Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C:7](=O)[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:4]1[N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH:7]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:8]1)=[O:17]
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Reactant: C1CCNC1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1CC(N2CCCC2)CN1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a solution of N-t-butoxycarbonyl-4-oxo-L-proline methyl ester (1.0 g, 4 mmol) (J. Org. Chem. 2001, 10, 3593), pyrrolidine (0.4 ml, 5 mmol), acetic add (0.3 ml, 5 mmol) in CH2Cl2 (20 ml) was added sodium triacetoxyborohydride (1.0 g, 5 mmol) and the mixture stirred for 2 h. After which time it was washed with saturated sodium hydrogen carbonate, dried (Na2SO4) and concentrated. Flash column chromatography (EtOAc:MeOH 95:5) afforded the title compound (1.0 g, 81%) as a yellow oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:34][CH:35]=1.O>CN(C)C=O>[C:14]1([C:12]2[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]([CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:30][C:31]4[N:32]=[C:33]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[S:34][CH:35]=4)=[CH:5][CH:6]=3)[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-phenylthiazole (315 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[4-phenyl-1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-pyrrolyl]propionate (717 mg, yield: 91%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[C:21]([CH:27]=O)[NH:22]2.N1CCCCC1>C(O)C>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:27][C:21]1[NH:22][C:23]2[C:19]([CH:20]=1)=[C:18]([O:17][CH3:16])[CH:26]=[CH:25][CH:24]=2)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: COc1cccc2[nH]c(C=O)cc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1cc3c(OC)cccc3[nH]1)C(=O)N2
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (194 mg, 0.86 mmol), 4-methoxy-1H-indole-2-carbaldehyde (150 mg, 0.86 mmol) and piperidine (36 mg, 0.43 mmol) in ethanol (0.2 M) was stirred at room temperature for a total of 5 days. The reaction was concentrated to ¼ of its volume and the precipitate was collected by vacuum filtration to give the title compound as a pale orangish-red solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].O>C(Cl)Cl>[O:4]1[CH2:5][CH2:6][N:1]([C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: C1COCCN1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of morpholine (479 mg, 5.5 mmol, 1.1 eq) and triethylamine (1.01 g, 10 mmol, 10 eq) in DCM (20 mL) at 0° C., ethyl 3-chloro-3-oxopropanoate (750 mg, 5 mmol, 1.0 eq) was added and the resulting mixture was stirred at RT for 1 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-50% ethyl acetate-hexanes) to afford the product ethyl 3-morpholino-3-oxopropanoate 33.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.C([Li])CCC.[O:14]=[C:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:15]2([OH:14])[CH2:16][CH2:17][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:20]2)=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC(O)(c2ncc(Br)cn2)CC1
Temperature: -55 °C
Reaction time: 0.33 h
Yield: 51.8 %

Procedure:
5-Bromo-2-iodopyrimidine (5 g, 17.55 mmol) was dissolved in dry toluene (90 mL) and cooled to −50 to −60° C. in a dry ice/acetone bath. n-Butyllithium (2.5M solution in hexanes, 7.3 mL) was added dropwise, and the reaction mixture was aged for 20 minutes. A solution of ethyl 4-oxocyclohexanecarboxylate (2.99 g, 17.55 mmol) in toluene (10 mL) was added in one portion, and the reaction mixture was allowed to warm to r.t. and stirred for 30 minutes. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The resulting crude brown oil (6 g) was purified by chromatography on silica (Biotage, 100 g cartridge), eluting with a gradient of 0-50% ethyl acetate in heptanes, to afford a mixture of diastereoisomers of the title compound (2.99 g, 51%) as a yellow oil. Method C HPLC-MS: MH+ m/z 330, RT 1.32, 1.36 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.BrCC1C=CC=C(Cl)C=1OC.[C-]#N.[Na+]>CCO.CCOCC>[Cl:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(Cl)cccc1CC#N
Agent: COc1c(Cl)cccc1CBr
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: COc1c(Cl)cccc1CCN
Temperature: 100 °C

