Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[N:11][C:10]=1[CH2:15][OH:16].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[N:9]1[CH:14]=[CH:13][CH:12]=[N:11][C:10]=1[CH2:15][O:16][C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1
Reactant: CSc1nsc(Cl)n1
Reactant: OCc1ncccn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2ncccn2)n1
Reaction time: 0.25 h
Yield: 63.7 %

Procedure:
Into 3.6 g of N,N-dimethylformamide were dissolved 304 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole and 200 mg of 2-pyrimidylmethyl alcohol, 87 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 15 minutes. After stirring for 1.5 hour at room temperature, the reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 278 mg of 5-(2-pyrimidylmethyloxy)-3-methylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (36)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:7]([CH:8]=O)[C:6]([OH:11])=[CH:5][CH:4]=1.[Br:12][C:13]1[CH:26]=[CH:25][C:16]([NH:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19])=[CH:15][CH:14]=1>C(O)(=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:17][S:18]([C:21]2[C:22](=[O:23])[O:11][C:6]3[C:7]([CH:8]=2)=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:20])=[O:19])=[CH:25][CH:26]=1
Reactant: COc1ccc(O)c(C=O)c1
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(Br)cc1
Solvent: CC(=O)O
Product: COc1ccc2oc(=O)c(S(=O)(=O)Nc3ccc(Br)cc3)cc2c1

Procedure:
A solution of 5-methoxysalicylaldehyde (1 mmol) and 4-bromoanilinosulfonyl acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 1, Method A to yield the title compound; m.p. 166-168° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[C:7]([OH:12])[CH:8]=2)[O:3]1.B(F)(F)F.[CH3:20][C:21](O)([CH:23]=[CH2:24])[CH3:22]>O1CCOCC1>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[C:7]([OH:12])[C:8]=2[CH2:24][CH:23]=[C:21]([CH3:22])[CH3:20])[O:3]1
Reactant: Cc1c(O)cc2c(c1C)OC(C)(C)CC2
Reactant: C=CC(C)(C)O
Agent: FB(F)F
Solvent: C1COCCO1
Product: CC(C)=CCc1c(O)c(C)c(C)c2c1CCC(C)(C)O2
Reaction time: 0.05 h
Yield: 60 %

Procedure:
To a solution of 2,2,7,8-tetramethyl-chroman-6-ol (305 mg, 1.39 mmol), in 5 mL dry dioxane was added boron trifluoride (296 mg, 2.1 mmol). It was stirred for 3 min followed by dropwise addition of 2-methyl-but-3-en-2-ol solution (143 mg, 1.66 mmol, in 3 mL of dioxane). The reaction was allowed to stir for 5 h at RT before quenching on to ice (80 g). The mixture was extracted with DCM (3×50 mL) and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by chromatography (hexane) to afford 2,2,7,8-tetramethyl-5-(3-methyl-but-2-enyl)-chroman-6-ol as a light brown oil (229 mg). 1H-NMR (300 MHz, CDCl3) δ (ppm): 5.16 (m, 1H), 4.70 (s, 1H), 3.34 (d, J=6.8 (2H), 2.18 (s, 3H), 2.14 (s, 3H), 1.86 (s, 3H), 1.81 (t, J=13.8, 2H), 1.77 (s, 3H), 1.32 (s, 6H); 13C-NMR δ (ppm): 145.7, 145.4, 134.1, 123.5, 122.2, 122.0, 121.8, 116.3, 72.5, 33.1, 26.7, 25.8, 20.8, 17.9, 12.1, 11.9; (ESI) m/z: 275 (M+H+, 100%).
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9](=[N:11][OH:12])[NH2:10])=[N:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19](Cl)=O>>[Cl:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]1[O:12][N:11]=[C:9]([C:7]2[S:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=2)[N:10]=1
Reactant: O=C(Cl)c1sccc1Cl
Reactant: NC(=NO)c1ncc([N+](=O)[O-])s1
Product: O=[N+]([O-])c1cnc(-c2noc(-c3sccc3Cl)n2)s1

