Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C(C(=O)C1CNCCO1)C(O)=O)C1C=CC=CC=1.[CH3:20][O:21][C:22](=[O:34])[CH:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:24]([OH:26])=O.C([O:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39])C.[OH-].[Na+]>CO.O>[CH3:20][O:21][C:22]([CH:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:24]([N:43]1[CH2:44][CH2:45][CH:40]([C:38]([OH:39])=[O:37])[CH2:41][CH2:42]1)=[O:26])=[O:34]
Reactant: CCOC(=O)C1CCNCC1
Reactant: COC(=O)C(Cc1ccccc1)C(=O)O
Agent: O=C(O)C(Cc1ccccc1)C(=O)C1CNCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C(Cc1ccccc1)C(=O)N1CCC(C(=O)O)CC1

Procedure:
In a manner analogous to that described for the preparation of α-benzyltetrahydro-β-oxo-4H-1,4-oxazinepropionic acid, benzylmalonic acid monomethyl ester was amidated with piperidine-4-carboxylic acid ethyl ester and the resulting compound [MS: 347 (M)+ ]was saponified with 1N sodium hydroxide solution in a mixture of methanol and water at 0° for 2 hours. The crude product obtained was purified by chromatography on silica gel with a 95:5:2 mixture of chloroform, ethanol and ethyl acetate and recrystallized from a mixture of methanol, methylene chloride and ether, to yield 1-[α-(methoxycarbonyl)hydrocinnamoyl]-4-piperidinecarboxylic acid, melting point 138°.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9]([OH:35])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2OCC(C)(C)C[O:18]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.CCCCCC>CC(C)=O>[C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9]([OH:35])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]=[O:18])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.1 %

Procedure:
In 4 ml of acetone was dissolved 4.9 mg (0.01 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-hydroxypregna-5-en-3β-yl acetate, followed by addition of 1 ml of a 1 mmol/1 solution of p-toluenesulfonic acid in acetone (containing 0.001 mmole of p-toluenesulfonic acid). The mixture was stirred at room temperature for 12 hours. From the reaction mixture thus obtained, the solvent was distilled off under reduced pressure and the residue was diluted with methylene chloride. This methylene chloride solution was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent:ethyl acetate-hexane =1:5, v/v) to recover 2.7 mg of 3β-acetoxy-1α,2α-epoxy-7α-hydroxypregna-5-ene-20-carbaldehyde (yield: 67%).
Reaction SMILES: [CH2:1]([N:8]1[C:18](=[O:19])[CH:12]2[CH2:13][C:14](=O)[CH2:15][CH2:16][CH:11]2[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:21][C:22]1[CH:23]=[C:24]([NH:29]N)[CH:25]=[C:26]([Cl:28])[CH:27]=1>[Cl-].[Zn+2].[Cl-].C(O)(=O)C>[CH2:1]([N:8]1[C:18](=[O:19])[CH:12]2[CH:11]([CH2:16][CH2:15][C:14]3[NH:29][C:24]4[C:23]([C:13]=32)=[C:22]([Cl:21])[CH:27]=[C:26]([Cl:28])[CH:25]=4)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([N:8]1[C:18](=[O:19])[CH:12]2[CH:11]([CH2:16][C:15]3[NH:29][C:24]4[C:23]([C:14]=3[CH2:13]2)=[C:22]([Cl:21])[CH:27]=[C:26]([Cl:28])[CH:25]=4)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC2C(=O)N(Cc3ccccc3)C(=O)C2C1
Reactant: NNc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: O=C1C2CCc3[nH]c4cc(Cl)cc(Cl)c4c3C2C(=O)N1Cc1ccccc1
Product: O=C1C2Cc3[nH]c4cc(Cl)cc(Cl)c4c3CC2C(=O)N1Cc1ccccc1
Yield: 28 %
Yield: 17 %

