Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH:10]=[C:11]=[CH2:12])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.CN(C)C=O.Cl[Si:24]([CH3:27])([CH3:26])[CH3:25]>O>[CH:10]([C:2]([O:1][Si:24]([CH3:27])([CH3:26])[CH3:25])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5])=[C:11]=[CH2:12]
Reactant: C#CCC(O)(C=C=C)CCCC
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCC(C=C=C)(CCCC)O[Si](C)(C)C
Reaction time: 70 h

Procedure:
To a stirred, ice-cold solution of 10.85 g. (66.1 mmol.) of 4-hydroxy-4-propadienyl-1-octyne and 13.2 g. (194 mmol.) of imidazole in 50 ml. of dimethylformamide at 0° C. is added 9.5 ml. of chlorotrimethylsilane. The solution is kept at 0° C. for 70 hours and diluted with petroleum ether. The resulting mixture is shaken with water at 0° C. The organic layer is washed with water and brine, dried over magnesium sulfate and concentrated to give the title compound as a liquid.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[SH:12][CH2:13][C:14](OC)=[O:15].[OH-].[Na+]>CCO.O>[N+:9]([C:6]1[CH:7]=[CH:8][C:2]2[S:12][CH2:13][C:14](=[O:15])[NH:4][C:3]=2[CH:5]=1)([O-:11])=[O:10]
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: COC(=O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1CSc2ccc([N+](=O)[O-])cc2N1
Temperature: 25 °C
Yield: 11.5 %

Procedure:
A mixture of 2-chloro-5-nitroaniline (15 g, 87 mmol), methyl 2-mercaptoacetate (13.8 g, 130 mmol) and sodium hydroxide (10.4 g, 261 mmol) in EtOH/water (250 mL, v/v=10:1) was heated at reflux for 16 h. The reaction mixture was cooled to ambient temperature, the solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluting with 17% EtOAc in petroleum ether) to give 6-nitro-2H-benzo[b][1,4]thiazin-3(4H)-one (2.1 g, 11%). LC/MS (Table 1, Method 2) Rt=0.790 min; MS m/z: 211 [M+H]+.
Reaction SMILES: C([N:8]([CH2:28][C@H:29]([O:38][Si:39]([CH2:44][CH3:45])([CH2:42][CH3:43])[CH2:40][CH3:41])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][C:18]([O:20]CC3C=CC=CC=3)=[CH:19][C:11]=2[CH2:10]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[O:31]([CH2:30][C@@H:29]([O:38][Si:39]([CH2:42][CH3:43])([CH2:44][CH3:45])[CH2:40][CH3:41])[CH2:28][NH:8][CH:9]1[CH2:10][C:11]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:12]=2[CH2:13][CH2:14][CH2:15]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(Cc1ccccc1)C1CCCc2ccc(OCc3ccccc3)cc2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC[Si](CC)(CC)O[C@@H](CNC1CCCc2ccc(O)cc2C1)COc1ccccc1
Yield: 95.8 %

Procedure:
A mixture of N-benzyl-N-(3-benzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]amine (25 g) and 10% palladium on activated carbon (50% wet, 2.5 g) in methanol (250 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 5 hours. After filtration, the filtrate was evaporated in vacuo to give 8-[(2S)-3-phenoxy-2-(triethylsilyloxy)propylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (17 g).
Reaction SMILES: N[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].N([O-])=O.[Na+]>>[S:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[CH:2]=[C:3]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1sc2ncccc2c1N
Agent: O=N[O-]
Agent: [Na+]
Product: COC(=O)c1cc2cccnc2s1