Procedure:
The title compound was prepared from 5-nitro-thiazole-2-amidoxime (17.2 mg, 0.0914 mmol) and 3-chloro-thiophene-2-carbonyl chloride (16.4 mg, 0.0905 mmol) similar to Example 16, and yielded 6.7 mg (23%) of yellow solid. 1H NMR (CDCl3): 8.74 (s, 1H), 7.70 (d, J=5.22 Hz, 1H), 7.18 (d, J=5.22 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][CH:14]=[CH2:15])=[O:12])=[CH:7][C:5]=1[NH2:6])([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+].N.O>C(O)C>[CH2:13]([S:11]([C:8]1[CH:9]=[CH:10][C:4]([NH2:1])=[C:5]([NH2:6])[CH:7]=1)=[O:12])[CH:14]=[CH2:15]
Reactant: C=CCS(=O)c1ccc([N+](=O)[O-])c(N)c1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCS(=O)c1ccc(N)c(N)c1

Procedure:
To a suspension of 0.0075 mole of 2-nitro-5-(2-propenylsulfinyl)aniline in 75 ml of absolute ethanol under N2 there is added a solution of 4.9 g of Na2S2O4, 4.9 ml of concentrated NH3 and 30 ml of water. The mixture is refluxed for 15 minutes and an additional 0.4 g of Na2S2O4 is added. After 15 minutes of reflux the ethanol is evaporated. The aqueous residue is made basic (pH 12) and extracted with dichloromethane. The combined, dried extracts are evaporated and the resulting oily residue is used immediately in the next reaction.
Reaction SMILES: [O:1]([CH2:5][CH3:6])[C:2]([S-])=[S:3].[K+].Br[NH:9][C:10](=[NH:15])[C:11]([Cl:14])([Cl:13])[Cl:12]>O.C(Cl)Cl>[Cl:12][C:11]([Cl:14])([Cl:13])[C:10]1[N:15]=[C:2]([O:1][CH2:5][CH3:6])[S:3][N:9]=1
Reactant: N=C(NBr)C(Cl)(Cl)Cl
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCOc1nc(C(Cl)(Cl)Cl)ns1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
32 g (0.2 mole) of potassium ethyl xanthate was dissolved in 175 ml of water. This was stirred rapidly while a solution of 48 g (0.2 mole) of N-bromotrichloroacetamidine in 150 ml of methylene chloride was added over 15 minutes. Then, the mixture was stirred one hour at room temperature. The dark methylene chloride layer was separated and the water layer extracted with 100 ml of methylene chloride. The combined methylene chloride fractions were dried over magnesium sulfate and filtered. Next, the solvent was evaporated and then the crude product was distilled at 75° C. under a vacuum of 0.9mm to give 26 g of 3-trichloromethyl-5-ethoxy-1,2,4-thiadiazole.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(Cl)Cl.[C:17](Cl)(=[O:21])[C:18](Cl)=[O:19]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:13])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4]3=[C:5]([C:17](=[O:21])[C:18](=[O:19])[N:3]13)[CH:6]=[CH:7][CH:8]=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1=CC(C)(C)Nc2ccccc21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1=CC(C)(C)N2C(=O)C(=O)c3cccc1c32
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1,2-dihydro-2,2,4-trimethylquinoline (34.6 g., 0.2 mole) in 50 ml. dry methylene chloride was added slowly dropwise to oxalyl chloride (26.4 g., 0.21 mole) in 300 ml. dry methylene chloride. Addition required 45 min., and when complete the resultant solution was stirred at ambient temperature 4 hrs. and refluxed 2 hrs. The dark red solution was freed of solvent at reduced pressure and the very dark solid residue taken up in chloroform. Dilution with ligroine and chilling produced a total yield of 32.6 g. (71.8%); m.p. 170°-176° C. A sample repeatedly recrystallized from toluene-ligroine (1:4) melted at 176°-177.5° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][CH:4]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C1COCC1>[CH3:16][C:11]1([CH3:17])[C:12]([CH3:15])([CH3:14])[O:13][B:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:4][CH:5]=2)[O:10]1
Reactant: C1COCCN1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.3 %

Procedure:
2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (200 mg, 0.673 mmol) was dissolved in THF (5 mL) and morpholine (0.088 mL, 1.01 mmol) was added. The mixture stirred overnight at room temperature and was then filtered and concentrated to afford the title compound (223 mg, 100%). 1H NMR (300 MHz, CDCl3): δ 7.79 (d, 2H), 7.36 (d, 2H), 3.73 (t, 4H), 3.55 (s, 2H), 2.47 (t, 4H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[N:30]=[C:31]=[O:32]>>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[NH:30][C:31]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:20])[CH3:21])[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:32]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CO)c1)OC(C)C
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1COC(=O)Nc1ccc(Cl)cc1Cl

