Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([NH:7][CH2:8][CH3:9])[CH3:6].CO[C:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[NH2:24])[N:15]=1)=[O:13].O>C1(C)C=CC=CC=1>[CH2:5]([N:7]([CH2:8][CH3:9])[C:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[NH2:24])[N:15]=1)=[O:13])[CH3:6]
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Reactant: CCNCC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1ccc2c(N)cccc2n1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A suspension that consists of 1.06 g (7.95 mmol) of aluminum chloride in 35 ml of toluene is mixed with 1.70 ml (15.7 mmol) of diethylamine while being cooled with ice. After one hour at room temperature, 350 mg (1.73 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester is added, and the reaction mixture is allowed to stir for 5 hours at 40° C. The reaction is halted by adding water. It is extracted with dichloromethane, and the combined organic phases are dried on sodium sulfate. After removal of the solvent and purification on silica gel with dichloromethane-methanol (0-10%), 210 mg (50% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[Cl:5][C:6]1[C:7]([F:32])=[C:8]([CH:29]=[CH:30][CH:31]=1)[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([O:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:18]=2)[N:13]=[CH:12][N:11]=1>ClCCl>[Cl:5][C:6]1[C:7]([F:32])=[C:8]([CH:29]=[CH:30][CH:31]=1)[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([C:3](=[O:4])[NH:2][CH3:1])[CH2:23][CH2:22]3)[CH:18]=2)[N:13]=[CH:12][N:11]=1
Reactant: CN=C=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Solvent: ClCCl
Product: CNC(=O)N1CCC(Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.5 %

Procedure:
Methylisocyanate (20.4 μl, 0.33 mmol) was added dropwise to a mixture of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline (120 mg, 0.3 mmol) in dichloromethane (5 ml) at room temperature. The mixture was stirred at room temperature for 4 hours. After evaporation of the solvents under vacuum, the residue was purified by chromatography on silica gel (eluant: 2% 7N methanolic ammonia in dichloromethane) to give the title compound as a white solid (100 mg, 72%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)[CH2:5][CH2:6][Cl:7].C(N(CC)CC)C.C(Cl)(Cl)(Cl)[Cl:25]>C1C=CC=CC=1.S(Cl)(Cl)=O.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:25])=[O:13])=[CH:10][CH:9]=1)[CH2:5][CH2:6][Cl:7]
Reactant: O=C(O)c1ccc(N(CCCl)CCCl)cc1
Reactant: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc(N(CCCl)CCCl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
p-N,N-Bis(2-chloroethyl)aminobenzoyl chloride was prepared by dissolving p-N,N-bis(2-chloroethyl)aminobenzoic acid (360.1 mg, 1.37 mmol) in benzene (3 mL) and thionyl chloride (3 mL) and heating to reflux under a drying tube for 1.25 h. The excess thionyl chloride and solvent were then removed under reduced pressure and the residue coevaporated with dry CH2Cl2 (10 mL, twice). To a stirred solution of N-(N',N'-dimethylaminoethyl)-1-methyl-4-[1-methyl-4-aminoimidazole-2-carboxamido]imidazole-2-carboxamide (457 mg, 1.37 mmol) in dry CH2Cl2 (40 mL) with dry triethylamine (210 μL, 1.51 mmol) was cooled to -20° C. (CCl4 /liq N2 bath) and the above acid chloride dissolved in dry CH2Cl2 (10 mL) was added dropwise under an atmosphere of argon. The reaction mixture was kept at 20° C. for an additional 15 minutes and then allowed to stir at room temperature (22.5 h). After TLC analysis indicated that all of the starting material was gone, the reaction was concentrated under reduced pressure to an orange foam. The residue was then dissolved in CH2Cl2 (100 mL) and washed with saturated NaHCO3 (100 mL) and water (100 mL) sequentially. TLC analysis of the organic layers indicated impurities so the product was purified by column chromatography (silica gel) with methanol (1%) in chloroform as eluant. The resulting pure product was precipitated from CH2Cl2 with ether and hexane and the off-white powder dried in vacuo at room temperature. Yield: 216 mg (0.37 mmol, 27%). mp (dec.) 165° C. TLC (10% MeOH/CHCl3)Rf 0.40. 1H NMR (CDCl3) δ2.27 (s, 6H, N',N'-dimethyls), 2.53 (t, 2H, CH2NMe2), 3.50 (q, 2H, NCH2C), 3.68 (m, 4H, chloroethyl-CH2 --), 3.82 (m, 4H, chloroethyl-CH2 --), 4.02 (s, 3H, imidazole-1-methyl), 4.06 (s, 3H, imidazole-1-methyl), 6.75 (d, 2H, phenyl), 7.39 (s, 1H, imidazole), 7.58 (s, 1H, imidazole), 7.83 (t, 1H, NH), 7.94 (d, 2H, phenyl), 8.71 (br s, 1H, NH), 9.31 (br s, 1H, NH). 13C--NMR (CDCl3): δ35.6, 36.7, 40.2, 45.2, 53.3, 57.9, 111.2, 113.3, 114.6, 122.0, 129.4, 133.5, 135.4, 136.9, 149.0, 158.8, 159.5, 163.9. IR(Nujol): υ3420, 1654, 1606, 1518, 1185, 668 cm-1. UV (H2O ): λmax 216 (ε34051 cm-1M-1), 316 nm (ε22570 cm-1M-1). MS (FAB, TFA-NBA) m/z (relative intensity): 578 (M+, 80). Anal. calcd. for C25H33Cl2N9O3. 1/2H2O: C, 51.10; H, 5.84. Observed C, 51.11; H, 5.72.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8](=[O:18])[NH:9][C:10]2[S:11][C:12]([C:15](O)=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:19]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:9][C:10]2[S:11][C:12]([C:15]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:16])=[CH:13][N:14]=2)=[O:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=C(O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: C1CCNC1
Product: O=C(c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1)N1CCCC1

