Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[CH3:12]I.C>[OH-].[Na+]>[CH3:12][S:1][C:2]1[N:7]=[C:6]([OH:8])[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1
Reactant: CI
Reactant: Oc1nc(S)nc2ccnn12
Agent: [Na+]
Agent: [OH-]
Product: CSc1nc(O)n2nccc2n1
Temperature: 5 °C
Reaction time: 0.29 h

Procedure:
Seven grams of 2-mercaptopyrazolo[1,5-a][1,3,5]triazin-4-ol (prepared according to the method described in Chemische Berichte, 1971, 104:3039-47) was dissolved in 5% aqueous NaOH (100 mL). The solution was cooled to 5° C. (ice bath) and 6 g. of methyl iodide was added dropwise. After 15-20 minutes, charcoal was added and the mixture was filtered then acidified with acetic acid. The precipitate (2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-ol was filtered, dried and isolated. Further recrystallization in AcOH gave 2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-ol. MS (ES+): 183.0 (M+1)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].Br[CH:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16]>C1C=CC=CC=1.CN(C)C=O>[O:16]=[C:12]1[CH:11]([N:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]2=[O:9])[CH2:15][CH2:14][O:13]1
Reactant: O=C1CCCCN1
Reactant: O=C1OCCC1Br
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C1OCCC1N1CCCCC1=O
Temperature: 60 °C
Reaction time: 5 h
Yield: 107 %

Procedure:
1.25 g (0.05 mol) of sodium hydride (2.5 g of a 50% commercial suspension in paraffin, previously washed twice with benzene) are suspended in 50 ml of anhydrous N,N-dimethylformamide. A solution of 4.95 g (0.05 mol) of 2-piperidinone in 20 ml of N,N-dimethylformamide is added dropwise to the suspension. The mixture is then heated to 60° C. until no more gas is evolved, whereafter it is cooled. A solution of 8.25 g (0.05 mol) of 3-bromodihydro-2(3H)-furanone in 20 ml of anhydrous N,N-dimethylformamide is added dropwise while keeping the temperature at 5° to 10° C. The mixture is then stirred at 60° C. for 5 hours. N,N-Dimethylformamide is evaporated off under reduced pressure. The residue is taken up in chloroform and the insoluble matter filtered off on Norit. The filtrate is again evaporated and 9.8 g of a heavy syrup are obtained. Mass spectrum: M+. at 183 m/e.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][CH2:12][OH:13])[N:3]=1.[CH3:14][NH2:15]>O>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([NH:15][CH3:14])[N:4]([CH2:11][CH2:12][OH:13])[N:3]=1
Reactant: O=[N+]([O-])c1c(Br)nn(CCO)c1Br
Reactant: CN
Solvent: O
Product: CNc1c([N+](=O)[O-])c(Br)nn1CCO
Yield: 91 %

Procedure:
3.15 g (10 mmoles) of 3,5-dibromo-1-(2'-hydroxyethyl)-4-nitropyrazole are heated in 70 ml of a 30-percent solution of methylamine in water for 1 hour at 60° C. After cooling, the product precipitates in the form of bright yellow crystals with a melting point of 158° to 160° C. 2.4 g (91 percent of theory) of 3-bromo-1-(2'hydroxyethyl)-5-methylamino-4-nitropyrazole are obtained.
Reaction SMILES: [F:1][C:2]1([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)[CH2:4][CH:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:20]CCl.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[F:1][C:2]1([C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:20])=[O:16])=[CH:13][CH:12]=2)[CH2:4][CH:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClCCl
Reactant: O=C(O)c1ccc(C2(F)CC2c2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(C2(F)CC2c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
0.35 g of 4-(1-fluoro 2-phenyl cyclopropyl) benzoic acid (mixture (B)), obtained according to Preparation 1, and 20 cm3 of dichloromethane are mixed together under an inert gas atmosphere, the mixture is cooled down to 0° C., 0.207 g of commercial oxalyl chloride and 0.01 cm3 of dimethylformamide are added, the whole is agitated for 3 hours at 20-25° C. and brought to dryness in order to collect the acid chloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH:9][CH3:10])[C:3]=1[N+:11]([O-:13])=[O:12].[NH3:14]>O.C(O)C>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH3:10])[C:3]([N+:11]([O-:13])=[O:12])=[C:2]([NH2:14])[CH:7]=1
Reactant: N
Reactant: CNc1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Solvent: CCO
Solvent: O
Product: CNc1cc(Cl)cc(N)c1[N+](=O)[O-]

