Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:20][C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][C:14]([C:17]([NH2:19])=O)=[CH:13][N:10]3[C:11](=[O:12])[C:6]=2[CH:5]=1)[CH3:3].C(Cl)(Cl)Cl>P(Cl)(Cl)(Cl)=O>[CH3:3][CH:2]([C:4]1[S:20][C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][C:14]([C:17]#[N:19])=[CH:13][N:10]3[C:11](=[O:12])[C:6]=2[CH:5]=1)[CH3:1]
Reactant: CC(C)c1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)c1cc2c(=O)n3cc(C#N)ccc3nc2s1

Procedure:
2-(1-Methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide (Example 15), 8.7 g (0.0303 mol), in 250 ml of phosphorus oxychloride and 250 ml of chloroform is refluxed on a steam bath for four hours under nitrogen. The chloroform and excess phosphorus oxychloride are evaporated in vacuo and the residue is treated with 2 L of ice water. The resulting precipitate is filtered to give 5.3 g of 2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile; mp 225°-226° C. after recrystallization from pyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][N:15]2[C:38]([N:40]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]C=C)[NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:39])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]>ClCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:9]=[CH:10][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][N:40]([NH:41][C:42]([O:44][C:45]([CH3:47])([CH3:48])[CH3:46])=[O:43])[C:38](=[O:39])[N:15]1[CH:14]([CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=3)[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCCN(NC(=O)OC(C)(C)C)C(=O)N1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCl
Product: CCOC(=O)C12CC1C=CCCCCCN(NC(=O)OC(C)(C)C)C(=O)N1CC(Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)CC1C(=O)N2
Yield: 20.6 %

Procedure:
Compound 16 (200 mg, 0.26 mmol) was dissolved in degassed dichloromethane (30 ml). Hoveyda-Grubbs catalyst II generation (16 mg, 0.026 mmol) was then added and the mixture was refluxed under argon atmosphere overnight. The solvent was then evaporated and the crude product was purified by silica chromatography (1% methanol in ether) which gave the title compound (39 mg, 20%). MS (M+H+) 728.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=[O:14])[O:12][CH2:11][CH2:10][N:9]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1>C(OC(C)C)(=O)C.C(#N)C>[CH2:15]([N:9]1[CH:10]=[CH:11][O:12][C:13](=[O:14])[C@@H:8]1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1OCCN(Cc2ccccc2)C1c1ccc(F)cc1
Solvent: CC(=O)OC(C)C
Solvent: CC#N
Product: O=C1OC=CN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.04 h

Procedure:
To a solution of 3-(4-fluorophenyl)-4-phenylmethyl-2-morpholinone (i.e. N-benzyl-4-fluorophenyl-1,4-oxazin-2-one) (10 g) in isopropyl acetate (110 ml) at room temperature was added a solution of (-)-3-bromocamphor-8-sulphonic acid ((-)-3BCS) (12 g) in acetonitrile (24 ml). Crystallisation began after 2-3 min. The slurry was stirred for 1 h at room temperature. Trifluoroacetic acid (7 ml) was added and the mixture stirred at 65° C. for 3 days. The mixture was cooled to 0-5° C., aged for 1 h. and the solid collected, washed with isopropyl acetate and dried in vacuo at 40° C., to give the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3BCS salt: yield 17.24 g, ee 98.6% (S) isomer. The chiral composition of the remaining liquors was determined as 79%(R), 21%(S). The liquors were stirred at 65° C. for 3 days, then cooled to 0-5° C. The solid was collected, washed with isopropyl acetate and dried in vacuo to give a further batch of the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3BCS salt: yield 0.84 g, ee 98.6% (S) isomer. The chiral composition of the remaining liquors was determined as 64%(R), 36%(S). The liquors were stripped in vacuo and the residue was dissolved in isopropyl acetate (20 ml) containing trifluoroacetic acid (1 ml) and stirred at 65° C. for 20 h. The mixture was cooled to 0-5° C. for 1 h and the solid collected, washed with isopropyl acetate and dried in vacuo to give a further batch of the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3BCS salt: yield 2.2 g, ee 99.2% (S) isomer. Total weight of (-)-3BCS salt: 20.28 g, 97% yield. A sample (0.5 g) of the (-)-3BCS salt was retained and the remainder converted back to free base. The salt was partitioned between isopropyl acetate (50 ml) and water (100 ml) containing 0.88 ammonia soln. (3 ml). The layers were separated and the aqueous phase extracted with isopropyl acetate (25 ml). The combined organic phases were washed with water (25 ml). The organic phase was concentrated to residue and flushed with isopropyl acetate to give the 3-(S)-(4-fluorophenyl)-4-phenylmethyl-2-morpholinone (i.e. N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one) as the free base: yield 8.7 g, 93% recovery, ee 98.4% (S) isomer.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22][CH2:23][C:24](O)=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[C:16](=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[CH2:22][CH2:23][C:24]2=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2CCC(=O)O)CC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)CCc3cc(Cl)ccc32)CC1
Yield: 51.6 %