Procedure:
The synthesis is carried out according to the general procedure; for work-up, the resulting precipitate is filtered off with suction and washed twice with water and three times with ethyl acetate. The organic phase of the resulting filtrate is separated off, dried and concentrated. Using 0.22 g (1.07 mmol) of methyl 3-aminothieno[2,3-b]pyridine-2-carboxylate and 0.24 g (3.41 mmol) of sodium nitrite, 84 mg (41% of theory) of the desired product are obtained.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([CH:42]=O)[CH:36]=3)=[CH:32][CH:33]=2)[CH:28]=[N:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].[C:44]([O:48][C:49](=[O:55])[N:50]([CH2:52][CH2:53][NH2:54])[CH3:51])([CH3:47])([CH3:46])[CH3:45]>ClC(Cl)C.O>[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([CH2:42][NH:54][CH2:53][CH2:52][N:50]([C:49]([O:48][C:44]([CH3:47])([CH3:45])[CH3:46])=[O:55])[CH3:51])[CH:36]=3)=[CH:32][CH:33]=2)[CH:28]=[N:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)n1ncc2cc(-c3ccc(F)c(C=O)c3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CN(CCNCc1cc(-c2ccc3c(cnn3C(=O)OC(C)(C)C)c2)ccc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
Sodium triacetoxyborohydride (250 mg, 1.2 mmol) and acetic acid (42 mg, 1.2 mmol) were added to a mixture of 5-(4-fluoro-3-formylphenyl)-indazole-1-carboxylic acid tert-butyl ester (270 mg, 0.8 mmol) and (2-amino-ethyl)-methyl-carbamic acid tert-butyl ester (210 mg, 1.2 mmol) in 8 mL of dichloroethane. The mixture was stirred at ambient temperature overnight, and then it was diluted with water, the layers were separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were washed with sequentially with water, saturated sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography (elution with methanol/dichloromethane) provided 400 mg of product. LC/MS: Retention time, 2.66 min; (M+H)=499.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:12]1([CH2:15]O)[CH2:14][CH2:13]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH2:15][CH:12]3[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: OCC1CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ncnc2c1c(I)cn2CC1CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (prepared according to: L. B. Townsend et al., J. Med. Chem. 1990, 33 (7), 1984-92) (419 mg, 1.50 mmol), cyclopropylmethanol (165 μL, 147 mg, 2.04 mmol), and PS—PPh3 (2.12 mmol/g; 1.41 g, 2.99 mmol) in dry THF (10 mL), cooled by ice/water, was added DIAD (440 μL, 452 mg, 2.23 mmol; 1.5 equiv.), then the cooling bath was removed and the mixture was vortexed overnight. The resin was filtered off and washed thoroughly with THF, and the filtrate and washings were combined and concentrated. Chromatography of the crude material thus obtained on silica gel (Jones Flashmaster, 2 columns, 10 g/70 mL cartridge each, eluting with CH2Cl2) gave the title compound as an off-white solid. 1H NMR (CDCl3, 400 MHz): δ=0.41-0.47 (m, 2H), 0.63-0.69 (m, 2H), 1.20-1.31 (m, 1H), 4.12 (d, J=7.2 Hz, 2H), 7.52 (s, 1H), 8.61 (s, 1H). MS (ES+): m/z 333.9/335.9 (100/38) [MH+]. HPLC: tR=3.7 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([O-:13])=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Na+].Cl[CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[N:17]1[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[N:29][C:30]([Cl:36])=[CH:31][CH:32]=2)[N:27]=1.N12CCCN=C1CCCCC2.O>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([O:13][CH:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]2[C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[N:29][C:30]([Cl:36])=[CH:31][CH:32]=3)[N:27]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(CC(=O)[O-])CC1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Agent: [Na+]
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(CC(=O)OC2c3ccccc3C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 38.6 %

