Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])[NH:2]1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CN(C)C=O>[CH3:14][N:15](/[CH:17]=[C:4]1/[C:3](=[O:11])[NH:2][CH2:1][C:10]2[C:5]/1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:16]
Reactant: O=C1Cc2ccccc2CN1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C1/C(=O)NCc2ccccc21
Temperature: 100 °C
Yield: 21.3 %

Procedure:
A N,N-dimethylformamide (1 mL) solution containing 1,4-dihydro-3(2H)-isoquinolinone (300 mg, 2.04 mmol) and N,N-dimethylformamide dimethylacetal (0.65 mL, 4.89 mmol) is heated at 100° C. for 2.5 hours. After removing the solvents, the residue is washed with ether, water and ether to give 88 mg of the product as a pink solid. The filtrate is evaporated to dryness, and the residue is treated with ether, water and ether to give 105 mg of a second crop of the product with a total yield of 47% (193 mg); MS (ESI) m/z 203.2 (M+1). Ref: Chemistry of Heterocyclic compd. 370-374 (1981).
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[CH:32]1([C:35]2[C:36]([NH:52][C@@H:53]3[C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[CH2:55][C@@H:54]3[OH:62])=[N:37][C:38]([CH:49]3[CH2:51][CH2:50]3)=[C:39]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=3[Cl:48])[N:40]=2)[CH2:34][CH2:33]1>>[CH:32]1([C:35]2[C:36]([NH:52][C@@H:53]3[C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[CH2:55][C@@H:54]3[O:62][CH2:2][CH3:3])=[N:37][C:38]([CH:49]3[CH2:50][CH2:51]3)=[C:39]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=3[Cl:48])[N:40]=2)[CH2:33][CH2:34]1
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: O[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2 S)-1-{[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.80–1.07, 1.17–1.20, 1.67, 1.79, 3.14–3.20, 3.46–3.50, 3.70–3.72, 4.35, 5.72, 5.97, 7.24–7.50; MS (ESI+) for C27H27Cl2N3O m/z 480 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:38]([CH3:40])[CH3:39])[C:6]2[O:10][C:9]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][C:19]4([CH3:34])[O:23][C:22](=[O:24])[N:21]([C:25]5[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][N:26]=5)[CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:37]=1)#[N:2].[H][H]>CO.O1CCCC1.[Pd]>[NH2:31][C:28]1[CH:29]=[CH:30][C:25]([N:21]2[CH2:20][C:19]([CH2:18][NH:17][C:15](=[O:16])[C:14]3[CH:13]=[CH:12][C:11]([C:9]4[O:10][C:6]5[C:5]([CH:38]([CH3:40])[CH3:39])=[CH:4][C:3]([C:1]#[N:2])=[CH:37][C:7]=5[N:8]=4)=[CH:36][CH:35]=3)([CH3:34])[O:23][C:22]2=[O:24])=[N:26][CH:27]=1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C)CN(c5ccc([N+](=O)[O-])cn5)C(=O)O4)cc3)oc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C)CN(c5ccc(N)cn5)C(=O)O4)cc3)oc12
Temperature: 25 °C
Yield: 83.9 %

Procedure:
To a mixture of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[5-methyl-3-(5-nitropyridin-2-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}benzamide (154 mg, EXAMPLE 57) in 10 ml of methanol and 10 ml of tetrahydrofuran was added 50 mg of palladium on carbon (10% wet). The mixture was stirred at 40° C. under a balloon of hydrogen for 15 h. The sample was cooled to room temperature, and was filtered through a small plug of Celite, eluting with methanol. The eluent was concentrated and purified via column chromatography on a Biotage Horizon 40M column eluting with 0% ethyl acetate in hexanes (1 column volume), followed by a gradient to 100% ethyl acetate in hexanes (over 10 column volumes), and held at 100% ethyl acetate for 6 column volumes to provide the title compound (122 mg, 84%). Mass spectrum (ESI) 511.1 (M+1).
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)([O-:3])=[O:2].[BH4-].[Na+].O>CO>[N+:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])/C=C/c1ccc(Oc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])CCc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.2 %