Procedure:
To 30 ml of acetic acid were added 1.54 g of N-benzyl-4-oxocyclohexane-1,2-dicarboximide, 3.0 g of zinc chloride and 1.54 g of 3,5-dichlorophenylhydrazine hydrochloride. The mixture was refluxed for 2 hours. Acetic acid was removed by distillation under reduced pressure. To the residue were added 150 ml of ethyl acetate and 50 ml of water. The organic layer was separated, washed with diluted hydrochloric acid, an aqueous saturated sodium chloride solution, an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=30/1 to 20/1) to obtain 670 mg (yield: 28%) of N-benzyl-5,7-dichloro-1,2,3,4-tetrahydrocarbazole-3,4-dicarboximide [IR (KBr) cm-1 : 3320, 1770, 1695] and 400 mg (yield: 17%) of N-benzyl-5,7-dichloro-1,2,3,4-tetrahydrocarbazole-2,3-dicarboximide [IR (KBr) cm-1 : 3310, 1765, 1690], both as colorless crystals.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[CH:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([N:26]4[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][C:34]5([CH3:45])[O:38][C:37]6=[N:39][C:40]([N+:42]([O-:44])=[O:43])=[CH:41][N:36]6[CH2:35]5)[CH2:28][CH2:27]4)=[N:24][CH:25]=3)=[C:16]([F:46])[CH:15]=2)[CH2:9]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[F:46][C:16]1[CH:15]=[C:14]([N:10]2[CH2:9][CH:8]([CH2:7][OH:6])[O:12][C:11]2=[O:13])[CH:19]=[CH:18][C:17]=1[C:20]1[CH:25]=[N:24][C:23]([N:26]2[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][C:34]3([CH3:45])[O:38][C:37]4=[N:39][C:40]([N+:42]([O-:44])=[O:43])=[CH:41][N:36]4[CH2:35]3)[CH2:28][CH2:27]2)=[N:22][CH:21]=1
Reactant: CC1(CN2CCCN(c3ncc(-c4ccc(N5CC(C(C)(C)O[SiH2]C(C)(C)C)OC5=O)cc4F)cn3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(CN2CCCN(c3ncc(-c4ccc(N5CC(CO)OC5=O)cc4F)cn3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
To a solution of 5-(tert-Butyl-dimethyl-silanyloxymethyl)-3-(3-fluoro-4-{2-[4-(2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethyl)-[1,4]diazepan-1-yl]-pyrimidin-5-yl}-phenyl)-oxazolidin-2-one (580 mg, 0.84 mmol) in THF (8.0 mL) was added TBAF (3.3 mL, 3.3 mmol, 1.0 M in THF). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc, washed with brine, dried with Na2SO4, purified by flash chromatography to give the title product (100 mg, 21%) as a yellow solid. ESI MS m/z 569 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.60 (dd, J=30, 3.0 Hz, 1H), 7.36 (t, J=20 Hz, 1H), 7.29 (d, J=3.0 Hz, 1H), 7.25 (s, 2H), 4.70 (m, 1H), 4.10 (d, J=25.0 Hz, 1H), 3.95-4.06 (m, 2H), 3.82-3.88 (m, 2H), 3.76 (d, J=23.0 Hz, 1H), 3.64 (dd, J=33, 10.0 Hz, 1H), 3.41-3.58 (m, 2H), 3.31 (bs, 3H), 3.02 (d, J=38.0, 1H), 2.94 (q, J=16.0 Hz, 1H), 2.82-2.84 (m, 1H), 2.70-2.78 (m, 1H), 2.60 (d, J=38.0, 1H), 1.64-1.72 (m, 1H), 1.50-1.58 (m, 1H), 1.48 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C@H:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])=[CH:4][C:3]=1[CH3:24].[C:25]([NH:28][C:29]1[NH:30][C:31](=[O:46])[C:32]([CH2:42][CH2:43][CH:44]=O)=[C:33]([N:35]([C:39](=[O:41])[CH3:40])[C:36](=[O:38])[CH3:37])[N:34]=1)(=[O:27])[CH3:26].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.CO>[C:25]([NH:28][C:29]1[NH:30][C:31](=[O:46])[C:32]([CH2:42][CH2:43][CH2:44][NH:1][C:2]2[CH:23]=[CH:22][C:5]([C:6]([NH:8][C@H:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])=[CH:4][C:3]=2[CH3:24])=[C:33]([N:35]([C:36](=[O:38])[CH3:37])[C:39](=[O:41])[CH3:40])[N:34]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Nc1nc(N(C(C)=O)C(C)=O)c(CCC=O)c(=O)[nH]1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)c(C)c1)C(=O)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CO
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCCCc2c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c2=O)c(C)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Both diethyl N-(4-amino-3-methylbenzoyl)-(L)-glutamate (2.18 g, 6.49 mmoles) and 3-(2-acetylamino-4-diacetylamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propionaldehyde (2.00 g, 6.49 mmoles) were stirred in absolute ethanol (50 mL) under nitrogen while glacial acetic acid (3 mL) was added dropwise during 1 minute. After solution was achieved (1 hour), activated 3 Å molecular sieves (10 mL) were added and stirring was continued 5 hours. The reaction mixture was chilled (ice bath) and sodium cyanoborohydride (408 mg, 6.49 mmoles) added in one portion. After stirring cold 0.5 hour, the bath was removed and the reaction mixture allowed to warm to ambient temperature. The solids were filtered and rinsed with ethanol (100 mL) after 16 hours. The filtrate was spin evaporated to a residue that was partitioned between ethyl acetate and water (100 mL each). The organic phase was separated, washed (1×100 mL 1:1 water/brine), dried (MgSO4), filtered, and spin evaporated to a small volume (15 mL). The solution was chromatographed on silica gel (175 g) using an ethyl acetate rinse (450 mL) followed by elution of the product with 5% added methanol. Like fractions were combined by spin evaporation and dried to give a clear semi-solid; yield, 1.45 g (36%); 1H-NMR (DMSO-d 6) δ 1.15 and 1.16 (2t overlapped, 6H), 1.66 (m, 2H), 2.00 (m, 2H), 2.08 (s, 3H), 2.11 (s, 3H), 2.19 (s, 6H), 2.29 (m, 2H), 2.39 (t, 2H), 3.11 (m, 2H), 3.9-4.1 (2q overlapped, 4H), 4.33 (m, 1H), 5.46 (m, 1H), 6.47 (d, Jo=8 Hz, 1H), 7.53 (s, 1H), 7.57 (d, Jo=8 Hz, 1H), 8.20 (d, 1H), 11.8 (v br s, 1H); uv (MeOH) 301 nm max (31000), 258 min (6050); mass spec (FAB) m/e 628 (8%), 426 (100), 384 (95).
Reaction SMILES: [NH:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:19]12([C:29](Cl)=[O:30])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>>[C:19]12([C:29]([N:1]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:30])[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]3)[CH2:20]1)[CH2:28]2
Reactant: C1COCCOCCOCCOCCOCCN1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Product: O=C(N1CCOCCOCCOCCOCCOCC1)C12CC3CC(CC(C3)C1)C2