Procedure:
Sodium (4-acetyl-1-piperazinyl)acetate (4.2 g) is added to a solution, maintained at a temperature in the region of 20° C., of 3-chloro-2-(7-chloro-1,8-naphthyridin-2yl)-1-isoindolinone (6.6 g) in anhydrous dimethylformamide (60 cc), and the reaction mixture is maintained for 15 hours at a temperature in the region of 20° C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (3g) is then added, and the mixture is then stirred again for 24 hours at a temperature in the region of 20° C. The reaction mixture is taken up with water (250 cc) and extracted with methylene chloride (3×150 cc). After the organic phase has been washed with water and concentrated to dryness under reduced pressure (2.7 kPa), the residue obtained is recrystallized in ethanol. 2-(7-Chloro-1,8-naphthyridin-2-yl-)-3-oxo-1-isoindolinyl (4-acetyl-1-piperazinyl)acetate (3.7 g), m.p. 192° C., is thereby obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:20]=[CH:19][C:14]3[B:15]([OH:18])[O:16][CH2:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].I[CH2:22][CH3:23].CN(C)C=O.[H-].[Na+]>O>[CH2:22]([O:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:20]=[CH:19][C:14]3[B:15]([OH:18])[O:16][CH2:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH3:23]
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.3 %

Procedure:
A solution of 2-hydroxy-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile (0.200 g, 0.749 mmol), iodoethane (0.182 mL, 2.25 mmol) and N,N-dimethylformamide (10 mL) under nitrogen balloon was put on an ice water bath. Sodium hydride (0.090 g, 2.25 mmol) was added and the mixture was stirred under nitrogen balloon at 0° C. for 15 minutes. The reaction was then stirred at room temperature for 2 hours. Water was added to quench the excess sodium hydride and the mixture was then neutralized using 1 M HCl. Water was added and the solution was extracted using ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was solidified by adding isopropylether. The precipitate was filtered and dried under reduced pressure to give 2-ethoxy-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile (0.131 g, 59% yield). ES(−)MS m/z=294 (M−H)−; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (t, J=6.9 Hz, 3H), 4.13 (q, J=7.0 Hz, 2H), 4.95 (s, 2H), 6.56 (dd, J=8.6, 1.9 Hz, 1H), 6.89 (d, J=1.9 Hz, 1H), 7.08 (dd, J=8.1, 1.6 Hz, 1H), 7.14 (s, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 9.19 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[N:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:38]CCl>C(Cl)(Cl)(Cl)Cl>[Cl:38][CH2:14][C:13]1[N:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[N:10]=[N:11][C:12]=1[CH:16]([CH3:18])[CH3:17]
Reactant: ClCCl
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1CCl
Yield: 86 %

Procedure:
To a solution of [3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol (0.100 g) in dichloromethane (2 mL) and carbon tetrachloride (2 mL) is added triphenyl phosphine (0.275 g). Upon completion, the reaction is concentrated under reduced pressure. The residue is dissolved in dichloromethane to aid in loading solubility and is purified via filter chromatography eluting with 10% ethyl acetate in toluene to give the desired product (0.091 g, 86%). 1H NMR (400 MHz, CDCl3) δ 7.58-7.54 (d, 2H), 7.52-7.50 (t, 1H), 4.48 (s, 2H), 3.24-3.21 (m, 1H), 1.51-1.49 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:18])[C:5]([C:15]([OH:17])=O)=[N:6][N:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:8]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:41][NH:42][O:43][CH3:44]>CN(C=O)C>[CH3:44][O:43][N:42]([CH3:41])[C:15]([C:5]1[C:4](=[O:18])[C:3]([O:2][CH3:1])=[CH:8][N:7]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[N:6]=1)=[O:17]
Reactant: CNOC
Reactant: COc1cn(-c2ccncc2)nc(C(=O)O)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cn(-c2ccncc2)nc(C(=O)N(C)OC)c1=O
Temperature: 25 °C
Yield: 100.2 %