Procedure:
To a solution of 1-((E)-2-nitro-vinyl)-4-phenoxy-benzene (1.40 g, 2.90 mmol, purity: 50%) described in Manufacturing Example 17-1-2 in methanol (15 mL) was added sodium borohydride (274 mg, 7.25 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 10 minutes at room temperature. Water was then added dropwise at room temperature while cooling appropriately. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:5) to obtain the title compound (199 mg, 28%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C[Si]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(C)C.[CH3:25][S:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:28]=1[CH:29]=O.Cl>C1COCC1>[CH3:25][S:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:28]=1[CH:29]=[CH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CCCCCCc1cccc(SC)c1C=O
Reactant: CC(C)(C)OC(=O)C[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCCCc1cccc(SC)c1C=CC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of lithium diisopropylamide, afforded by combining 3.4 g of diisopropylamine with 26 ml of n-butyllithium, at -40° C. in THF is added tert-butyl trimethylsilylacetate (8 g, 0.042 mmol) and the mixture stirred for 1 hour. To the reaction mixture is added 2-methylthio-6-n-hexylbenzaldehyde (7.08 g, 0.03 mmol) dropwise and stirred for 2 hours at -40° C. The reaction mixture is allowed to warm to -10° C. and cold lN HCl poured in. The mixture is extracted with diethyl ether. The extracts are washed with water and then brine, dried over MgSO4 and concentrated to afford tert-butyl 2-methylthio-6-n-hexylcinnamate which is hydrolyzed in methylene chloride with trifluoroacetic acid by refluxing overnight to afford the subtitle compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Fc1ccc(Br)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(-c2cccc3[nH]ccc23)cc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 79.4 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 4.0 g, 16.4 mmol), and 4-bromofluorobenzene (3.45 g, 19.7 mmol) in THF (80 mL)) were added Palladium catalyst Pd(PPh3)4 (0.57 g, 0.49 mmol) and the freshly prepared sodium hydroxide solution (2.0 g, 49.3 mmol in 25 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 2.75 g (80%) of the product 4-(4-fluoro-phenyl)1H-indole as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][CH:5]=1)[CH3:2].[N+:13]([O-])([OH:15])=[O:14].[OH-].[Na+]>S(=O)(=O)(O)O>[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]1[N:9]=[C:8]([CH3:10])[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=1)[CH3:12]
Reactant: O=[N+]([O-])O
Reactant: CCN(CC)c1cccc(C)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCN(CC)c1ccc([N+](=O)[O-])c(C)n1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a 1900 ml of concentrated sulfuric acid 630 g of 6-diethylamino-2-picoline were dropwise added while cooling with ice water. A 70% nitric acid solution of 347 g were dropwise added at not more than 5° C. over about 2 hours to the resulting mixture and stirred at 5° C. for additional one hour. The reation mixture was added to 4 kg of ice, neutralized with a sodium hydroxide solution, and extracted two times with ethyl acetate. The extract solution was washed two times with water, dried over anhydrous magnesium sulfate, concentrated and dried. Thus, 775 g of 6-diethylamino-3-nitro-2-picoline were obtained.
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14](=[O:26])[NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[F:25])[CH3:17])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[Cl:24][C:20]1[C:19]([F:25])=[C:18]([C@H:16]([NH:15][C:14]([C@@H:13]2[CH2:12][C@@H:11]3[C@@H:9]([CH2:10]3)[NH:8]2)=[O:26])[CH3:17])[CH:23]=[CH:22][CH:21]=1
Reactant: C[C@@H](NC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)OC(C)(C)C)c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)[C@@H]1C[C@H]2C[C@H]2N1)c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1R,3S,5R)-3-[(R)-1-(3-chloro-2-fluoro-phenyl)-ethylcarbamoyl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (3.2 g, 8.36 mmol) in CH2Cl2 (30 mL) was added TFA (15 mL, 195 mmol) and the solution was stirred at RT for 1 h. The crude reaction mixture was concentrated under vacuum, the residue was suspended in MeOH and concentrated again under vacuum. The crude product was used without further purification in the next step. MS (LC/MS): 283.0 [M+H]+; tR (HPLC conditions c): 3.41 min.
Reaction SMILES: Cl.[O:2]1[C:7]2=[CH:8][CH2:9][CH2:10][CH:6]2[NH:5][CH2:4][CH2:3]1.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][N:16]2[C:21](=[O:31])[CH2:22][C:23]1[NH:28][C:27](=[O:29])[CH:26]=[C:25](Cl)[N:24]=1.O>C(N(C(C)C)CC)(C)C>[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][N:16]2[C:21](=[O:31])[CH2:22][C:23]1[NH:28][C:27](=[O:29])[CH:26]=[C:25]([N:5]2[CH:6]3[CH2:10][CH2:9][CH2:8][CH:7]3[O:2][CH2:3][CH2:4]2)[N:24]=1
Reactant: O=C(Cc1nc(Cl)cc(=O)[nH]1)N1CCc2c(F)cccc21
Reactant: C1=C2OCCNC2CC1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1nc(N2CCOC3CCCC32)cc(=O)[nH]1)N1CCc2c(F)cccc21
Temperature: 100 °C
Yield: 23.2 %