Procedure:
0.034 mole (7.5 g) of 2,4-dichloro-6-methylaminonitrobenzene is added in an autoclave to 100 ml of a 28% strength solution of ammonia in water and 50 ml of ethanol. The reaction mixture is heated to 145°-150° C. for 12 hours, the pressure being 12 kg/cm2. After cooling, the expected product precipitates from the reaction mixture. After being filtered off and reslurried in water, it is dried hot under vacuum in the presence of phosphorus pentoxide. Recrystallized from isopropanol, it melts at 129° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[CH:12][C:7]=2[N:6]=[CH:5]1)([CH3:3])[CH3:2].[Br:14]Br.N.CO.C(Cl)Cl>CC(O)=O>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[C:12]([Br:14])[C:7]=2[N:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cnc2cc(N)ccc21
Reactant: BrBr
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)n1cnc2c(Br)c(N)ccc21
Yield: 35 %

Procedure:
To a solution of 1-isopropyl-5-aminobenzimidazole (2.4 g, 14 mmol) in 20 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 1.2 g (4.5 mmol, 35%) of the product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:27])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl.O>[CH3:15][O:14][C:13]1[C:12]([O:16][CH3:17])=[CH:11][CH:10]=[C:9]([C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:27])[C:8]=1[O:7][CH2:6][C:3]1([CH2:2][NH:1][C:35](=[O:37])[CH3:36])[CH2:4][CH2:5]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)CC2)c1OC
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CNC(C)=O)CC2)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 4-[2-(1-aminomethyl-cyclopropylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 182) (100 mg, 0.272 mmol) in dichloromethane (10 mL), were added triethylamine (0.082 g, 0.811 mmol) and acetyl chloride (42 mg, 0.544 mmol) and the resultant reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined dichloromethane layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-2% methanol in dichloromethane) afforded the title compound as a solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[CH2:14][NH:15][CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1)[CH2:6][NH:7][C:8](=[O:10])[CH3:9].[Cl:26][C:27]1[CH:28]=[C:29]([CH3:35])[C:30]([CH:33]=O)=[N:31][CH:32]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:26][C:27]1[CH:28]=[C:29]([CH3:35])[C:30]([CH2:33][N:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:5]([CH2:6][NH:7][C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[CH2:2][OH:1])[CH:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)=[N:31][CH:32]=1
Reactant: CC(=O)NCc1ccc(CNC2CCCc3cccnc32)c(CO)c1
Reactant: Cc1cc(Cl)cnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCc1ccc(CN(Cc2ncc(Cl)cc2C)C2CCCc3cccnc32)c(CO)c1

Procedure:
Using General Procedure B: Reaction of N-{3-hydroxymethyl-4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzyl}-acetamide in CH2Cl2 with 5-chloro-3-methyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave N-(4-{[(5-chloro-3-methyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzyl)-acetamide as a white foam. 1H NMR (CDCl3) δ 1.58 (m, 1H), 2.03 (s, 3H), 2.04 (m, 1H), 2.18 (m, 1H), 2.24 (s, 3H), 2.65 (m, 1H), 2.79 (m, 1H), 3.69 (dd, 2H, J=12.0, 3.0 Hz), 3.79 (d, 1H, J=12.0 Hz), 3.89 (t, 1H, J=9.0 Hz), 4.12 (d, 1H, J=12.0 Hz), 4.21 (m, 1H), 4.39 (d, 2H, J=6.0 Hz), 4.41 (m, 1H), 5.67 (br s, 1H), 7.01 (dd, 1H, J=7.5, 3.0 Hz), 7.14 (d, 1H, J=6.0), 7.24-7.30 (m, 3H), 7.39 (s, 1H), 8.28 (s, 1H), 8.36 (d, 1H, J=3.0 Hz). 13C NMR (CDCl3) δ 18.2, 20.8, 21.7, 23.3, 29.3, 43.4, 53.0, 54.0, 54.3, 57.7, 62.6, 65.9, 121.7, 127.1, 130.6, 131.1, 131.3, 134.6, 135.4, 136.1, 136.7, 137.6, 138.1, 142.4, 144.5, 146.6, 154.6, 156.7, 169.8. HPLC: 97%. ES-MS m/z 479 [M+H]+, 501 [M+Na]+. Anal. Calcd. for C27H31N4O2Cl.0.5 CH2Cl2: C, 62.69; H, 6.24; N, 10.63; Cl, 13.46. Found: C, 62.52; H, 6.18; N, 10.47; Cl, 13.59.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:24]1([C:30](=[O:33])[CH2:31][CH3:32])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH:18]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:27]3[CH2:28][CH2:29][N:24]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:25][CH2:26]3)=[CH:14][N:15]=2)=[O:9])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CCC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Yield: 14.4 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (60 mg, 0.18 mmol), 1-piperazinyl-1-propanone (39 mg, 0.22 mmol), catalytic acetic acid and sodium triacetoxyborohydride (47 mg, 0.22 mmol) to afford 12 mg (15%) of the desired product after purification.
Reaction SMILES: C[SiH2][O:3][Si:4]([CH3:7])([CH3:6])C.[Cl:8][Si:9]([Cl:12])(Cl)Cl.C(N(CCCC)CCCC)CCC>C(Cl)Cl>[CH3:6][SiH:4]([CH3:7])[O:3][Si:9]([Cl:12])([Cl:8])[O:3][SiH:4]([CH3:6])[CH3:7].[CH3:6][SiH:4]([CH3:7])[O:3][Si:9]([Cl:12])([O:3][SiH:4]([CH3:6])[CH3:7])[O:3][SiH:4]([CH3:7])[CH3:6]
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: C[SiH2]O[Si](C)(C)C
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: C[SiH](C)O[Si](Cl)(Cl)O[SiH](C)C
Product: C[SiH](C)O[Si](Cl)(O[SiH](C)C)O[SiH](C)C
Temperature: 25 °C
Reaction time: 116 h