Procedure:
2-(3-chloro-2-methoxyphenyl)acetonitrile. A solution of 1-(bromomethyl)-3-chloro-2-methoxybenzene (30.8 g, 131 mmol) in EtOH (150 mL) at RT and under N2 was treated with an aq. solution of NaCN (12.8 g, 262 mmol in 50 mL H2O) and the mixture was heated to 100° C. for 3 h. The reaction was then cooled to RT and taken up in Et2O. The mixture was washed with H2O and brine, and the aq. phase was extracted again with Et2O. The combined org. layers dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, Hexane to Hexane/AcOEt 4:1) to afford the title compound (15.8 g) as brown oil. UPLC (2 min) rt 1.383.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]1.[O:19]=[C:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][C:24]([C:30](O)=[O:31])=[CH:25][CH:26]=2)[NH:21]1.N1C2C(=CC=CC=2)C=CC1=O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:30]([C:24]2[CH:23]=[C:22]3[C:27]([CH2:28][CH2:29][C:20](=[O:19])[NH:21]3)=[CH:26][CH:25]=2)=[O:31])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCCN)CC1
Reactant: O=C1CCc2ccc(C(=O)O)cc2N1
Agent: O=c1ccc2ccccc2[nH]1
Solvent: O
Product: COc1ccccc1N1CCN(CCCNC(=O)c2ccc3c(c2)NC(=O)CC3)CC1

Procedure:
N-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxamide (35) (Scheme 6) was prepared from 3-(4-(2-methoxyphenyl)piperazin-1-yl)propan-1-amine (34) and 2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (22) according to the protocol described for the compound 23 (Scheme 4, Example 35). Colorless oil (0.1 g, 20%). 1H NMR (400 MHz, CDCl3): δ 1.67 (quintet, J=6.4 Hz, 2H); 1.73-1.78 (m, 2H); 2.62 (t, J=8.0 Hz, 2H); 2.70 (broad s, 4H); 3.05-3.08 (m, 5H); 3.47-3.49 (m, 2H); 3.85 (s, 3H); 4.21 (t, J=5.6 Hz, 2H); 6.86 (d, J=7.6 Hz, 1H); 6.92-6.95 (m, 2H); 6.98-7.03 (m, 1H); 7.35 (d, J=1.2 Hz, 1H); 7.52 (dd, J=6.0, 3.6 Hz, 1H); 7.70 (dd, J=6.0, 3.6 Hz, 1H). MS (ESI): m/z=404.5 (M+−H2O).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Cl:12])[CH:6]=1)[OH:4].O=[C:14]([CH3:28])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:27][O:26][C:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH:14]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Cl:12])[CH:6]=2)[OH:4])[CH3:28])=[CH:22][CH:21]=1)=[O:25]
Reactant: NCC(O)c1ccc(F)c(Cl)c1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2ccc(F)c(Cl)c2)cc1
Yield: 52.9 %