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13,16-pentaoxacyclooctadecane and 1-adamantylcarbonyl chloride.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:17]#[N:18])[CH3:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:28][CH2:29][CH2:30][CH2:31]CBr.O>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2([C:17]#[N:18])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:16]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C#N)CN1CCN(Cc2ccccc2)CC1
Reactant: BrCCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC1(CN2CCN(Cc3ccccc3)CC2)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of l-[(4-benzyl-1-piperazinyl)methyl]ethanecarbonitrile (9.0 g/39.3 mmol) in tetrahydrofuran (300 ml) was added dropwise 2.0 M solution of lithium diisopropylamide (98 ml/197 mmol) at −78° C., and then the resulting mixture was stirred for 30 minutes. 1,5-Dibromopentane (8 ml/59 mmol) was added to the mixture in one portion and the resulting mixture was allowed to warm to ambient temperature. The mixture was stirred for 3 hours. Then, H2O (150 ml) was added for quenching. The mixture was extracted with ethyl acetate (200 ml×2). The combined extracts were washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (Si, 230-400 mesh/150 g/dichloromethane:methanol=100:0-100:4) to give a brown solid (11 g/94%).
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][CH2:5][OH:6].Cl.Cl[C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[F:27])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[N+:28]([O-:30])=[O:29]>C(O)(=O)C.O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:13]2[C:12]3[C:17](=[CH:18][CH:9]=[C:10]([N+:28]([O-:30])=[O:29])[CH:11]=3)[N:16]([O:6][CH2:5][CH2:4][O:3][CH3:2])[CH2:15][N:14]=2)=[C:21]([F:27])[CH:22]=1
Reactant: COCCO
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1Cl
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: COCCON1CN=C(Nc2ccc(Cl)cc2F)c2cc([N+](=O)[O-])ccc21
Reaction time: 0.25 h
Yield: 60 %