Procedure:
To a mixture of 5-methoxy-4-oxo-1-pyridin-4-yl-1,4-dihydropyridazine-3-carboxylic acid (8.2 g, 33 mmol), HOBt (7.6 g, 50 mmol) and WSC (9.5 g, 50 mmol) in DMF (160 mL) was added N,O-dimethylhydroxylamine hydrochloride (6.5 g, 66 mmol) and TEA (14 mL, 100 mmol), and the mixture was stirred at room temperature overweekend. The mixture was concentrated under reduced pressure. The residue was diluted with water, saturated with K2CO3, and extracted with AcOEt. (There were three layers.) The highest organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The middle layer was extracted with CH2Cl2 (50 mL×4), and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure. Two of the residues were combined and chromatographed on basic silica gel (0/100-10/90 MeOH/AcOEt) to give the title compound (9.6 g, 100% yield) as a pale yellow oil: 1H NMR (300 MHz, CDCl3): δ ppm 3.40 (3H, s), 3.68 (3H, s), 3.98 (3H, s), 7.61 (2H, dd, J=4.8, 1.5 Hz), 8.08 (1H, s), 8.73 (2H, dd, J=4.8, 1.5 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]1[N:30]=[C:31]([C:35]2[S:36][CH:37]=[CH:38][CH:39]=2)[O:32][C:33]=1[CH3:34].C(=O)([O-])[O-].[K+].[K+].Cl.[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C=O>[CH3:34][C:33]1[O:32][C:31]([C:35]2[S:36][CH:37]=[CH:38][CH:39]=2)=[N:30][C:29]=1[CH2:28][O:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2cccs2)nc1CCl
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1oc(-c2cccs2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
A mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (1.30 g), 4-chloromethyl-5-methyl-2-(2-thienyl)oxazole (0.95 g), potassium carbonate (1.20 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and an oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). A mixture of the oily substance obtained, 1N aqueous sodium hydroxide solution (8 ml), tetrahydrofuran (10 ml) and ethanol (8 ml) was stirred at room temperature for 3 hours and the organic solvent was removed under reduced pressure. After adding water, the residue was acidified by adding 1N hydrochloric acid. The colorless crystals obtained were collected by filtration to yield 3-[1-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionic acid (1.43 g, yield: 77%). This was recrystallized from ethyl acetate-hexane. Melting point: 117–118° C.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7](=[O:34])[C@H:8]([CH2:31][CH2:32][CH3:33])[NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18](C3C=CC(S(C)(=O)=O)=CC=3)=[CH:17][CH:16]=2)[C:11]([F:14])([F:13])[F:12])CC1)#[N:2].NCC#N.[Br:39]C1C=CC([C@H](N[C@@H](CCC)C(O)=O)C(F)(F)F)=CC=1>>[Br:39][C:18]1[CH:19]=[CH:20][C:15]([CH:10]([NH:9][C@H:8]([C:7]([NH:6][CH2:3][C:1]#[N:2])=[O:34])[CH2:31][CH2:32][CH3:33])[C:11]([F:14])([F:13])[F:12])=[CH:16][CH:17]=1
Reactant: CCC[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)O
Reactant: CCC[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Agent: N#CCN
Product: CCC[C@H](NC(c1ccc(Br)cc1)C(F)(F)F)C(=O)NCC#N

Procedure:
N2-[1-(4-Bromophenyl)-2,2,2-trifluoroethyl]-N1-(cyanomethyl)-L-norvalinamide was prepared in similar manner to N1-(1-cyanocyclopropyl)-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-norvalinamide using aminoacetonitrile in the coupling step with (2S)-2-[(S)-1-(4-bromophenyl)-2,2,2-trifluoroethylamino]-pentanoic acid.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(#N)C.O.C(N(CC)CC)C>[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:12][C@@H:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:38])=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](c2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc(Cl)cc2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.8 %