Procedure:
4-[2-(2-Carboxy-ethyl)-4-chloro-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (3.9 g, 10.1 mmol) and EDC (2.9 g, 15.3 mmol) were set stirring in CH2Cl2 (50 mL) for 2 h. The reaction mixture was dissolved in CH2Cl2 (150 mL), washed with water (2×50 mL) and brine (1×50 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica, 30-50% EtOAc/hexanes) to obtain 1.9 g (52%) of the desired product. TLC (silica, 50% EtOAc/hexanes): Rf=0.67. MS (electrospray): exact mass calculated for C19H25ClN2O3, 364.16. m/z found, 365.1 [M++H]. 1H NMR (400 MHz, CDCl3): 7.14-7.08 (m, 2H), 6.98 (d, J=8.61 Hz, 1H), 4.33-3.98 (m, 3H), 2.75 (t, J=7.83 Hz, 4H), 2.55-2.36 (m, 4H), 1.70-1.65 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:59])[CH:5]=[C:6]([Cl:58])[C:7]=1[CH2:8][C@@H:9]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH:50]([F:52])[F:51])=[C:45]([O:53][CH2:54][CH:55]2[CH2:57][CH2:56]2)[CH:44]=1)[O:10][C:11]([C@H:13]1[N:17]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:42])[NH:28][CH2:29][CH2:30][NH:31][C:32](=[O:41])[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]=O)[CH:34]=3)[CH:22]=2)(=[O:20])=[O:19])[CH2:16][CH2:15][S:14]1)=[O:12].[NH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:59])[CH:5]=[C:6]([Cl:58])[C:7]=1[CH2:8][C@@H:9]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH:50]([F:51])[F:52])=[C:45]([O:53][CH2:54][CH:55]2[CH2:57][CH2:56]2)[CH:44]=1)[O:10][C:11]([C@H:13]1[N:17]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:42])[NH:28][CH2:29][CH2:30][NH:31][C:32](=[O:41])[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][NH:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)[CH:34]=3)[CH:22]=2)(=[O:20])=[O:19])[CH2:16][CH2:15][S:14]1)=[O:12]
Reactant: Nc1ccccc1
Reactant: O=Cc1cccc(C(=O)NCCNC(=O)c2cccc(S(=O)(=O)N3CCS[C@H]3C(=O)O[C@@H](Cc3c(Cl)c[n+]([O-])cc3Cl)c3ccc(OC(F)F)c(OCC4CC4)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(NCCNC(=O)c1cccc(S(=O)(=O)N2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1)c1cccc(CNc2ccccc2)c1
Temperature: 25 °C
Yield: 105.9 %

Procedure:
3,5-Dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((S)-3-((3-((2-(3-formylbenzamido)ethyl)carbamoyl)phenyl)sulfonyl)thiazolidine-2-carbonyl)oxy)ethyl)pyridine 1-oxide (30 mg, 0.034 mmol) was dissolved in DCM (300 μl, 4.66 mmol). Aniline (3.75 mg, 0.040 mmol) and acetic Acid (2.306 μl, 0.040 mmol) were added, and the mixture was stirred at RT for 30′. Sodium triacetoxyborohydride (8.54 mg, 0.040 mmol) was added, and the mixture was stirred at room temperature for 8 hrs to achieve completion. The reaction mixture was diluted with DCM and extracted with water. The organic phase was dried over Na2SO4 and concentrated under vacuum to give 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((S)-3-((3-((2-(3-((phenylamino)methyl)benzamido)ethyl)carbamoyl)phenyl)-sulfonyl)thiazolidine-2-carbonyl)oxy)ethyl)pyridine 1-oxide (35 mg, 0.036 mmol, 107% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][N:20]([CH2:24][CH3:25])[CH2:21][CH2:22][OH:23])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:26][C:27](O)=[O:28]>CO.[Pd]>[C:27]([O:23][CH2:22][CH2:21][N:20]([CH2:19]/[CH:18]=[CH:17]\[C:15]1[CH:14]=[CH:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][S:10][C:11]=2[CH:16]=1)[CH2:24][CH3:25])(=[O:28])[CH3:26]
Reactant: CCN(CC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1)CCO
Reactant: CC(=O)O
Agent: [Pd]
Solvent: CO
Product: CCN(C/C=C\c1ccc2c(-c3ccc(Cl)cc3)nsc2c1)CCOC(C)=O
Yield: 69.9 %