Procedure:
532 mg of hexahydrocyclopenta[1,4]oxazine hydrochloride are added to a solution of 100 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-chloro-3H-pyrimidin-4-one in 5 ml of diisopropylethylamine. The reaction medium is heated at 100° C. for 2 hours. The reaction medium is taken up with 10 ml of water. The solid formed is filtered off and washed with water and then dried so as to give 30 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(hexahydrocyclopenta[1,4]oxazin-4-yl)-3H-pyrimidin-4-one in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=1.Cl[C:23]1[C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]=[C:25]([Cl:32])[C:24]=1[F:33]>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:23]2[C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]=[C:25]([Cl:32])[C:24]=2[F:33])=[C:16]([F:21])[CH:15]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: O=C(O)c1cnc(Cl)c(F)c1Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)c(F)c1Nc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
nBuLi (14.7 mL, 36.7 mmol, 2.5 M solution in hexanes) was added to a stirred solution of diisopropylamine (5.15 mL, 36.7 mmol) in THF (20 mL) at 0° C. After 20 minutes, the reaction mixture was cooled to −78° C. and a solution of 4-bromo-2-fluorophenylamine (4.65 g, 24.5 mmol) in THF (10 mL) was added. After 20 minutes, a solution of 4,6-dichloro-5-fluoro-nicotinic acid (Sanchez et al J Heterocylc. Chem. 1993, 30 (4), 855-9) (2.57 g, 12.25 mmol) in THF (10 mL) was added. After 10 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. After quenching the reaction mixture with 10% HCl (20 mL), it was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Trituration with methylene chloride yielded 3.21 g (72%) of clean desired product.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[NH2:8][C:9]1[CH:13]=[C:12]([Cl:14])[S:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16].[CH3:19][CH:20]([CH3:26])[CH2:21][CH2:22][N:23]=[C:24]=[S:25]>CN(C)C=O>[NH2:8][C:9]1[CH:13]=[C:12]([Cl:14])[S:11][C:10]=1[S:15]([NH:18][C:24]([NH:23][CH2:22][CH2:21][CH:20]([CH3:26])[CH3:19])=[S:25])(=[O:16])=[O:17]
Reactant: CC(C)CCN=C=S
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCNC(=S)NS(=O)(=O)c1sc(Cl)cc1N
Reaction time: 0.17 h
Yield: 30.7 %

Procedure:
Potassium tert-butoxide (0.49 g, 4.4 mmol) was added to a solution of 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride (0.5 g, 2.0 mmol) in dry N,N-dimethylformamide (5 ml) with stirring on an ice bath. After 10 min, 3-methylbutyl isothiocyanate (0.31 g, 2.4 mmol) was added dropwise to the resulting suspension, and the mixture was stirred for 3.5 h at 0 to 20° C. Most of the solvent was evaporated at 40° C., and the residue was taken up in 25 ml of water, treated with decolourising charcoal, and filtered. Acidification of the filtrate with acetic acid to pH 3-4 and filtration afforded 0.21 g (29%) of the title compound; mp 114-115° C. decomp., 1H-NMR (DMSO-d6): δ0.85 (d, 6H, 2×CH3), 1.40 (q, 2H, CH2), 1.50 (m, 1H, CH), 3.45 (q, 2H, CH2), 6.45 (br, 2H, NH2), 6.65 (s, 1H, H4), 8.30 (br t, 1H, NH), 11.3 (br s, 1H).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH2:33])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>>[CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH:33][S:43]([C:40]2[CH:39]=[CH:38][C:37]([O:36][CH3:35])=[CH:42][CH:41]=2)(=[O:45])=[O:44])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccccc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2cc3nc(-c4ccccc4)n(-c4ccccc4)c3cc2OCCCCCC(=O)OC(C)C)cc1