Procedure:
Following a procedure similar to that described in Example 3, but using 3.0 g of 2-amino-1-(3-chloro-4fluorophenyl)ethanol (prepared as described in Preparation 40), 4.22 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 80 ml of benzene, 60 ml of absolute methanol and 3.5 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 3.31 g of the title compound were obtained having an Rf=0.22 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [CH:1]1([C:8]2[N:13]3[N:14]=[CH:15][N:16]=[C:12]3[N:11]=[C:10](O)[C:9]=2[C:18]2[C:36]([F:37])=[CH:35][C:21]([O:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:20][C:19]=2[F:38])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:41])=O.C(N(CC)C1C=CC=CC=1)C>>[Cl:41][C:10]1[C:9]([C:18]2[C:19]([F:38])=[CH:20][C:21]([O:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[CH:35][C:36]=2[F:37])=[C:8]([CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:13]2[N:14]=[CH:15][N:16]=[C:12]2[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(CCCOc1cc(F)c(-c2c(O)nc3ncnn3c2C2CCCCCC2)c(F)c1)C(=O)OC(C)(C)C
Solvent: CCN(CC)c1ccccc1
Product: CN(CCCOc1cc(F)c(-c2c(Cl)nc3ncnn3c2C2CCCCCC2)c(F)c1)C(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
To tert-butyl 3-[4-(7-cycloheptyl-5-hydroxy[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy]propyl(methyl)carbamate (876 mg, 1.64 mmol) is added 5.8 mL of phosphorous oxychloride and 2.9 mL of N,N-diethylaniline, and the mixture is heated at 90° C. for 3 h. The excess phosphorous oxychloride is removed in vaccuo, and the resulting residue is diluted with ethyl acetate. The organic layer is washed with ice water and saturated sodium chloride (x2), dried over magnesium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel, eluting with a gradient of hexanes to 40% ethyl acetate in hexanes. Concentration provides tert-butyl 3-[4-(5-chloro-7-cycloheptyl [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy]propyl(methyl)carbamate as a light yellow oil (452 mg). MS: m/z 550.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:34]1[CH2:37][CH:36]([OH:38])[CH2:35]1>CN1C(=O)CCC1>[OH:38][CH:36]1[CH2:37][N:34]([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:35]1
Reactant: OC1CNC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CC(O)C4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and azetidin-3-ol in NMP. ES-MS m/e (%): 442 (M+H+, 100).
Reaction SMILES: [Si]([O:8][C:9]1[CH:26]=[C:25]2[C@:20]([CH3:28])([CH2:21][CH2:22][C:23](=[O:27])[NH:24]2)[C@@H:19]2[C:10]=1[C@H:11]1[C@@:15]([CH2:17][CH2:18]2)([CH3:16])[C@@H:14]([NH:29][CH:30]2[CH2:32][CH2:31]2)[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:30]1([NH:29][C@H:14]2[CH2:13][CH2:12][C@H:11]3[C@H:10]4[C@H:19]([CH2:18][CH2:17][C@:15]23[CH3:16])[C@:20]2([CH3:28])[C:25]([NH:24][C:23](=[O:27])[CH2:22][CH2:21]2)=[CH:26][C:9]4=[O:8])[CH2:32][CH2:31]1
Reactant: CC(C)(C)[Si](C)(C)OC1=C2[C@@H]3CC[C@H](NC4CC4)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)NC2=C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](C(=O)C=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2NC1CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
17β-Cyclopropylamino-7-(t-butyldimethylsilyloxy)-4-aza-androst-5,7-dien-3-one (5.000 g, 10.947 mmol) prepared in Example 19B or otherwise obtained is dissolved into THF (50 mL) under nitrogen, and added to this solution is tetrabutylammonium fluoride (1.0 M in THF; 12.00 mL, 12.00 mmol). The reaction mixture is stirred for 90 minutes at ambient temperature, then quenched with water (200 mL). The crude product solution is extracted with EtOAc (2×200 mL), and the combined organic extracts are washed with brine (3×200 mL). The organic solution is dried over MgSO4, filtered and concentrated. The residue is purified by flash chromatography (1:1 EtOAc/CH2Cl2) to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.Cl.[Cl:33][CH2:34][CH2:35][NH2:36].CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:33][CH2:34][CH2:35][NH:36][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:29]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: NCCCl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCCCl)[nH]2)c1
Reaction time: 2 h
Yield: 60.9 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (150 mg, 0.34 mmol) synthesized in Example (18a), 2-chloroethylamine hydrochloride (78 mg, 0.68 mmol) and 4-dimethylaminopyridine (41 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL), WSCI•HCl (71 mg, 0.37 mmol) was added at room temperature, and stirring was carried out for 2 hours under nitrogen atmosphere. The reaction solution was diluted with dichloromethane (150 mL), washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-60%) to afford the desired product (105 mg, yield 62%) as a white solid.
Reaction SMILES: [C:1]([S:4][CH:5]1[N:8]([CH:9](O)[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:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2].N1C=CC=CC=1.S(Cl)([Cl:33])=O>O1CCCC1>[C:1]([S:4][CH:5]1[N:8]([CH:9]([Cl:33])[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:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)SC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a cooled (-10°) and stirred solution of p-nitrobenzyl 2-(4-acetylthio-2-oxo-1-azetidinyl)-2-hydroxy-acetate (102 g., 0.250 mole) in tetrahydrofuran (2000 ml.) were added in succession pyridine (27.1 ml., 0.287 mole) and thionyl chloride (25.2 ml., 0.287 mole); the thionyl chloride addition was done over ca 15 minutes. The mixture was stirred for 30 minutes at -10° and filtered. Concentration of the filtrate left a yellow oil which was partially purified by absorption on a pad of silica gel (800 ml.) and elution with chloroform (ca 3000 ml.). Concentration of the eluates gave an oil (92.9 g., 100%) which was found to contain a minimum of 90% of the title ester as a mixture of epimers.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([CH:24]2[CH2:28][NH:27][C:26](=[O:29])[CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>O1CCOCC1.C(Cl)Cl.[Cu]I>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([N:27]2[CH2:28][CH:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:25][C:26]2=[O:29])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccccc2)CN1
Reactant: Cn1cc(Br)cc(OCc2ccccc2)c1=O
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1cc(N2CC(c3ccccc3)CC2=O)cc(OCc2ccccc2)c1=O
Temperature: 110 °C
Yield: 102.9 %