Procedure:
Prepared as described in general procedure (K) using 2-(3,3-dicyclohexyl-ureido)-thiazole-5-carboxylic acid and pyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=O.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][C:20]#[N:21]>>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]1[C:20]([NH2:21])=[N:1][C:2]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[N:4][CH:3]=2
Reactant: Nc1cnccc1C=O
Reactant: COc1ccccc1CCC#N
Product: COc1ccccc1Cc1cc2ccncc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 3-amino-4-pyridine carboxaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](SC)[N:29]=3)[CH:25]=[C:24]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:23]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:2]>CO.C1COCC1.[Ni]>[CH2:1]([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][N:29]=3)[CH:25]=[C:24]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:23]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccnc(SC)n3)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccncn3)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(2-(2-ethoxycarbonyl-ethyl)-3-{6-[3-methanesulfonyl-5-(2-methylsulfanyl-pyrimidin-4-yl)-phenoxy]-hexyl}-phenoxy)-butyric acid ethyl ester (292 mg, 0.423 mmol) in MeOH (15 ml) and THF (15 mL), Raney Ni (2 mL) was added, and stirred at r.t. for 3 h. The reaction was filtered, the residue was washed with MeOH, concentration gave an oil which was used in the next step without further purification. (164 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=2)[CH:17]=[CH:16][N:15]=1.N1C=CC=CC=1.Cl[C:36]([C:38]1[CH:39]=[C:40]([CH:49]=[CH:50][CH:51]=1)[CH2:41][S:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])=[O:37]>O1CCCC1>[CH3:28][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:3]3[CH:4]=[C:5]([N:8]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]4)[CH:6]=[CH:7][C:2]=3[NH:1][C:36]([C:38]3[CH:39]=[C:40]([CH:49]=[CH:50][CH:51]=3)[CH2:41][S:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])=[O:37])[CH:19]=2)[CH:26]=[CH:25][C:24]=1[CH3:27]
Reactant: COC(=O)CCSCc1cccc(C(=O)Cl)c1
Reactant: Cc1ccc(Nc2ccnc(-c3cc(N4CCCCC4)ccc3N)c2)cc1C
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(Nc3ccc(C)c(C)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Into a 50-mL 3-necked round bottom flask, was placed a solution of 2-(2-amino-5-(piperidin-1-yl)phenyl)-N-(3,4-dimethylphenyl)pyridin-4-amine (270 mg, 0.72 mmol, 1.00 equiv) in tetrahydrofuran (10 mL), pyridine (170 mg, 2.15 mmol, 2.97 equiv), and methyl 3-(3-(chlorocarbonyl)benzylthio)propanoate (197.6 mg, 0.72 mmol, 1.00 equiv). The resulting solution was stirred for 1.5 h at room temperature. This reaction was used directly in next step without workup.
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([C@H:11]([OH:13])[CH3:12])[CH2:7][CH2:6]1.C([O-])([O-])=O.[K+].[K+].Cl[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]>O.C(Cl)Cl.CO>[OH:13][C@@H:11]([CH:8]1[CH2:9][CH2:10][N:5]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:6][CH2:7]1)[CH3:12]
Reactant: C[C@@H](O)C1CCNCC1
Reactant: CC(C)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)OC(=O)N1CCC([C@@H](C)O)CC1
Reaction time: 2 h
Yield: 97.6 %