Procedure:
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid isopropyl ester was reacted according to general operating instructions 13 with 4-methoxybenzenesulfonic acid chloride.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([C:15]([CH3:19])([CH3:18])[C:16]#[CH:17])[C:9]2=[O:20])=[N:5][N:4]=1.C(N(CC)CC)C.[CH3:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>C1C=CC=CC=1>[F:22][C:2]([F:1])([F:21])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[CH3:30])[CH2:12][CH2:11][N:10]([C:15]([CH3:18])([CH3:19])[C:16]#[CH:17])[C:9]2=[O:20])=[N:5][N:4]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: C#CC(C)(C)N1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C#CC(C)(C)N1CCC(OC(=O)c2ccccc2C)N(c2nnc(C(F)(F)F)s2)C1=O

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol- 2-yl)-3-(1,1-dimethylprop-2-ynyl)-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Methylbenzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product tetrahydro-1 -(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-(1,1-dimethylprop- 2-ynyl)-6-(2-methylbenzoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1>CO.[Pd]>[CH3:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:14])=[CH:11][CH:10]=1
Reactant: COC(=O)C=Cc1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(OC)cc1
Reaction time: 2 h
Yield: 98.8 %

Procedure:
Methyl-4-methoxycinnamate (11.7g, 61 mmol) was dissolved in 300 mL of methanol. Palladium (5% on activated carbon powder; 1.1 g) was added slowly under strong argon stream. Hydrogen gas was bubbled in and the reaction mixture was stirred vigorously for 2 hours. The solid was filtered off and the filtrates were dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain methyl 3-(4-methoxyphenyl)propanoate [15823-04-8] (11.7 g, 99%).
Reaction SMILES: [CH2:1]([C:5]1[N:21](CC(=O)C2C=CC=CC=2)[C:8]2=[N:9][C:10]([CH2:19][OH:20])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C.CO.[Zn]>[CH2:1]([C:5]1[NH:21][C:8]2=[N:9][C:10]([CH2:19][OH:20])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(-c3ccccc3)c(CO)nc2n1CC(=O)c1ccccc1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCc1nc2cc(-c3ccccc3)c(CO)nc2[nH]1
Reaction time: 4 h
Yield: 85.3 %

Procedure:
4 g(0.010 mole) of the compound obtained in step 8 was dissolved in a mixture of 40 ml of acetic acid and 40 ml of methanol and to the resulting solution was added 13.1 g(0.0002 mole) of zinc powder. The resultant was stirred under ultrasonification for 4 hours, filtered and washed with acetic acid(10 ml×3). To the filtrate was added 50 ml of saturated aqueous ethylene diamine tetraacetic acid solution and then the resultant was stirred for 10 minutes. After adding 100 ml of ethyl acetate, the solution was filtered and washed with 100 ml of aqueous 10% NaHCO3 solution. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified with column chromatography(CH2Cl2 → 10% MeOH/CH2Cl2) to obtain 2.4 g of the title compound(yield 86%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:6][CH:5]([C:7]2[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH3:14])[CH2:4][O:3]1>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:15])[CH2:6][CH:5]([CH:7]2[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[CH:8]2[CH3:14])[CH2:4][O:3]1
Reactant: CC1=C(C2COC(C)(C)C2)CCC1(C)C
Agent: [Pd]
Solvent: CCO
Product: CC1C(C2COC(C)(C)C2)CCC1(C)C
Yield: 100 %