Procedure:
Sodium (148 mg, 6.4 mmol) was added to 2-methoxyethanol (10 ml), the mixture stirred for 15 minutes to give a complete solution and the volatiles removed by evaporation. The residue was dissolved in DMSO (5 ml) and 7-chloro-4-(4-chloro-2-fluoroanilino)-6 nitroquinazoline hydrochloride (500 mg, 1.3 mmol) was added. The mixture was stirred at ambient temperature for 18 hours then diluted with a solution of acetic acid (1 ml) in water (20 ml). The resulting precipitate was collected by filtration, washed with water, dried and purified by column chromatography eluting with methylene chloride/methanol (96/4). The purified product was recrystallized from methylene chloride/isohexane to give 4-(4-chloro-2-fluoroanilino)-1-(2-methoxyethoxy)-6-nitroquinazoline (304 mg, 60%) as a yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[CH:13](O)([OH:15])[CH3:14]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:7]1([C:5]2([CH2:4][CH2:3][CH2:2][Cl:1])[O:15][CH2:13][CH2:14][O:6]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(O)O
Reactant: O=C(CCCCl)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: ClCCCC1(c2ccccc2)OCCO1
Yield: 111.6 %

Procedure:
4-Chlorobutyrophenone (15.18 g, 0.083 moles), ethanediol (6.80 g, 0.110 moles) and p-toluene sulphonic acid (0.20 g) were heated in toluene at reflux and water was removed from the reaction using a Dean and Stark apparatus. After 17 hours the solvent was removed by distillation in vacuo to leave crude 2-phenyl-2-(3-chloropropyl)-1,3-dioxolane (21 g).
Reaction SMILES: [Cl:1][CH2:2][CH:3]=O.[SH2:5]>S(=O)(=O)(O)O>[Cl:1][CH2:2][CH:3]1[S:5][CH:3]([CH2:2][Cl:1])[S:5][CH:3]([CH2:2][Cl:1])[S:5]1
Reactant: S
Reactant: O=CCCl
Agent: O=S(=O)(O)O
Product: ClCC1SC(CCl)SC(CCl)S1

Procedure:
One typical example of the method for producing an episulfide compound of the invention, 2,4,6-tris(epithiomethylthiomethyl)-1,3,5-trithiane (a compound of the general formula (1) wherein n is 0), is shown as Scheme 1 mentioned below. An aqueous 40 wt. % chloroacetaldehyde solution is dissolved in 70 wt. % sulfuric acid, and hydrogen sulfide is introduced thereinto at −20 to 40° C. for 2 to 100 hours to give 2,4,6-tris(chloromethyl)-1,3,5-trithiane. Alternatives to sulfuric acid as the acidic solvent include any of 60/40 (v/v) 95 wt. % sulfuric acid-acetic acid, or hydrogen sulfide-saturated acetic acid, ether, or 95 wt. % ethanol. To the resulting methanol solution of the thus-formed chlorine compound is added potassium hydroxide with which the chlorine compound is processed at −10 to 40° C. for 0.5 to 10 hours for removal of hydrogen chloride from it to give 2,4,6-trimethylene-1,3,5-trithiane. This is thermally reacted with 3-mercaptopropene sulfide at 0 to 100° C. for 6 to 100 hours in the presence of a radical generator (described below), to obtain the intended product, 2,4,6-tris(epithiomethylthiomethyl)-1,3,5-trithiane.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11](Cl)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[CH2:15]([N:17](CC)CC)C.Cl.CN.C(Cl)(Cl)Cl>ClCCl>[CH3:15][NH:17][S:11]([C:6]1[C:5]2[CH:4]=[CH:3][N:2]=[CH:1][C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1cccc2cnccc12
Reaction time: 18 h
Yield: 77 %