Procedure:
A mixture containing 536 g (4.0 mol) of tetramethyldisiloxane, 170 g (1.0 mol) of tetrachlorosilane and 2 ml of a 25% solution of phosphonitrile chloride in methylene chloride is stirred at room temperature for 116 hours. About 1.1 ml of tri-n-butylamine are then added to deactivate the phosphonitrile chloride. The reaction mixture is stirred for 30 minutes and then subjected to fraction distillation. About 17 g of 1,1,5,5-tetramethyl-3,3-dichlorotrisiloxane are obtained at 30° to 43° C. and at 10 mbar, and 98 g of 1,1,5,5-tetra methyl-3-chloro-3-dimethylsiloxytrisiloxane are obtained at 44° to 47° C. and at 10 mbar, but the desired 1,1,5,5-tetramethyl-3,3-bis(dimethylsiloxy)trisiloxane is not obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16].O=[C:26]([CH3:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1>[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]2[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=3)[C:10](=[O:11])[NH:12]2)=[CH:19][CH:18]=1)#[N:16]
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1ccc(C=O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
7.0 g (34.29 mmol) N-[3-(trifluoromethyl)phenyl]urea, 8.99 g (68.58 mmol) 4-cyanobenzaldehyde, 8.92 g (68.58 mmol) ethyl 3-oxobutanoate and 20 g polyphosphoric acid ethyl ester are suspended in 250 ml of tetrahydrofuran. The mixture is stirred at reflux for 18 hours. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate as eluent.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[N:8]=[CH:7][C:6]([C:9](=[CH2:13])C([O-])=O)=[CH:5][CH:4]=1.NC1N=CC(/C=C/[C:24]([O:26]CC2C=CC=CC=2)=[O:25])=CC=1>>[CH3:14][N:2]([CH3:1])[C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:13]/[C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1
Reactant: C=C(C(=O)[O-])c1ccc(N(C)C)nc1
Reactant: Nc1ccc(/C=C/C(=O)OCc2ccccc2)cn1
Product: CN(C)c1ccc(/C=C/C(=O)O)cn1
Yield: 36 %

Procedure:
According to the procedure of Preparation 2 (b), except substituting benzyl (E)-3-[6-(dimethylamino)pyridin-3-yl-acrylate for benzyl (E)-3-(6-aminopyridin-3-yl)acrylate, the title compound (0.20 g, 36%) was prepared as a white solid: MS (ES) m/e 193 (M+H)+.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:9]2[C:10](=[O:24])[N:11]([CH3:23])[CH2:12][C:13]3[N:14]([CH:15]=[N:16][C:17]=3[C:18]#[C:19][CH:20]([OH:22])[CH3:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH3:25]I>CN(C)C=O>[Cl:3][C:4]1[C:9]2[C:10](=[O:24])[N:11]([CH3:23])[CH2:12][C:13]3[N:14]([CH:15]=[N:16][C:17]=3[C:18]#[C:19][CH:20]([O:22][CH3:25])[CH3:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CC(O)C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(C)C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reaction time: 1 h

