Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:15])=O.[Br-].[CH2:17]([O:19][C:20]([CH2:22][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:21])[CH3:18].C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C>[C:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[C:3]([CH:1]=[CH:22][C:20]([O:19][CH2:17][CH3:18])=[O:21])=[C:4]([OH:15])[CH:5]=[CH:6]2)#[N:14]
Reactant: CCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc2c(C=O)c(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1c(O)ccc2cc(C#N)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.2 %

Procedure:
A solution prepared by dissolving 19.3 g of 1-formyl-6-cyano-2-naphthol and 42.1 g of ethoxycarbonylmethyltriphenylphosphonium bromide in 140 ml of DMF was added dropwise to a solution comprising 13.6 g of anhydrous potassium carbonate and 250 ml of anhydrous methanol, followed by stirring for 3 hours under cooling with ice in a nitrogen stream and 24 hours at room temperature. The precipitate was filtered, and 2.7 liters of water was added to the filtrate, followed by stirring for 2 hours. Then, the precipitate was collected by filtration and washed with 90 ml of methanol to obtain 12.6 g of the desired product.
Reaction SMILES: O.NN.[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:34]=[CH:35][CH:36]=1)[CH2:21][O:22][N:23]1C(=O)C2=CC=CC=C2C1=O.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:34]=[CH:35][CH:36]=1)[CH2:21][O:22][NH2:23]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CON2C(=O)c3ccccc3C2=O)c1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CON)c1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
Hydrazine monohydrate (0.661 ml) was added to a solution of N-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]phthalimide (3.00 g) in ethanol (25 ml)-tetrahydrofuran (25 ml) and heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, an aqueous solution of potassium carbonate was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (2.04 g, yield 97%) as pale-yellow crystals. m.p. 81-82° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].C(N(CC)CC)C.[C:21]([O:25][CH2:26][C@H:27]([C:36](O)=[O:37])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([CH3:24])([CH3:23])[CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.C(OCC)(=O)C>[C:32]([O:31][C:29]([NH:28][C@H:27]([CH2:26][O:25][C:21]([CH3:24])([CH3:23])[CH3:22])[C:36]([NH:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])=[O:37])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H]1CCc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
To a solution of 200 mg (1.13 mmol) of 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step B) in 8 mL of dry methylene chloride was added 0.206 mL (1.48 mmol) of triethylamine, 553 mg (1.25 mmol) of BOC-D-serine t-butyl ether followed by 602 mg (1.36 mmol) of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate. The reaction mixture was stirred at room temperature for 2 hours then diluted with 100 mL of ethyl acetate, washed with 25 mL of 5% aqueous citric acid, 25 mL of saturated sodium bicarbonate and 25 mL of brine. The organic layer was dried over magnesium sulfate, filtered and the solvents removed under vacuum. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate-hexane (55:45) to afford 480 mg (200%) of the product as a white foam. 1H NMR (200 MHz,CDCl3): 1.20 (s,9H), 1.47 (s,9H), 1.92 (m,1H), 2.55-3.02 (m,3H), 3.38 (t,8 Hz,1H), 3.78 (m,1H), 4.15 (m,1H), 4.52 (m,1H), 5.45 (s,1H), 7.00 (m,1H), 7.10-7.35 (m,3H), 7.68 (d,4 Hz,1H), 8.05 (s,1H). FAB-MS: calculated for C22H33N3O5 419; found 420 (M+H,205), 426 (M+Li,40%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](OS(C(F)(F)F)(=O)=O)=[CH:11][C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:9]1.[SH:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH:33]([CH2:38][CH3:39])[CH2:34][CH2:35][CH2:36][CH3:37])=[O:30].C(N(C(C)C)C(C)C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH:33]([CH2:38][CH3:39])[CH2:34][CH2:35][CH2:36][CH3:37])=[O:30])=[CH:11][C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:9]1
Reactant: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)n(-c2ccccc2Cl)n1
Reactant: CCCCC(CC)COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(CC)COC(=O)CCSc1cc(C(=O)OCC)nn1-c1ccccc1Cl
Temperature: 110 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
A solution of ethyl 1-(2-chlorophenyl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazole-3-carboxylate (2.85 g), 2-ethylhexyl 3-mercaptopropionate (2.34 g) and N-ethyldiisopropylamine (1.85 g) in toluene (30 mL) was sufficiently deaerated, tris(dibenzylideneacetone)dipalladium (0) (327 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (414 mg) were added, and the mixture was further deaerated. Under an argon atmosphere, the reaction mixture was stirred at 110° C. for 4 hr, and allowed to cool to room temperature. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→7:1) to give the title compound as a yellow oil (yield 2.87 g, yield 86%).