Procedure:
A solution of (1R)-1-(4-piperidinyl)ethanol acetic acid salt (1 g, 5.28 mmol) in water (10 mL) was cooled to 0° C. in an ice bath. A solution of K2CO3 (3.65 g, 26.4 mmol) in water (8 mL) was added, followed by dropwise addition of isopropyl chloroformate (1M in toluene, 21.1 mL, 21.1 mmol). The reaction mixture was stirred from 0° C. to ambient temperature over 2 h, then at ambient temperature overnight, diluted with CH2Cl2 (100 mL), washed with 1N HCl, water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give a brown oil, which was dissolved in MeOH (15 mL). K2CO3 (1 g, 7.24 mmol) and water (5 mL) were added, and the mixture was stirred at ambient temperature overnight and extracted with CH2Cl2. The organic extracts were combined and washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give 1.11 g (98%) of 1-methylethyl 4-[(1R)-1-hydroxyethyl]-1-piperidinecarboxylate as a colorless oil, which was used without further purification (% ee not determined). 1H NMR (400 MHz, CDCl3): δ 4.88 (septet, 1H, J=6.2 Hz), 4.25-4.10 (m, 2H), 3.60-3.50 (m, 1H), 2.75-2.60 (m, 2H), 1.85-1.75 (m, 1H), 1.65-1.55 (m, 1H), 1.50-1.35 (m, 1H), 1.25-1.10 (m, 11H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-])=O)=[C:6]([NH:8][C:9]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][C:10]=2[C:11]#[N:12])[CH:7]=1.[Sn](Cl)[Cl:24]>C(O)C.Cl>[ClH:24].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:20]=[C:11]([NH2:12])[C:10]3[CH:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[CH:15]=[CH:16][C:9]=3[NH:8][C:6]=2[CH:7]=1
Reactant: Cl[Sn]Cl
Reactant: CC(C)c1ccc(Nc2cc(F)ccc2[N+](=O)[O-])c(C#N)c1
Agent: Cl
Solvent: CCO
Product: CC(C)c1ccc2c(c1)C(N)=Nc1ccc(F)cc1N2
Yield: 96 %