Procedure:
To a solution of the compound (0.50 g) obtained in step 4, 4-chlorobenzoic acid (0.35 g) and triethylamine (0.16 mL) in acetonitrile (15 mL) were added WSC.HCl (0.43 g) and HOBt (0.34 g), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; 33% ethyl acetate/hexane) to give the title compound (0.42 g, 91%) as a white powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[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.[NH2:34][C@@H:35]([CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:36][CH2:37][NH:38][CH2:39][CH:40]([CH3:42])[CH3:41].C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:27]=[CH:28][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:2])[N:34]4[C@@H:35]([CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:36][CH2:37][N:38]([CH2:39][CH:40]([CH3:41])[CH3:42])[C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:24][CH:25]=1
Reactant: CC(C)CNCC[C@@H](N)CC(C)C
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)C[C@H]1CCN(CC(C)C)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(OCc4ccccc4)c3C(=O)N12
Yield: 24.7 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (25 mg, 0.055 mmol) and free based [(3S)-3-amino-5-methylhexyl](2-methylpropyl)amine (21 mg, 0.11 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-1,4-bis(2-methylpropyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (8 mg, 25%) as a film. This material was hydrogenated in a second step as described in example Z-2 to give (4S,12aS)—N-[(4-fluorophenyl)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 (5 mg, 78%) 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), 1.37-1.66 (m, 5H), 1.75-1.82 (m, 1H), 2.05-2.09 (m, 2H), 2.21-2.26 (m, 1H), 2.72-2.79 (m, 1H), 2.87-2.93 (m, 1H), 4.16-4.26 (m, 2H), 4.38 (m, 1H), 4.55-4.66 (m, 2H), 4.93-4.99 (m, 1H), 6.97-7.02 (m, 2H), 7.31-7.34 (m, 2H), 8.27 (s, 1H), 10.49 (m, 1H), 12.61 (s, 1H); ES+ MS: 499 (M+1).
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH:23]=O)[CH2:6]1)(=[O:3])[CH3:2].[CH2:25]([SH:28])[CH2:26][SH:27].B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[C@H:7]([CH:23]2[S:28][CH2:25][CH2:26][S:27]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: SCCS
Reactant: CC(=O)S[C@H]1C[C@@H](C=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)S[C@H]1C[C@@H](C2SCCS2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (2S,4S)-4-acetylthio-2-formyl-1-(4-nitrobenzyloxycarbonyl) pyrrolidine (1.00 g) and 1,2-ethanedithiol (0.36 ml) in dichloromethane (20 ml) was added boron trifluoride etherate (0.1 ml), and the solution was stirred for 14 hours at ambient temperature. To the mixture was added saturated aqueous sodium hydrogen carbonate and the organic layer was separated, and washed with brine. The organic layer was dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (50 ml) and eluted with a mixture of acetone and dichloromethane (2:98, V/V) to give (2S, 4S)-4-acetylthio-2-(1,3-dithiolan-2-yl) -1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.14 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:17](Br)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl.[Ag]=O>[C:19]1([CH2:18][CH2:17][N:13]2[CH2:14][CH2:15][CH2:16][CH:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:12]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCCc1ccccc1
Reactant: COc1ccc(C2CCCNC2)cc1OC
Agent: O=[Ag]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2CCCN(CCc3ccccc3)C2)cc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
500 mg of silver oxide were added to a mixture of 1 g of 3-(3',4'-dimethoxyphenyl)-piperidine in 5 ml of chloroform and then 0.7 ml of phenethyl bromide was added thereto dropwise. The mixture was stirred for 6 hours at room temperature and then 250 mg of silver oxide and 0.35 ml of phenethyl bromide were added thereto. The mixture was stirred at room temperature for 16 hours and was filtered to remove insolubles. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 6-3-1 cyclohexane-chloroform-triethylamine mixture yielded 1.045 g of amorphous N-(β-phenylethyl)-3-(3',4'-dimethoxyphenyl)-piperidine.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][N:6]1[C:7]2[C:12](=[C:11]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:10]=[CH:9][CH:8]=2)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5]1)[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)Cc1cccc2[nH]cc([N+](=O)[O-])c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc([N+](=O)[O-])c2c(CC(=O)OC(C)(C)C)cccc21
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl [3-nitro-1H-indol-4-yl]acetate from Step D (385 mg, 1.39 mmol) in DMF (5 mL) at ambient temperature was added sodium hydride (60 mg of a 60% dispersion in mineral oil, 1.50 mmol). The reaction mixture was stirred for 5 min, then ethyl bromoacetate (256 mg, 1.53 mmol) was added and stirring was continued for 10 min. The reaction was quenched with saturated aqueous NaHCO3 (5 mL) and extracted with CHCl3 (2×25 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 40:60, to give the title compound. MS: m/z=307 (M−C4H7).