Procedure:
Using ethyl 3-[3-(hydroxymethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 2,4-dichlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([C:35]2[CH2:36][CH2:37][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:39][CH:40]=2)([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>ClCCl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[CH2:41]([N:38]1[CH2:37][CH:36]=[C:35]([C:32]([CH3:34])([CH3:33])[CH2:31][CH:10]2[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[F:20])[C:11]2([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])[C:21]#[N:22])[CH2:40][CH2:39]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)C1NC(CC(C)(C)C2=CCN(Cc3ccccc3)CC2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C1=CCN(Cc2ccccc2)CC1
Yield: 98 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-[2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 127b (1.5 g, 2.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-5-[2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow solid (1.6 g, 98%).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:20])/[CH2:9][CH2:10]/[CH:11]=[C:12](\[CH3:19])/[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])(=O)=O.[I-:28].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O>[CH3:20]/[C:8](/[CH2:9][CH2:10]/[CH:11]=[C:12](\[CH3:19])/[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:7]\[CH2:6][CH2:5][I:28]
Reactant: [I-]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCOS(=O)(=O)c1ccc(C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCI
Yield: 76 %

Procedure:
The (E,E)-4,8,12-trimethyl-3,7,11-tridecatrienyl tosylate obtained from previous step was dissolved in acetone (50 mL), then added sodium iodide (3.30 g, 22 mmol) and the resulting mixture was stirred at room temperature for 0.5 hours followed by heating at reflux for 3 hours. After cooling, the reaction mixture was poured into cold aqueous sodium thiosulfate solution and extracted with ether. The ethereal extract was washed with water, dried and filtered. Evaporation of the filtrate left a residue which was purified by flash chromatography on a silica gel column. Elution of the column with Hexane:ether (50:1, v:v) provided the title compound (1.85 g, 5.34 mmol, 76% for two steps) as a colorless oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[N:9][C:10]([Cl:23])=[CH:11][C:12]=1[C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([F:22])[CH:18]=[CH:17][CH:16]=2)(=O)=O.[CH2:26]([Sn](CCCC)(CCCC)C(C)=C)[CH2:27][CH2:28]C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:23][C:10]1[CH:11]=[C:12]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([F:22])[CH:18]=[CH:17][CH:16]=3)[C:7]([C:27]([CH3:28])=[CH2:26])=[CH:8][N:9]=1
Reactant: C=C(C)[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(Oc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(C)c1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Reaction time: 5 h
Yield: 69.8 %

Procedure:
To a suspension of 6-chloro-4-(4-fluoro-1H-indol-2-yl)pyridin-3-yl trifluoromethanesulfonate (100 mg, 0.25 mmol) and tributyl(prop-1-en-2-yl)stannane (100 mg, 0.28 mmol) in DMF (2 mL) was added Pd(PPh3)4 (10 mg, 0.02 mmol) at 100° C. under N2, and the mixture was stirred for 5 hours. After concentrated in vacuum, the residue was suspended in H2O and extracted with EA. The combined organic layer was washed with H2O, brine, dried over Na2SO4, filtrated and concentrated to give 2-(2-chloro-5-(prop-1-en-2-yl)pyridin-4-yl)-4-fluoro-1H-indole (50 mg, yield: 70%). 1H-NMR (CDCl3, 400 MHz) δ 8.96 (s, 1H), 8.14 (s, 1H), 7.47 (s, 1H), 7.08˜7.13 (m, 2H), 6.95 (s, 1H), 6.72˜6.76 (m, 1H), 5.39 (s, 1H), 5.23 (s, 1H), 1.77 (s, 3H). MS (M+H)+: 287/289.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][CH2:2][CH2:3][O:4][C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(OCCN)cc1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCNC(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C

Procedure:
Methyl 4-(2-aminoethoxy)benzoate (5.86 g) and 4.08 g of p-methylbenzoic acid were dissolved in 100 ml of N,N-dimethylformamide and then 6.19 g of N,N'-dicyclohexylcarbodiimide was gradually added thereto with stirring at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7](=[CH:18][N+:19]([O-])=O)[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[CH2:24](O)[CH3:25]>CN(C)C=O.[Ni]>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]3[C:24]([CH3:25])=[N:19][CH2:18][CH:7]3[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: O=C1CC(=C[N+](=O)[O-])Nc2ccc(Cl)cc2N1c1ccccc1
Reactant: CCO
Agent: [Ni]
Solvent: CN(C)C=O
Product: CC1=NCC2CC(=O)N(c3ccccc3)c3cc(Cl)ccc3N12
Temperature: 25 °C
Reaction time: 21 h