Procedure:
In 50 ml of dichloromethane was dissolved 1.73 g of 5-isoquinolinesulfonyl chloride, and to the solution were added 1.54 g of triethylamine and 8.0 g of monomethylamine hydrochloride. The mixture was stirred at a temperature of 10° C. to 15° C. for 18 hours. The reaction solution obtained was washed with water, dried with magnesium sulfate, and then the dichloromethane was distilled therefrom under reduced pressure. The residue obtained was subjected to a silica gel column chromatography (silica: 50 g; solvent: chloroform) to give 1.30 g of N-methyl-5-isoquinolinesulfonamide, i.e., Compound (25) in a yield of 77%.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10](=[O:31])[NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:7][CH2:8][CH2:9][C:10]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][CH:23]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH3:24])=[O:31]
Reactant: CC(Nc1ncnc2ccc(NC(=O)CCNC(=O)OC(C)(C)C)cc12)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(Nc1ncnc2ccc(NC(=O)CCN)cc12)c1ccccc1
Yield: 46.7 %

Procedure:
250 mg of 2-[4-(1-phenyl-ethylamino)-quinazolin-6-ylcarbamoyl]-ethyl-carbamic acid t-butylester dissolved in 5 ml of methylene chloride was reacted with 5 ml of trifluoroacetic acid at room temperature for 4 hours. The residue obtained from distillation of the reacted solution under a reduced pressure was stirred in 50 ml of saturated aqueous sodium bicarbonate solution for 30 mins, filtered under a reduced pressure, and dried to obtain the title compound (90 mg, 52%).
Reaction SMILES: [CH3:1][S:2]([CH:5]([CH2:15][C:16]#[C:17][C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:4])=[O:3].[H][H]>C(OCC)(=O)C.C1CCCCC1.[Pt]>[CH3:1][S:2]([CH:5]([CH2:15][CH2:16][CH2:17][C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:3])=[O:4]
Reactant: CCCCC[C@H](O)C#CCC(CCCCCCC(=O)O)S(C)(=O)=O
Reactant: [H][H]
Agent: [Pt]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCCCC[C@H](O)CCCC(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
8-Methylsulfonyl-12(S)-hydroxy-10-heptadecynoic acid (36.0 g., 0.10 mole) and 5% platinum-on-charcola catalyst (4.0 g.) are placed in a mixture of ethyl acetate (100 ml.) and cyclohexane (200 ml.) and hydrogenated in a Parr apparatus with an initial hydrogen pressure of 45 pounds per square inch. The uptake of the required 0.2 mole of hydrogen is complete in 20 minutes. The catalyst is removed by filtration and the solvents evaporated to leave the product as a residual oil weighing 33.5 g. It is purified by chromatography on silica gel with benzene-dioxane-acetic acid elution. The title compound is obtained as a nearly colorless viscous oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22].Cl.[N:28]1([CH:33]2[CH2:37][CH2:36][NH:35][CH2:34]2)[CH:32]=[CH:31][N:30]=[N:29]1.N1(C2CCCCCCCCCC2)CCCCCCCCCN1>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:35]2[CH2:36][CH2:37][CH:33]([N:28]3[CH:32]=[CH:31][N:30]=[N:29]3)[CH2:34]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22]
Reactant: c1cn(C2CCNC2)nn1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Agent: Cl
Solvent: CC#N
Product: Nc1c(F)c(N2CCC(n3ccnn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Yield: 56.9 %

Procedure:
A mixture of 5-amino-1-(2,4-difluorophenyl) -6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (200 mg, 0.54 mmol), 3-(1,2,3-triazol-1-yl)pyrrolidine hydrochloride (231 mg, 1.25 mmol) and diazabicycloundecane (200 mg, 1.31 mmol) in acetonitrile (25 ml) was refluxed for 45 h. The separated solid was filtered, washed with acetonitrile and ether to give 150 mg (57%) of desired product, m.p. 307.5°-309° C. 1H NMR (TFA) δ: 2.81 (m, 2H), 4.06-4.53 (m, 4H), 5.73 (m, 1H), 7.15-7.23 (m, 2H), 7.59-7.66 (m, 1H), 8.52 (d, 1H), 8.62 (d, 1H), 8.82 (d, 1H).
Reaction SMILES: FC1C=C(F)C=CC=1C[NH:10][C:11]([C:13]1[C:14](=[O:37])[C:15]([OH:36])=[C:16]2[C:33](=[O:34])[N:20]3[C@@H:21]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:22][CH2:23][N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[C@@H:19]3[CH2:18][N:17]2[CH:35]=1)=[O:12].N[C@@H:39]([CH2:47][CH:48]([CH3:50])[CH3:49])[CH2:40][CH2:41]NCC(C)C.C(O)(=O)C.[Cl:55]CCl>>[ClH:55].[ClH:55].[NH2:20][C@@H:21]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:22][CH2:23][NH:24][CH2:25][CH:26]([CH3:27])[CH3:28].[O:34]=[C:33]1[N:20]2[CH2:21][CH2:22][CH2:23][NH:24][CH:19]2[CH2:18][N:17]2[CH:35]=[C:13]([C:11]([NH2:10])=[O:12])[C:14](=[O:37])[C:15]([O:36][CH2:50][C:48]3[CH:47]=[CH:39][CH:40]=[CH:41][CH:49]=3)=[C:16]12
Reactant: ClCCl
Reactant: CC(C)C[C@H]1CCN(CC(C)C)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(O)c3C(=O)N12
Agent: CC(C)CNCC[C@@H](N)CC(C)C
Solvent: CC(=O)O
Product: Cl
Product: NC(=O)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1CCCNC1C2
Yield: 66 %