Procedure:
75 mg (0.2 mmol) 2-({3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-ethyl-amino)-ethanol in 2 ml MeOH with 0.012 ml (0.2 mmol) AcOH were hydrogenated in the presence of 7 mg Pd/C 10% (16 h), filtration over decalite and evaporation yielded 58 mg (66%) Z-2-({3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-allyl}-ethyl-amino)-ethanol acetate as light brown oil, MS: 373 (MH+, 1Cl).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(O)(=O)C.[CH:15](N)=[NH:16]>C(OCCO)C>[N:1]1[C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[N:16][CH:15]=1
Reactant: N=CN
Reactant: Nc1ncccc1C(=O)O
Solvent: CC(=O)O
Solvent: CCOCCO
Product: Oc1ncnc2ncccc12
Reaction time: 2 h
Yield: 55.8 %

Procedure:
A mixture of 2-aminonicotinic acid (880 mg, 6.4 mMol) and formamidine acetate (2.0 g, 19.1 mMol) in 2-ethoxyethanol (25 mL) was heated at reflux overnight. The solution was allowed to come to room temperature and stand for 2 hours, then the resulting precipitate was collected by filtration, rinsed with 2-ethoxy ethanol (2×5 mL), diethyl ether (20 mL), and air dried to yield 525 mg of a gray powder as product. MS (ES+)=148 (M+H)+. Yield=56%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:5][NH:6][C:7]([O:9]C(C)(C)C)=O.CS(O)(=O)=O.[C:31]([NH:38][CH2:39][CH2:40]C(O)=O)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(#N)C.O.C(N(CC)CC)C.CN(C=O)C>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[CH2:5][NH:6][C:7](=[O:9])[CH2:40][CH2:39][NH:38][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@H](CNC(=O)CCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product (6.0 g) obtained in the above (3) is dissolved in acetonitrile (10 ml), and thereto is added dropwise a solution of methanesulfonic acid (8.181 g) in acetonitrile (15 ml) at a temperature below 20° C., and the mixture is stirred at room temperature for 30 minutes. At a temperature below 20° C., to the mixture are added dropwise DMF (20 ml), triethylamine (8.608 g) successively, and the mixture is stirred for 10 minutes. To the mixture are added N-Boc-β-alanine (3.547 g) and HOBT.H2O (3.13 g), and then further added thereto WSC.HCl (3.928 g) at a temperature of from 5° to 10° C., and the mixture is stirred for 30 minutes. The mixture is further stirred at room temperature for 12 hours, and poured into water, and extracted three time with ethyl acetate. The organic layer is washed successively with 1N HCl (twice), a saturated aqueous sodium hydrogen carbonate solution (twice) and a saturated brine (twice), and dried over anhydrous magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (silica gel; 400 g, solvent; chloroform/acetone=3:1 to 2:1). The fractions containing the title compound are concentrated under reduced pressure to give the title compound (6.974 g).
Reaction SMILES: [F:1][CH:2]([CH3:13])[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH:9](Br)[CH2:8][CH2:7]1.Cl[SiH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.Cl[SiH]1CCC(C2C=CC(F)=C(F)C=2)CC1>>[F:1][CH:2]([CH3:13])[CH2:3][CH2:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([Si@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH2:8][CH2:7]1
Reactant: FC(F)(F)Oc1ccc(C2CC[SiH](Cl)CC2)cc1
Reactant: CC(F)CCCC1CCC(Br)CC1
Agent: Fc1ccc(C2CC[SiH](Cl)CC2)cc1F
Product: CC(F)CCC[C@H]1CC[C@H]([Si@H]2CC[C@H](c3ccc(OC(F)(F)F)cc3)CC2)CC1