Procedure:
4.0 g (69.5 mmol) of freshly powdered potassium hydroxide was stirred for 10 minutes in 40 ml of N,N-dimethylformamide and cooled to 10°. 5.48 g (17.3 mmol) of 7-chloro-4,5-dihydro-3-(3-hydroxy-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one and 4.94 g (35 mmol) of methyl iodide were added thereto in succession, the ice-bath was removed and the mixture was stirred for a further 1 hour. The reaction mixture was poured into 200 ml of water and extracted five times with methylene chloride. The combined organic extracts were washed four times with water, dried over magnesium sulphate and evaporated. After recrystallization of the residue from ethyl acetate there was obtained 7-chloro-4,5-dihydro-3-(3-methoxy-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]-benzodiazepin-6-one of melting point 139°-141°.
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:12]2([CH2:17][CH2:16][C:15](=[CH:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:13]2)[S:11][CH:10]([CH2:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[C:9]1=[O:30])(C)(C)C.Cl>C(OCC)C.O1CCOCC1>[CH:27]([O:26][C:24](=[O:25])[CH2:23][CH:10]1[C:9](=[O:30])[N:8]([CH2:7][C:6]([OH:31])=[O:5])[C:12]2([CH2:13][CH2:14][C:15](=[CH:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:17]2)[S:11]1)([CH3:29])[CH3:28]
Reactant: CC(C)CC=C1CCC2(CC1)SC(CC(=O)OC(C)C)C(=O)N2CC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)CC=C1CCC2(CC1)SC(CC(=O)OC(C)C)C(=O)N2CC(=O)O
Reaction time: 2 h
Yield: 27.7 %

Procedure:
In 3 ml of diethyl ether was dissolved 0.33 g of isopropyl 2-[4-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-2-yl]-acetate. Then, 1 ml of a 5.39 mol/L solution of dry hydrogen chloride in dioxane was added and the resulting mixture was stirred at the same temperature as above for 2 hours. Further, 1 ml of 5.39 mol/L solution of dry hydrogen chloride in dioxane was added and the resulting mixture was stirred for one hour, after which 3 ml of 5.39 mol/L solution of dry hydrogen chloride in dioxane was added and the resulting mixture was stirred for one hour. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography [eluent: chloroform]. Then, hexane was added, and the deposited crystal was collected by filtration. Thus, 0.08 g of 2-[2-(2-isopropoxy-2-oxoethyl)-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-acetic acid was obtained as a colorless crystalline product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[N:32]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1.CN(C1C=CC=CN=1)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][N:8]([C:37]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:38])[CH2:7][CH2:6]1)=[O:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Reactant: O=C(Cl)N1CCCC1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)N3CCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.6 %

Procedure:
To a solution of 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (400 mg, 1.03 mmol) in chloroform (10 ml) was added triethylamine (208 mg, 2.06 mmol), pyrrolidinecarbonyl chloride (206 mg, 1.54 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 400 mg (87%) of the product as a solid; MS-ES: m/z 449.3 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:11](Cl)(=[O:13])=[O:12])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl.O>[C:15]([NH:19][S:11]([C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10])(=[O:13])=[O:12])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)N
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)NC(C)(C)C)s1

Procedure:
To a suspension of 2-(acetylamino)-4-methyl-1,3-thiazole-5-sulfonyl chloride (1.0 g) in DCM (10 ml) was added tert-butylamine (0.92 ml) and the mixture was stirred at room temperature for 2d. The mixture was diluted with H2O and extracted with DCM (×3). The combined organic extracts were dried (MgSO4), filtered and evaporated to give the subtitle compound as a beige foam. Yield 1.1 g.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[C:9]([CH:12]=C)[CH:8]=[CH:7][C:6]=2[C:5]2=[N:14][O:15][C:16]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])=[C:4]2[CH2:3]1.[O:32]=[O+][O-].C(N(CC)CC)C>ClCCl>[CH3:1][N:2]1[C:11]2[CH:10]=[C:9]([CH:12]=[O:32])[CH:8]=[CH:7][C:6]=2[C:5]2=[N:14][O:15][C:16]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])=[C:4]2[CH2:3]1
Reactant: O=[O+][O-]
Reactant: C=Cc1ccc2c(c1)N(C)Cc1c-2noc1-c1onc(-c2ccccc2)c1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1Cc2c(noc2-c2onc(-c3ccccc3)c2C(F)(F)F)-c2ccc(C=O)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-methyl-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-4,5-dihydroisoxazolo[4,3-c]quinoline (Preparation 77F, 0.020 g, 0.047 mmol) in Dichloromethane (5 mL) at −78° C. was passed ozone from an ozone generator until the solution turned a deep blue. The reaction mixture then was purged with oxygen until the blue color disappeared, then with nitrogen for five minutes. The reaction mixture was allowed to warm to room temperature and triethylamine (5.07 μl, 0.036 mmol) was added. The reaction mixture was stirred at room temperature for fifteen minutes, and then concentrated under vacuum to give 5-methyl-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydroisoxazolo[4,3-c]quinoline-7-carbaldehyde as a tan solid. (0.015 mg, 0.035 mmol, 74%). The product had an HPLC ret. time=3.61 min. (condition B). LC/MS M+1=426.1 min
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:5]=[N:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1.ClCC1C(C(F)(F)F)=NC=CC=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@:26]2([C:44]3[C:35](=[CH:36][C:37]4[O:42][CH2:41][CH2:40][O:39][C:38]=4[CH:43]=3)[O:34][CH2:33]2)[C:25]1=[O:45].N1C2C(=CC=CC=2)C2(C3C(=CC4OCCOC=4C=3)OC2)C1=O>>[CH3:11][O:10][C:7]1[N:6]=[CH:5][C:4]([CH2:3][N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C@@:26]3([C:44]4[C:35](=[CH:36][C:37]5[O:42][CH2:41][CH2:40][O:39][C:38]=5[CH:43]=4)[O:34][CH2:33]3)[C:25]2=[O:45])=[CH:9][N:8]=1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: COc1ncc(CCl)cn1
Agent: Cl
Agent: FC(F)(F)c1ncccc1CCl
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Product: COc1ncc(CN2C(=O)[C@@]3(COc4cc5c(cc43)OCCO5)c3ccccc32)cn1

