(O)O
Reactant: COC(=O)CNc1cnccc1I
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)CNc1cnccc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-ylamino)-acetic acid methyl ester and 4-fluoro-2-methoxyphenylboronic acid (CAS RN 179899-07-1) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light yellow oil (73%). MS (ESI): m/z=291.113 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:23]#[N:24])=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[NH:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1.CC(C)([O-])C.[K+].[CH2:31]([O:33][CH2:34]Cl)[CH3:32]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([C:23]#[N:24])=[C:4]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[N:5]([CH2:34][O:33][CH2:31][CH3:32])[C:6]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1
Reactant: N#Cc1c(-c2ccc(Cl)cc2)[nH]c(Sc2ccc(Cl)c(Cl)c2)c1Br
Reactant: CCOCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOCn1c(Sc2ccc(Cl)c(Cl)c2)c(Br)c(C#N)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
A solution of 4-bromo-2-(p-chlorophenyl)-5-[(3,4-dichlorophenyl)thio]pyrrole-3-carbonitrile (0.644 g, 1.40 mmol) and potassium tert-butoxide (0.173 g, 1.54 mmol) in tetrahydrofuran is stirred at room temperature for 30 minutes, treated with chloromethyl ethyl ether (0.16 mL, 1.54 mmol), stirred overnight at room temperature, diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a solid. The solid is recrystallized from an ethyl acetate/hexanes solution to give the title product as a white solid (0.554 g, mp 105°-107° C.).
Reaction SMILES: [CH2:1]([C:3]1[C:10]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=3)=[N:13][CH:12]=2)=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O)[CH3:2].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:39]1[CH2:44][CH2:43][CH:42]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:41][CH2:40]1>CO>[CH2:1]([C:3]1[C:10]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([C:26]([F:28])([F:29])[F:27])[CH:17]=3)=[N:13][CH:12]=2)=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:39]1[CH2:44][CH2:43][CH:42]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:41][CH2:40]1)[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1CCN(Cc2cccc(-c3cnc(-c4ccc(OC(C)C)c(C(F)(F)F)c4)s3)c2CC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 187 %

Procedure:
To a solution of 2-ethyl-3-{2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}benzaldehyde (D72) (64 mg), acetic acid (0.044 mL) and sodium acetate (62.6 mg) in methanol (10.00 mL) stirred under nitrogen at room temperature was added ethyl 4-piperidinecarboxylate (120 mg) in one charge. The reaction mixture was stirred at room temperature for 1 h, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (10 mL), sodium triacetoxyborohydride (97 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product ethyl 1-[(2-ethyl-3-{2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}phenyl)methyl]-4-piperidinecarboxylate (D81) (160 mg). The crude product was used for next step without further purification. MS (ES): C30H35F3N2O3S requires 560. found 561.3 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:27][C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])=[CH:25][C:24](=O)[O:23]1>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[CH:10][C:9]=1[NH:19][C:24](=[O:23])[CH2:25][C:26]([C:28]1[CH:35]=[CH:34][CH:33]=[C:30]([C:31]#[N:32])[CH:29]=1)=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (2-amino-4-thiophen-3-yl-phenyl)-carbamic acid tert.-butyl ester (Example G6) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according the general procedure K. Obtained as a brown solid (104 mg) and used crude in the next step (Example 7).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][CH:9]=1)(=[O:3])[CH3:2].S(C1C=CC(C)=CC=1)(O[CH3:20])(=O)=O.[H-].[Na+]>C(#N)C>[C:1]([N:4]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][CH:9]=1)[CH3:20])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1csc(-c2ccccc2)n1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)N(C)c1csc(-c2ccccc2)n1

Procedure:
A mixture of 4-acetamido-2-phenylthiazole, prepared according to Example 1, and methyl tosylate in acetonitrile may be treated with sodium hydride to give the title compound.