Procedure:
The above compound was obtained in the same manner as Example 6, using 4-(4-fluoropentyl)cyclohexylbromide and 4-(4-chloro-4-silacyclohexyl)-1-trifluoromethoxybenzene instead of 4-(4-fluorobutyl)cyclohexylbromide and 4-(4-chloro-4-silacyclohexyl)-1,2-difluorobenzene, respectively.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=1)(=[O:3])[NH2:2].[Cl:21][C:22]1[CH:23]=[C:24]([S:29]Cl)[CH:25]=[C:26]([Cl:28])[CH:27]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C1(C)C=CC=CC=1.CO.O.C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:8]([S:29][C:24]2[CH:25]=[C:26]([Cl:28])[CH:27]=[C:22]([Cl:21])[CH:23]=2)=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=1)(=[O:3])[NH2:2]
Reactant: ClSc1cc(Cl)cc(Cl)c1
Reactant: CC(C)c1cn(Cc2ccncc2)c(COC(N)=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)c1nc(COC(N)=O)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 153.9 %

Procedure:
The compound (13) (250 mg, 0.91 mmol) was dissolved in N,N-dimethylformamide (4 ml). The solution was cooled down to −30° C. under nitrogen atmosphere. To the solution were added, alternately each four time, a solution of the compound (3) (77 mg, 0.36 mmol) in toluene (150 mg) and a solution of triethylamine (36 mg, 0.36 mg) in toluene (150 mg), and additionally added a solution of the compound (3) (77 mg, 0.36 mmol) in toluene (150 mg). The reaction mixture was stirred at −30° C. for 30 minutes, and ethyl acetate and aqueous sodium hydrogen carbonate were added thereto. The objective (14) was extracted into the ethyl acetate layer. Diluted aqueous hydrochloric acid was added to the ethyl acetate layer to transfer the objective compound into the aqueous layer. The aqueous solution was neutralized by aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give oily residue. The oily residue was dissolved in methanol (0.9 ml), and water (0.7 ml) was added dropwise thereto for 1–2 minutes at room temperature for crystallization. The suspension was stirred for 30 minutes at room temperature, additionally for 30 minutes under ice-cooling, filtered, washed with 50% aqueous methanol, and dried to yield the objective (14) (250 mg) as a white crystal. Yield 61%.
Reaction SMILES: [C:1]1([CH:7]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[C:9]([NH2:23])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN.O1C=CC[CH2:27]1.O>CO>[C:1]1([CH:7]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=3)=[C:9]([NH:23][CH3:27])[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1=COCC1
Reactant: NC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1
Agent: CN
Solvent: CO
Solvent: O
Product: CNC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1

Procedure:
In this example, a mixture containing 0.5 g of 2-phenyl-3-oxo-4-(3-trifluoromethylphenyl)-5-amino-2,3-dihydrofuran ("dihydrofuran starting material") and 25 ml of aqueous 40 wt. % methylamine in 10 ml of methanol was refluxed for 18 hours. The mixture was analyzed by thin-layer chromatography for the dihydrofuran starting material. Another 10 ml of aqueous 40 wt. % methylamine was added and the mixture refluxed for about four hours. The mixture was cooled, poured into 100 ml of water and extracted several times with ethyl ether. The organic extracts were dried over magnesium sulfate, concentrated in vacuo and chromatographed using 3% tetrahydrofuran/chloroform as eluent to yield 0.36 g of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](Cl)(=[O:18])[CH3:17].O>N1C=CC=CC=1>[C:16]([O:15][CH:10]([CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]([F:13])([F:14])[F:12])(=[O:18])[CH3:17]
Reactant: OC(CCCc1ccccc1)C(F)(F)F
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC(CCCc1ccccc1)C(F)(F)F
Reaction time: 2 h
Yield: 98.1 %