Procedure:
[(3S)-3-Amino-5-methylhexyl](2-methylpropyl)amine dihydrochloride was prepared in a similar manner as described in example Z-32. 1H NMR (400 MHz, CDCl3/CD3OD) δ 0.87 (d, J=6.4 Hz, 6H), 0.97 (d, J=6.8 Hz, 6H), 1.34-1.41 (m, 1H), 1.45-1.52 (m, 1H), 1.58-1.66 (m, 1H), 2.01-2.13 (m, 2H), 2.72-2.73 (m, 2H), 3.03-3.06 (m, 2H), 3.29 (m, 2H), 8.07 (br, <1H), 8.71 (br, <1H). b) (4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropyl)-6,8-dioxo 1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide. The title compound was made in two steps using a similar process to that described in example Z-2. 16a (80 mg, 0.17 mmol) and free based [(3S)-3-amino-5-methylhexyl](2-methylpropyl)amine (117 mg, 0.63 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(2,4-difluorophenyl)methyl]methylpropyl)-6,8-dioxo-7-[(phenyl methyl)oxy]-1,2,3,4,6,8,12,12a octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (68 mg, 66%) as a film. This material was hydrogenated in a second step as described in example Z-2 to give (4S,12aS)—N-[(2,4-difluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (56 mg, 97%) as an off-white solid, 1H NMR (400 MHz, CDCl3) δ 0.74 (d, J=6.4 Hz, 3H), 0.84 (d, J=6.4 Hz, 3H), 0.97-1.00 (m, 6H), 1.37-1.83 (m, 5H), 2.03-2.12 (m, 2H), 2.21-2.28 (m, 1H), 2.77 (m, 1H), 2.90-2.93 (m, 1H), 4.19-4.40 (m, 3H), 4.59-4.70 (m, 2H), 4.96-4.97 (m, 1H), 6.77-6.83 (m, 2H), 7.33-7.39 (m, 1H), 8.28 (s, 1H), 10.47 (s, 1H), 12.59 (br, 1H); ES+ MS: 517 (M+1).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([NH2:12])([CH3:11])[CH3:10].[SH:13][CH:14]([CH2:18][C:19]([OH:21])=[O:20])[C:15](O)=[O:16]>CN(C=O)C.O>[CH:9]([N:12]1[C:15](=[O:16])[CH:14]([CH2:18][C:19]([OH:21])=[O:20])[S:13][CH:1]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:11])[CH3:10]
Reactant: CC(C)N
Reactant: O=C(O)CC(S)C(=O)O
Reactant: O=Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)C(CC(=O)O)SC1c1ccccc1
Temperature: 80 °C

Procedure:
A solution of benzaldehyde (0.75 mmol, 79.6 mg) and isopropylamine (53.1 mg, 0.9 mmol) in DMF (0.5 ml) with 4 Å molecular sieves was heated at 80° C. for 2 hours. A solution of mercaptosuccinic acid (1.13 mmol, 168 mg) in DMF (0.2 ml) was added and the reaction was heated at 80° C. for an additional 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with 1N HCl, water and evaporated to dryness to give the desired product which was used without further purification.