Procedure:
Following the procedure as described in Example 5.9 and making non-critical variations using 5-(chloromethyl)-2-methoxypyrimidine hydrochloride to replace 3-(chloromethyl)-2-(trifluoromethyl)pyridine, and (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, (8S)-1′-[(2-methoxypyrimidin-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (54%) as a colorless solid: mp 102-104° C.; 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 2H), 7.30-7.22 (m, 1H), 7.21-7.15 (m, 1H), 7.11-7.02 (m, 1H), 6.85-6.81 (m, 1H), 6.51 (s, 1H), 6.17 (s, 1H), 4.98-4.77 (m, 3H), 4.66-4.61 (m, 1H), 4.24-4.09 (m, 4H), 4.00 (s, 3H); 13C NMR (300 MHz, CDCl3) δ 177.5, 165.4, 158.8, 155.2, 144.7, 141.2, 138.4, 132.2, 128.9, 124.3, 123.9, 122.7, 120.5, 111.4, 108.5, 99.5, 80.1, 64.5, 63.9, 57.9, 55.1, 38.9; MS (ES+) m/z 417.8 (M+1); Anal. Calcd for C23H19N3O5: C, 66.18; H, 4.59; N, 10.07. Found: C, 65.94; H, 4.68; N, 9.77.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH2:31][CH:32]=[O:33])[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[NH2:34][C@@H:35]([CH3:38])[CH2:36]O.C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:5]3[C:3](=[O:4])[N:34]4[C@@H:35]([CH3:38])[CH2:36][O:33][C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: C[C@H](N)CO
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(OCc4ccccc4)c3C(=O)N12
Yield: 95.2 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (100 mg, 0.22 mmol) and (2S)-2-amino-1-propanol (0.10 mL, 1.28 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (3S,11aR)—N-[(4-fluorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (100 mg, 95%). This material was hydrogenated in a second step as described in example Z-2 to give (3S,11aR)—N-[(4-Fluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (80 mg, 99%) as a white solid, 1H NMR (CDCl3) δ 11.43 (br, 1H), 10.28 (br, 1H), 8.35 (s, 1H), 7.28 (m, 2H), 6.97 (m, 2 E), 5.29 (m, 1H), 4.55-4.38 (m, 5H), 3.89 (apparent t, J=10.8 Hz, 1H), 3.70 (m, 1H), 1.45 (d, J=5.6 Hz, 3H); ES+ MS: 386 (M−1),
Reaction SMILES: [OH:1][CH:2]([PH:4](=[O:6])[OH:5])[CH3:3].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>CO>[OH:1][CH:2]([PH:4](=[O:5])[O-:6])[CH3:3].[NH2+:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: CC(O)[PH](=O)O
Reactant: C1COCCN1
Solvent: CO
Product: C1COCC[NH2+]1
Product: CC(O)[PH](=O)[O-]

Procedure:
To a solution of α-hydroxyethylphosphinic acid (330 mg) in methanol, a solution of morpholine (261 mg) in methanol (1 ml) was added, and the resultant mixture was stirred for 2 hours. After removal of methanol by distillation, there was obtained morpholinium α-hydroxyethylphosphinate (Compound No. 14) (556 mg). nD24.5 1.4621.