Procedure:
Heat a solution of 2-(5-fluoro-2-nitro-phenylamino)-5-isopropyl-benzonitrile (0.372 g, 1.24 mmol) in ethanol (6 ml) to 60° C. Add a solution of tin (II) chloride (0.707 g, 3.73 mmol) in 5.0 N hydrochloric acid (6 ml) and heat the resulting mixture to reflux for 16 hours. Cool the reaction to room temperature, add 30 ml of 5.0 N hydrochloric acid and place the mixture in a freezer for 16 hours. Precipitate the product from the solution and collect by filtration. Wash solid with 5.0 N hydrochloric acid to obtain 0.365 g of the title compound (1.19 mmol, 96% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 270(M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[CH2:19][C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:27][C:22]1[CH:21]=[C:20]([C@H:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH:8]([NH2:7])[CH3:9])[CH2:19]2)[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: CC(NC(=O)OC(C)(C)C)C1=Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)C1=Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of tert-butyl-1-((S)-4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-2-yl)ethylcarbamate 49a (Example 21.3) (100 mg, 0.24 mmol) in CH2Cl2 (2 mL) was added TFA (2 mL). The reaction mixture was stirred for 1 h before being concentrated. The residue was subjected to reverse phase column chromatography (CH3CN/H2O/0.1% formic acid=5% to 100%) to give 46 (66 mg, 86%). 1HNMR (400 MHz, CDCl3) δ 7.34 (d, J=8.4 Hz, 1 H), 7.26 (d, J=2.0 Hz, 1 H), 7.20 (m, 1 H), 7.16-7.08 (m, 2 H), 7.01 (dd, J=1.6, 8.0 Hz, 1H), 6.80 (d, J=7.2 Hz, 1H), 6.46 (s, 1H), 4.09 (t, J=7.6 Hz, 1H), 3.59 (q, J=6.0 Hz, 1 H), 2.60 (dd, J=6.8, 16.4 Hz, 1 H), 2.53 (dd, J=8.4, 16.4 Hz, 1 H), 1.38 (broad, 2 H), 1.14 (d, J=6.8 Hz, 3 H); 13CNMR (100 MHz, CDCl3) δ 144.81, 144.36, 136.15, 134.67, 132.51, 130.52, 130.41, 127.98, 127.77, 127.60, 127.34, 126.70, 120.93, 120.90, 51.91, 43.77, 32.86, 22.11; ESI MS m/z 318.0.
Reaction SMILES: C(OC([N:8]1[CH:12]([CH:13]=[C:14]=[CH2:15])[CH2:11][C:10]([SeH])(C2C=CC=CC=2)[C:9]1=[O:23])=O)(C)(C)C.C=C=C.C[OH:28]>>[NH2:8][CH:12]([CH:13]=[C:14]=[CH2:15])/[CH:11]=[CH:10]/[C:9]([OH:23])=[O:28]
Reactant: CO
Reactant: C=C=CC1CC([SeH])(c2ccccc2)C(=O)N1C(=O)OC(C)(C)C
Agent: C=C=C
Product: C=C=CC(N)/C=C/C(=O)O

Procedure:
To ethyl 4-amino-5,6-heptadienoate hydrochloride in chloroform containing one equivalent of NEt3, was added 1.0 equivalent of di-tert-butyl-dicarbonate at 0° C. The reaction mixture was then warmed to room temperature and left overnight. Dilution with chloroform was followed by washing with water, brine, drying over anh. MgSO4, and concentration in vacuo to give ethyl-4-N-tert-butoxycarbonyl-5,6-heptadienoic as an oil. This was added in dry THF to an LDA solution (2.2 equivalents) at -70° C., dropwise, and under argon. One hour after the addition, 1.0 equivalents of phenylselenium bromide was added according to the method of Sharpless et al, JACS, 6137, 1973. After 1 hour the reaction mixture was warmed to 0° C. and quenched with 10% acetic acid and extracted repeatedly with CH2Cl2. The organic fractions were combined, washed with 5% NaHCO3, brine, dried over anh. MgSO4 and concentrated to an oil. Partial purification by chromatography on SiO2 gave three allene products; starting material, ethyl-4 -N-tert-butoxycarbonyl-2-phenylselenyl-5,6-heptadienoate, and N-tert-butoxycarbonyl-5-(1,2-propadien-1-yl)-3-phenylselenyl-2-pyrrolidone. The allene samples were dissolved in methanol and treated with 3.0 equivalents of NaIO4 at room temperature overnight. The reaction mixture was then concentrated, diluted with water and extracted repeatedly with CH2Cl2 to give after drying over anh. MgSO4 and concentration, an oil consisting of cis- and trans-ethyl-4-N-tert-butoxycarbonyl-2,5,6-trienoate. This was partially purified on SiO2. The allene fractions were combined and treated with a 1:1 solution of THF: 20% HCl at reflux for two days. Water was added to the reaction mixture and the latter extracted with ether. Ion-exchange chromatography (Ag 50 W×8), eluting with 20% pyridine water gave a residue which on purification by HPLC (RP-18) gave trans-4-amino-2,5,6-heptatrienoic acid. 'H NMR (δD2O): 4.5 (m, 1H, HCN), 5.1-5.3 (m, 2H, H2C=C=C), 5.35-5.65 (m, 1H, CH=C=C), 6.1 (dd, 1H, J=0.65, 15.8 Hz, HC=C), 6.5 (dd, 1H, J=6.3, 15.8 Hz, HC=C); mass spectrum, m/e 100; MH+ 140, (MH-H2O 122), (MH±NH2 124), 100.
Reaction SMILES: [Br:1][CH:2]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][C:17]([CH2:19][CH3:20])=[CH:18][C:5]=2[NH:4][C:3]1=[O:21].[CH3:22][C:23]1([NH:29][C:30](=[O:33])[CH2:31]I)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:22][C:23]1([NH:29][C:30](=[O:33])[CH2:31][N:4]2[C:5]3[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[CH:15][C:6]=3[CH:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:8][CH:2]([Br:1])[C:3]2=[O:21])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC1(NC(=O)CI)CCCCC1
Reactant: CCc1ccc2c(c1)NC(=O)C(Br)CC2c1ccccc1
Product: CCc1ccc2c(c1)N(CC(=O)NC1(C)CCCCC1)C(=O)C(Br)CC2c1ccccc1
Yield: 80 %