Procedure:
3-(Benzyloxy)-5-bromo-1-methylpyridin-2(1H)-one (100 mg, 0.340 mmol), 4-phenylpyrrolidin-2-one (71 mg, 0.440 mmol), K3PO4 (144 mg, 0.680 mmol), CuI (4 mg, 0.021 mmol), and N,N′-dimethylethylenediamine (5 μl, 0.046 mmol) were combined in 1,4-dioxane (1 mL) in a screw cap vial. The vial was sealed then heated to 110° C. After heating overnight the mixture was cooled to RT and diluted with CH2Cl2. The resulting mixture was filtered through a pad of Celite®, washing with CH2Cl2, and concentrated. Flash column (Biotage-SNAP-25 g, 0-10% MeOH/CH2Cl2) gave the title compound (131 mg, 103%) as an off-white foam which was sufficiently pure for use in the next step. 1H NMR (500 MHz, CDCl3): δ 7.44-7.24 (m, 11 H); 7.09 (s, 1 H); 5.15 (s, 2 H); 3.97 (s, 1 H); 3.71-3.65 (m, 2 H); 3.59 (s, 3 H); 3.00-2.92 (m, 1 H); 2.74 (dd, S=16.9, 8.1 Hz, 1 H). LC/MS (M+H)+ 375.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[C:12]([O:17][CH3:18])[CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][S:20]SC>>[CH3:19][S:20][C:11]1[C:12]([O:17][CH3:18])=[CH:13][C:14]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:16][CH:15]=2
Reactant: COc1ccc2cc(-c3ccccc3)ccc2c1
Reactant: CSSC
Product: COc1cc2ccc(-c3ccccc3)cc2cc1SC

Procedure:
3-Methylthio-6-phenyl-2-methoxynaphthalene (compound (4)-31) was synthesized from 6-phenyl-2-methoxynaphthalene (compound (3)-31) and dimethyl disulfide by the same method as that in Example 14.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:18][CH:19]([CH3:29])[CH2:20][NH:21]C(OC(C)(C)C)=O)[C@@H:12]([C:14]([O:16][CH3:17])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[NH2:21][CH2:20][CH:19]([CH3:29])[CH2:18][N:11]([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C@@H:12]([C:14]([O:16][CH3:17])=[O:15])[CH3:13]
Reactant: COC(=O)[C@@H](C)N(CC(C)CNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](C)N(CC(C)CN)C(=O)OCc1ccccc1