Procedure:
7-Chloro-5-phenyl-1,2,3,4-tetrahydro-2-nitromethylene-5H-1, 5-benzodiazepin-4-one 18.3 g (.055 mole) was dissolved in 300 ml of dimethylformamide by gentle heating on a steam bath. The solution was cooled to room temperature and 400 ml of ethanol and 55 g of Raney nickel were added. The mixture was hydrogenated at atmospheric pressure for 21 hours. The catalyst was filtered off and washed well with tetrahydrofuran and methylene chloride. The filtrate was evaporated and the residue was dissolved in 325 ml of xylene, and 40 ml of triethyl orthoacetate was added to the solution which was then refluxed for 1 hour. The mixture was evaporated and the residue was crystallized from ethyl acetate to yield end product with mp 248°-251°. The analytical sample was recrystallized from methylene chloride/ethyl acetate to give colorless crystals with mp 250°-252°.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][P:18](=[O:31])([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=2)[N:3]=1.[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([CH:46]2[CH2:51][CH2:50][CH:49]([OH:52])[CH2:48][CH2:47]2)=[C:39]2[C:43]=1[C:42](=[O:44])[N:41]([CH3:45])[CH2:40]2>>[OH:52][C@H:49]1[CH2:50][CH2:51][C@H:46]([C:38]2[CH:37]=[CH:36][C:35]([NH:34][C:2]3[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:33]=[CH:32][C:16]([CH2:17][P:18](=[O:31])([O:25][CH2:26][C:27]([F:29])([F:30])[F:28])[O:19][CH2:20][C:21]([F:23])([F:24])[F:22])=[CH:15][CH:14]=4)[N:3]=3)=[C:43]3[C:39]=2[CH2:40][N:41]([CH3:45])[C:42]3=[O:44])[CH2:47][CH2:48]1
Reactant: O=P(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)(OCC(F)(F)F)OCC(F)(F)F
Reactant: CN1Cc2c(C3CCC(O)CC3)ccc(N)c2C1=O
Product: CN1Cc2c(c(Nc3nc(Nc4ccc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)cc4)ncc3C(F)(F)F)ccc2[C@H]2CC[C@H](O)CC2)C1=O

Procedure:
The title compound was prepared according to the procedure from Example 102 using bis(2,2,2-trifluoroethyl) (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Compound 165A, 35.7 mg, 0.0671 mmol) and 7-amino-4-(4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (18.5 mg, 0.0711 mmol). The crude material was first purified on a Teledyne/ISCO system eluting with 50-100% EtOAc:Heptane followed by MDP (under acidic conditions; formic acid). The desired fractions were collected and concentrated in vacuo, giving the title material as an off-white solid, 24.3 mg (47%, 0.0315 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.59 (br s, 1H), 9.93 (s, 1H), 8.47 (s, 1H), 8.15-9.25 (m, 1H), 7.63 (d, J=6.1 Hz, 2H), 7.34 (d, J=8.6 Hz, 1H), 7.26 (dd, J=8.6, 2.5 Hz, 2H), 4.58-4.72 (m, 5H), 4.53 (s, 2H), 3.43-3.61 (m, 3H), 3.08 (s, 3H), 1.94 (dd, J=11.7, 2.1 Hz, 2H), 1.77 (d, J=11.6 Hz, 2H), 1.56 (dtd, J=12.9, 12.7, 2.1 Hz, 2H), 1.21-1.37 (m, 2H). MS (ES+): m/z 756.16 (100) [MH+]. HPLC: tR=4.14 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]([C:7]1[S:11][C:10]([N:12]=[C:13]=[O:14])=[N:9][N:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:15]([NH:18][CH:19]([CH2:22][O:23][CH3:24])[CH:20]=[O:21])[C:16]#[CH:17]>C1C=CC=CC=1>[CH2:15]([N:18]([CH:19]([CH2:22][O:23][CH3:24])[CH:20]=[O:21])[C:13]([NH:12][C:10]1[S:11][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:8][N:9]=1)=[O:14])[C:16]#[CH:17]
Reactant: CCCCCCc1nnc(N=C=O)s1
Reactant: C#CCNC(C=O)COC
Solvent: c1ccccc1
Product: C#CCN(C(=O)Nc1nnc(CCCCCC)s1)C(C=O)COC