Procedure:
31.7 g of [rac]-2,2-dimethyl-4-(2,3,3-trimethylcyclopent-1-en-1-yl)tetrahydrofuran (from Example 4), at a purity of 92.7% (0.14 mole) were hydrogenated on a Parr shaker using 2.0 g of 5% Pd on carbon in 50 ml of ethanol. The product, 31.6 g, was distilled to afford 30 g (100% yield). BP 52°-54° C./0.2 mmHg; 1H-NMR (300 MHz), δ 0.74 (3H, s), 0.85 (3H, d, J=6.9 Hz), 0.94 (3H, s), 1.2 (1H, m), 1.19 (3H, s), 1.28 (3H, s), 1.3-1.6 (5H, m), 1.65-1.95 (2H, m), 2.33 (1H, m), 3.47 (1H, m), 3.94 (1H, m); 13C-NMR (75 MHz), δ 13.83, 22.07, 26.75, 28.29, 28.56, 28.82, 40.64, 43.57, 44.72, 45.76, 49.56, 49.69, 71.84, 81.25; IR (Neat), 2980, 1460, 1055 cm-1 ; MS (m/e), 195 (M+ -15), 137, 43 (Base);
Reaction SMILES: [CH2:1]([C:3]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:4]=1[C:5]([CH:7](C(OCC)=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([C:3]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:4]=1[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1c(F)c(F)c(F)c(F)c1CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1CC
Yield: 80.4 %

Procedure:
Employing diethyl 2-ethyl-3,4,5,6-tetrafluoro-benzoylmalonate (17.2 g) and p-toluenesulfonic acid (0.25 g), the procedure of Reference Example 19 is repeated to give ethyl 2-ethyl-3,4,5,6-tetrafluorobenzoylacetate (11.09 g).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH:3]=[CH:4][CH2:5][OH:6].[CH2:9]=[C:10]1[O:14][C:12](=[O:13])[CH2:11]1>O1CCCC1.C(OCC)C.C([O-])(=O)C.[Na+]>[C:12]([O:6][CH2:5]/[CH:4]=[CH:3]/[C:2]([F:8])([F:7])[F:1])(=[O:13])[CH2:11][C:10]([CH3:9])=[O:14]
Reactant: C=C1CC(=O)O1
Reactant: OCC=CC(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)CC(=O)OC/C=C/C(F)(F)F
Temperature: 25 °C
Yield: 154.6 %

Procedure:
To a refluxing solution of 4,4,4-trifluoro-2-buten-1-ol (10 g, 79 mmol) and sodium acetate (0.51 g, 6.2 mmol) in anhydrous tetrahydrofuran (27 mL) under nitrogen, a solution of diketene (6.7 mL, 43.1 mmol) in anhydrous tetrahydrofuran (14 mL) was added dropwise over a period of 1 hour. The reaction mixture was heated at reflux for an additional 30 min upon completion of the addition. Then, the reaction mixture mixture was cooled to room temperature and diluted with diethyl ether (100 mL). The resulting solution was washed with a saturated aqueous sodium chloride solution (2×20 mL) and the organic layer was dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The brown residue was purified by column chromatography using a mixture 4:1 of hexane and ethyl acetate as eluent to afford 14.0 g (84% yield) of trans-4,4,4-trifluoro-2-buten-1-yl acetoacetate as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[CH2:10])[C:6]([F:11])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CC(O)C>[F:11][C:6]1[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[CH2:9][CH2:10][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C=Cc1cc(OC)c([N+](=O)[O-])cc1F
Reactant: C1COCCN1
Solvent: CC(C)O
Product: COc1cc(CCN2CCOCC2)c(F)cc1[N+](=O)[O-]
Temperature: 180 °C
Yield: 64.1 %

Procedure:
To 5-ethenyl-4-fluoro-2-nitrophenyl methyl ether (0.43 g, 2.2 mmol) in 10 mL of iPrOH was added, morpholine (0.56 g, 6.54 mmol). The mixture was heated to 180° C. 1.5 h in the microwave. The solvent was rotovaped down and the residue purified by flash chromatography to give the title compound of step A (0.4 g, 1.41 mmol, 64%). 1H NMR (400 MHz, CDCl3) δ ppm 7.62 (d, J=8.80 Hz, 1H), 6.99 (d, J=6.23 Hz, 1H), 3.94 (s, 3H), 3.70-3.75 (m, 4H), 2.87 (t, J=7.33 Hz, 2H), 2.58-2.66 (m, 2H), 2.49-2.56 (m, 4H).