Procedure:
Methyl N-[(benzyloxy)carbonyl]-N-{3-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-D-alaninate (1.6 g, 3.9 mmol) was treated with 4N hydrogen chloride in dioxane (10 mL) at room temperature for 2 hr. The solvent was removed under a stream of nitrogen, and the crude product was purified by flash chromatography on a Biotage® system (silica, 7% pre-mixed 2N ammonia/methanol in dichloromethane) to yield methyl N-(3-amino-2-methylpropyl)-N-[(benzyloxy)carbonyl]-D-alaninate as colorless viscous oil. MS (M+1): 309.4
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].Cl[C:8]1([F:23])[C:12](Cl)([F:13])[O:11][C:10]([F:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[O:9]1>C1COCC1.[Ti](Cl)(Cl)(Cl)Cl>[F:22][C:10]1([C:15]([F:20])([F:21])[C:16]([F:17])([F:18])[F:19])[O:9][C:8]([F:23])=[C:12]([F:13])[O:11]1
Reactant: FC(F)(F)C(F)(F)C1(F)OC(F)(Cl)C(F)(Cl)O1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: FC1=C(F)OC(F)(C(F)(F)C(F)(F)F)O1
Temperature: 30 °C
Reaction time: 0.12 h
Yield: 54 %

Procedure:
To a 300 mL round-bottomed flask was charged lithium aluminum hydride (8.0 g, 0.211 mole) in THF (120 mL). Titanium (IV) chloride (9.84 g, 5.70 mL, 0.052 mole) was added with cooling. This mixture was heated to reflux for 30 minutes. After cooling to 30° C., the 4,5-dichloro-2,4,5-trifluoro-2-pentafluoroethyl-1,3-dioxolane (32.0 g, 0.102 mole) was introduced via a syringe while the temperature of the system was kept between 25° and 35° C. during the addition by cooling. After the addition was complete, the reaction mixture was stirred for an additional 5 to 10 minutes before distillation. 12.8 G (6.6 mL) of the desired product perfluoro-2-ethyl-1,3-dioxole (54% yield) was obtained: boiling point 40° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]#[N:8].C[O-].[Na+].[NH:12]([C:14]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=O)[NH2:13].C(O)(=O)C>CO>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[NH:13][N:12]=[C:14]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reactant: N#Cc1cnccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(-c3cnccn3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of pyrazinecarbonitrile (2.0 g, 19 mmol) in methanol (20 mL) was treated with sodium methoxide in methanol (25 wt %, 1.3 mL, 5.7 mmol) at room temperature. After 30 minutes, a solution of tert-butyl 4-(hydrazinocarbonyl)piperidine-1-carboxylate (4.6 g, 19 mmol) in methanol (20 mL) was added and the reaction was heated to reflux for 19 hours. The reaction mixture was concentrated, dissolved in ethoxyethanol (50 mL) and heated to reflux for 22 hours. The reaction was cooled to room temperature, quenched with acetic acid (0.38 mL, 6.6 mmol) and concentrated. The residue was suspended in ether and filtered to give tert-butyl 4-(5-pyrazin-2-yl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate as a solid. HRMS (M+H+): observed=331.1876, calculated=331.1877; 1H NMR (400 MHz, CD3OD): δ 9.29 (d, J=1.6 Hz, 1H), 8.70 (dd, J=2.4, 1.6 Hz, 1H), 8.64 (d, J=2.4 Hz, 2H), 4.19-4.15 (m, 2H), 3.15-3.09 (m, 1H), 2.97 (m, 2H), 2.07-2.03 (m, 2H), 1.84-1.75 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:13])[NH:8][C:9]2=O)=[CH:4][CH:3]=1.O(Cl)[Cl:15]>>[Cl:15][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[C:7]([CH3:13])[N:8]=1
Reactant: Cc1cc2ccc(Cl)cc2c(=O)[nH]1
Reactant: ClOCl
Product: Cc1cc2ccc(Cl)cc2c(Cl)n1
Reaction time: 5 h

Procedure:
A solution of 7-chloro-3-methyl-2H-isoquinoline-1-one (7.1 g, 36.7 mmol) in 100 mL of phosporous oxychloride is heated to 100° C. After 5 h, the solution is concentrated to dryness. The residue is dissolved in CH2Cl2. The solution is washed with H2O. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 3% EtOAc/hexanes to 5% EtOAc/hexanes. The title compound is obtained as a white solid (6.0 g, 28 mmol). 1H NMR (CDCl3, 300 MHz) δ8.23 (s, 1H), 7.68 (m, 1H), 7.63 (m, 1H), 7.40 (s, 1H), 2.64 (s, 3H).