Procedure:
5-Hexyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-propargylamino-3-methoxy-propionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 30 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-propargyl-3-(5-hexyl-1,3,4thiadiazol-2-yl)-ureido]-3-methoxypropionaldehyde.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:6].[NH3:24]>CO>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:24])=[O:2])=[CH:9][CH:10]=2)=[CH:17][CH:18]=1
Reactant: N
Reactant: COC(=O)CC(=O)Nc1ccc(CCc2ccc(F)cc2)cc1
Solvent: CO
Product: NC(=O)CC(=O)Nc1ccc(CCc2ccc(F)cc2)cc1
Yield: 94 %

Procedure:
Prepared in analogy to example 3 from N-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-malonamic acid methyl ester and 7M ammonia in methanol. Yield=94%. Colorless solid. MS: m/e=301.1 (M++H).
Reaction SMILES: C([NH:9][C:10]([NH:12][C@H:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])=[S:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:18][C@@H:13]([NH:12][C:10]([NH2:9])=[S:11])[C:14]([F:17])([F:16])[F:15]
Reactant: C[C@@H](NC(=S)NC(=O)c1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@@H](NC(N)=S)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
Dissolve (R)-1-benzoyl-3-(1-methyl-2,2,2-trifluoroethyl)-thiourea (6.2 g, 22.5 mmol) in methanol and add a solution of potassium carbonate (13.8 g, 100 mmol) in water (30 mL). Stir vigorously at room temperature overnight. Evaporate to dryness, dissolve residue in hot water (ca. 100 mL) and filter the resulting white crystals. Cool filtrate to 0° C., seed with crystals from hot water filtration, filter and collect resulting white crystals to obtain the desired intermediate (2.9 g, 74%). MS (ES+) m/z: 173 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]=[C:13](OCC)[NH:12]3)[CH2:10][C:9]([CH3:21])([CH3:20])[O:8][C:5]2=[CH:6][CH:7]=1.[NH3:22].O>CCO>[NH2:22][C:13]1[NH:12][C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][C:9]([CH3:20])([CH3:21])[CH2:10]2)[C:15](=[O:16])[N:14]=1
Reactant: N
Reactant: CCOC1=NC(=O)C2(CC(C)(C)Oc3ccc(Br)cc32)N1
Solvent: CCO
Solvent: O
Product: CC1(C)CC2(NC(N)=NC2=O)c2cc(Br)ccc2O1
Yield: 30 %

Procedure:
To a solution of 6-bromo-2′-ethoxy-2,2-dimethylspiro[chroman-4,4′-imidazol]-5′(3′H)-one (500 mg, 1.42 mmol) in EtOH (30 mL) was added NH3.H2O (30 mL). The mixture was refluxed for 18 h. The solvent was removed in vacuo to give a residue, which was purified by preparative TLC to give 2′-amino-6-bromo-2,2-dimethylspiro[chroman-4,4′-imidazol]-5′(3′H)-one (120 mg, 30%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:20][CH2:19]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Reactant: IC1CCCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCN(C4CCCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 35 from 2-(butyloxy)-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and iodocyclohexane.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].O.[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Pd]>[C:1]([O:4][CH2:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccccc1
Reactant: CC(=O)O
Agent: [Pd]
Solvent: O
Product: CC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
A mixture of 70.7 wt. % acetic acid, 23.2 wt. % toluene and 6.1 wt. % water was first, at the rate of 0.198 gm./min., vaporized and then fed into a 3/8" I.D. stainless-steel tubular reactor packed with about 4.7 gm. of palladium on alumina support, at 160°-170° C. and about 30 psig. The palladium content contained in the supported catalyst was about 2% by weight. After about two hours of continuously running the reaction, the gaseous reaction product was directly sent to an on-line G.C. analyzer. The G.C. analysis showed that about 15% of toluene was converted; and that no product other than benzyl acetate was formed from the vapor phase reaction. A check based on the feed/product material balance indicated that the yield of benzyl acetate was over 90 mole % of toluene reacted.