Procedure:
Prepared as in Example 20I from 3-bromo-5-phenyl-8-ethyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one using N-(1-methylcyclohexyl)-iodoacetamide, M.P. 156°-158° C., 80% yield for the trans isomer.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:19])([CH3:18])[O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([O:12][CH3:13])=[O:11])([CH3:4])[CH3:3].[Br:20]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:17][C:16]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:18])[CH3:19]
Reactant: COC(=O)c1ccc(C)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 3-[(1,1-dimethylethyl)dimethylsilyl]oxy-4-methylbenzoate (11.36 g, 40.5 mmol) from Preparation 13, N-bromosuccinimide (6.5 g, 36.5 mmol), and AIBN 100 mg, 0.61 mmol) in CCl4. The reaction mixture is stirred at room temperature for 1 hour while exposed to a high intensity light bulb. The precipitate is removed by suction filtration and the filtrate is concentrated. The residue is purified by silica gel chromatography (1% tetrahydrofuran/petroleum ether). An oil of methyl 4-(bromomethyl)-3-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]benzoate is obtained 99.87 g, 75%).
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([NH:24][CH2:25][C:26]2[CH:30]=[CH:29][S:28][CH:27]=2)[N:20]=[C:19]([Cl:31])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C>CO.Cl>[Cl:31][C:19]1[NH:20][C:21]([NH:24][CH2:25][C:26]2[CH:30]=[CH:29][S:28][CH:27]=2)=[C:22]([F:23])[C:17](=[N:9][NH2:8])[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NCc2ccsc2)c1F
Agent: Cl
Solvent: CO
Product: NN=c1nc(Cl)[nH]c(NCc2ccsc2)c1F
Reaction time: 8 h

Procedure:
Tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(3-thienylmethyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (1.6214 g, 2.83 mmol) was dissolved in MeOH (28 mL) and HCl (4M in 1,4-dioxane) (28 mL). The reaction mixture was left to stir overnight and then evaporated to provide 2-chloro-5-fluoro-6-[(3-thienylmethyl)amino]-4(1H)-pyrimidinone hydrazone, presumed dihydrochloride, as a wine colored solid (1.0828 g). LCMS: (M+H−2HCl)+=273.9.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][S:10]([CH3:12])=[O:11].[NH3:14]>>[NH:14]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])[CH2:9][S:10]([CH3:12])=[O:11]
Reactant: N
Reactant: CS(=O)CC(=O)c1ccccc1O
Product: CS(=O)CC(=N)c1ccccc1O
Yield: 79 %