Procedure:
18.5 g (85 mmol) of the above product (15-1) was dissolved in 100 ml of pyridine, then added with 7.1 g (90 mmol) of acetyl chloride at 0°-5° C. and stirred at the same temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The resulting organic layer was washed with 10% hydrochloric acid, water, a 5% sodium bicarbonate solution and brine successively in that order, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 21.7 g of 2-acetoxy-5-phenyl-1,1,1-trifluoropentane (16-1) as a pale yellow liquid. Yield: 98%.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH2:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[OH:25]>>[Cl:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][C:5]([C:6]([NH:18][C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[OH:25])=[O:8])=[CH:4][N:3]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 5 d from 6-chloro-5-(4-chloro-phenyl)-nicotinic acid (Example 5 b) and (1R,2R)-2-amino-1-cyclohexanol to yield 6-chloro-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide as a colorless solid, MS (ISP) 364.9, 366.9 (M+H)+.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([CH2:25][CH2:26][NH:27][C:28]([C:30]1[C:35]2[CH:36]=[C:37]([C:40]([F:46])([F:45])[C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:39][C:34]=2[O:33][C:32]([CH3:48])([CH3:47])[CH:31]=1)=O)#[N:24]>C1C=CC=CC=1>[C:23]([CH2:25][CH2:26][NH:27][C:28]([C:30]1[C:35]2[CH:36]=[C:37]([C:40]([F:46])([F:45])[C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:39][C:34]=2[O:33][C:32]([CH3:48])([CH3:47])[CH:31]=1)=[S:10])#[N:24]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)C=C(C(=O)NCCC#N)c2cc(C(F)(F)C(F)(F)F)ccc2O1
Solvent: c1ccccc1
Product: CC1(C)C=C(C(=S)NCCC#N)c2cc(C(F)(F)C(F)(F)F)ccc2O1
Yield: 82.2 %

Procedure:
227 mg of Lawesson's reagent was added to a mixture of 210 mg of N-(2-cyanoethyl)-6-pentafluoroethyl-2,2-dimethyl-2H-1-benzopyran-4-carbamide obtained according to Example 1 and 20 ml of benzene, and the resulting mixture was heated while refluxing for 1 hour. After concentrating the mixture under reduced pressure, the resulting residue was purified by silica gel column chromatography (a developing solution: methylene chloride) to obtain 180 mg of N-(2-cyanoethyl)-6-pentafluoroethyl-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].[CH:15]([C:17]1[CH:18]=[C:19]([O:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])=[O:16]>O1CCCC1.O>[CH:3]1([N:2]([CH3:1])[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][O:26][C:19]2[CH:20]=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:17]([CH:15]=[O:16])[CH:18]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=Cc1cc(OCCCC(=O)Cl)ccc1[N+](=O)[O-]
Reactant: CNC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)CCCOc1ccc([N+](=O)[O-])c(C=O)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a well-stirred solution of N-methyl-N-cyclohexylamine (29.5 ml) and sodium carbonate (28.8 g) in tetrahydrofuran (250 ml) and water (500 ml) cooled to 0° C. in an ice bath was added the tetrahydrofuran solution of the 4-(3-formyl-4-nitrophenyl)oxybutanoic acid chloride from Preparation 3 dropwise. When addition of the acid chloride was completed, the cooling bath was removed and the mixture allowed to stir at room temperature for 1 hour. Most of the tetrahydrofuran was removed by evaporation and the aqueous residue partitioned between ethyl acetate and saturated sodium carbonate (500 ml each). The combined organic layers were washed with additional saturated sodium carbonate (2×20 ml), water (1×100 ml), 1M HCl (2×200 ml) and with brine (2×200 ml) and dried with sodium sulfate. The ethyl acetate was evaporated to give a residue which was crystallized from ethyl acetate to give N-cyclohexyl-N-methyl-4-(3-formyl-4-nitrophenyl)oxybutanamide, (m.p. 98°-100° C.). Alternatively, the extraction residue was chromatographed on silica gel (10% ethyl acetate in dichloromethane as eluant.)
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].O1C[CH2:18][CH2:17][CH2:16]1.C=C([Mg]Br)C>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[C:17]([CH3:18])=[CH2:16])([CH3:14])([CH3:13])[CH3:12]
Reactant: C1CCOC1
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Agent: C=C(C)[Mg]Br
Solvent: CCCCCC
Product: C=C(C)[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Yield: 47 %

Procedure:
In an argon atmosphere, 8.71 g (37.4 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 20 mL of hexane and after adding a (prop-1-en-2-yl)magnesium bromide tetrahydrofuran solution (0.57 mol/L, 69.0 mL, 39.3 mmol), the resulting solution was refluxed for 14 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 80° C./4.3×102 Pa) to obtain 1,3-di-tert-butyl-2-(prop-1-en-2-yl)-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)C(CH3)CH2) as a yellow liquid (yielded amount: 4.18 g, yield: 47%).