Procedure:
A solution of 2'-hydroxy-2-(methylsulfinyl)acetophenone (23.5 g, 0.12 mole) in liquid ammonia (450 ml) was stirred at -33° for 9 hrs. The ammonia was allowed to evaporate. The residue was recrystallized from methanol to give yellow crystals (18.5 g, 79%), mp 194°-195°.
Reaction SMILES: S([O-])(O)(=O)=O.[Na+].[CH2:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15]OC=C)[CH:8]1[O:10][CH2:9]1.C(=O)([O-])[OH:20].[Na+]>O>[CH2:7]([O:11][CH:12]([OH:20])[CH2:13][CH2:14][CH3:15])[CH:8]1[O:10][CH2:9]1
Reactant: C=COCCCCOCC1CO1
Reactant: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: CCCC(O)OCC1CO1
Reaction time: 1 h
Yield: 94 %

Procedure:
A 1-L four-necked separable flask was charged with 5.0 g of sodium hydrogen sulfate and 140 g of pure water and then provided with a stirrer, a thermometer, an air-introducing tube, and a vacuum pump with a cooling trap. With stirring, 500 g of vinyloxybutyl glycidyl ether synthesized in Example 1 was gradually added to the flask while the liquid temperature was controlled to be kept at 40° C. After the addition was completed, the pressure was reduced to 20 kPa. The mixture was continuously stirred for 1 hour while dry air was introduced at 100 ml/minute. The reaction liquid was then analyzed by gas chromatography. As a result, no peak was observed for vinyloxybutyl glycidyl ether. Subsequently, 26 g of a 0.04% sodium hydrogen sulfate aqueous solution was added to the reaction liquid. While the temperature was kept at 40° C., the mixture was subjected to an acetal decomposition reaction at a pressure of 5 kPa. After 1 hour, the reaction was completed. After 2.1 g of sodium hydrogen carbonate was added to neutralize the completed reaction liquid, the liquid was concentrated by removing water from the system by distillation using a rotary evaporator. After it was checked that the content of water in the system was 800 ppm or less, the liquid concentrate was filtered and then subjected to distillation (0.4 kPa, distillation temperature 82° C.) using a reduced-pressure distillation apparatus with a Vigreux column, so that butanediol glycidyl ether was obtained with a purity of 99% and a yield of 94%. At the time, the resulting product contained 0.03% of butanediol, and no acetal dimer was detected.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH:7](=O)[CH:8]([CH3:10])[CH3:9].C1CCCCC1>O>[CH3:1][N:2]1[CH2:3][CH2:4][CH2:5][NH:6][CH:7]1[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)C=O
Reactant: CNCCCN
Solvent: C1CCCCC1
Solvent: O
Product: CC(C)C1NCCCN1C

Procedure:
530 g of N-methyl-1,3-diaminopropane are slowly added dropwise to a mixture of 650 ml of isobutyraldehyde and 400 ml of cyclohexane cooled with ice. When the exothermic reaction has died down, the reaction mixture is boiled under reflux on a water separator until approximately 108 ml of water have been separated. Cyclohexane and isobutyraldehyde are distilled off at reduced pressure. Fractional distillation of the residue (b.p.15 : 68° to 75° C.) yields 680 g of 1-methyl-2-isopropylhexahydropyrimidine.
Reaction SMILES: [Br:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([SH:7])=[N:5][N:6]=1.Br[C:22]([CH3:31])([CH3:30])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([S:7][C:22]([CH3:31])([CH3:30])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[N:5][N:6]=1
Reactant: Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Yield: 75.4 %

Procedure:
A solution of 5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (prepared as described above; 500 mg, 1.444 mmol) and tert-butyl 2-bromo-2-methylpropanoate (270 μL, 1.444 mmol) and diisopropylethylamine (755 μL, 4.332 mmol) in DMF (3 mL) was heated at 60° C. for 20 hours. The mixture was then concentrated, diethyl ether (15 mL) was added and the mixture was sonicated until all solids dissolved. The solution was then washed with HCl with (1N, 10 mL) and extracted with diethyl ether (2×15 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to afford tert-butyl 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate as a light brown foam (532 mg, 75% yield).