Reaction SMILES: [O:1]1[C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]5[N:28]=[CH:27][N:26](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[N:25]=5)[CH:22]=4)[N:17](C4CCCCO4)[N:16]=3)[CH:10]=2)=[O:7])=[CH:4][CH:3]=[N:2]1>Cl.O1CCOCC1>[NH:26]1[CH:27]=[N:28][C:24]([C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[C:11]2[CH:10]=[C:9]([NH:8][C:6]([C:5]3[O:1][N:2]=[CH:3][CH:4]=3)=[O:7])[CH:14]=[CH:13][CH:12]=2)=[N:25]1
Reactant: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccno1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)c1ccno1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
Isoxazol-5-yl-N-(3-{1-perhydro-2H-pyran-2-yl-5[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature overnight. After neutralization with aqueous NaHCO3, the crude product was extracted in ethyl acetate and purified by preparative HPLC (0.005 g, 5% yield over 2 steps): 1H NMR (CD3OD) 8.65 (t, 1H), 8.73 (s, 1H), 8.45 (s, 1H), 8.38 (br s, <1H), 8.10 (d, 1H), 7.92 (d, 1H), 7.82 (d, 1H), 7.58 (t, 1H), 7.32 (d, 1H); ES-MS (m/z) 372 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.CCN(CC)CC.[Br:22][CH:23]([CH3:27])[C:24](Br)=[O:25]>C(Cl)Cl.O>[Br:22][CH:23]([CH3:27])[C:24]([N:8]([CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:25]
Reactant: CN1CCC(Nc2ccccc2)CC1
Reactant: CC(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(Br)C(=O)N(c1ccccc1)C1CCN(C)CC1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
A solution of compound 1-methyl-N-phenylpiperidin-4-amine (1.0 g, 5.255 mmol) in dry CH2Cl2 (10 mL) was treated with Et3N (2.19 mL, 15.766 mmol) followed by 2-bromopropionyl bromide (0.61 mL, 5.780 mmol) at 0° C. and stirred at same temperature for 1 h. The reaction was diluted with water (25 mL) and product was extracted into CH2Cl2 (2×25 mL). The combined CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (MeOH:CH2Cl2, 5:95) to obtain compound 2-Bromo-N-(1-methylpiperidin-4-yl)-N-phenylpropanamide (1.5 g, 88%) as a solid. 1H NMR (DMSO-d6) δ: 1.09-1.33 (m, 2H), 1.59 (d, 3H, J=6.3 Hz), 1.66-1.74 (m, 2H), 1.89-1.98 (m, 2H), 2.09 (s, 3H), 2.68-2.74 (m, 2H), 4.01 (q, 1H), 4.28-4.36 (m, 1H), 7.26-7.30 (m, 2H), 7.46-7.50 (m, 3H); ESI-MS (m/z, %) 327 and 325 (MH+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[N:4]=[C:5]([S:30][CH3:31])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([OH:28])[C:21]=1[F:29])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44].[Cl-].[NH4+]>O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:32])[N:4]=[C:5]([S:30][CH3:31])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH2:40][CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[C:21]=1[F:29])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(O)c1F
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCO[Si](C)(C)C(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To 15 ml of a DMF solution containing 522 mg of [2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (3d)), 173 mg of potassium carbonate and 0.269 ml of (2-bromoethoxy)-t-butyldimethylsilane were added. The resulting mixture was stirred at room temperature for 15 hours, and then 25 ml of water and 25 ml of saturated ammonium chloride aqueous solution were added thereto. The mixture was extracted with 150 ml of ethyl acetate. The organic layer was washed with 50 ml of water and then with 50 ml of saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (210 mg).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[Br:11][C:12]1[C:13]([O:24][CH3:25])=[C:14]([C:19]2[NH:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[C:16]([Br:18])[CH:17]=1.C([O-])(=O)C.[Na+]>ClCCCl>[Br:11][C:12]1[C:13]([O:24][CH3:25])=[C:14]([C:19]2[NH:20][C:21]([CH:8]=[O:9])=[CH:22][CH:23]=2)[CH:15]=[C:16]([Br:18])[CH:17]=1
Reactant: CN(C)C=O
Reactant: COc1c(Br)cc(Br)cc1-c1ccc[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1c(Br)cc(Br)cc1-c1ccc(C=O)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Phosphorus oxychloride (0.18 ml, 1.9 mmol) was added to N,N-dimethylformamide (0.15 ml, 1.9 mmol) at 0° C. under argon with constant stirring. The resulting mixture was allowed to warm to room temperature and was then stirred for 1.5 h. 1,2-Dichloroethane (1.5 ml) was added and a solution of 2-(3,5-dibromo-2-methoxyphenyl)-1H-pyrrole (0.30 g, 0.91 mmol) in 1,2-dichloroethane (3 ml) was then added at 0° C. The reaction mixture was stirred at room temperature for 16 h. On cooling, the mixture was poured onto crushed ice and basified with aqueous sodium acetate (50%, 20 ml). The organic phase was separated and the aqueous layer was extracted with ether. The combined organic extracts were washed with aqueous sodium hydrogen carbonate, dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography on alumina (Brockmann grade 1) with ether - methanol (0-1% ) gradient elution gave the title compound (D29) as a beige solid (0.18 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:18][CH3:19])[CH:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1.F[B-](F)(F)F.[O:25]=[N+:26]=[O:27].C(OCC)(=O)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:18][CH3:19])[C:17]([N+:26]([O-:27])=[O:25])=[C:13]2[CH:12]=[CH:11][CH:10]=1
Reactant: CCc1cc2cccc(-c3ccc(Cl)cc3Cl)n2n1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCc1nn2c(-c3ccc(Cl)cc3Cl)cccc2c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 35.6 %

Procedure:
After dissolving 7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridine (280 mg) in acetonitrile (20 mL), nitronium tetrafluoroborate (255 mg) was added 4 times at 30 minute intervals while stirring on ice. The reaction mixture was added to ice water, extraction was performed with ethyl acetate and the extract washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (115 mg) was obtained from the n-hexane:ethyl acetate (20:1) fraction as yellow crystals.
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.C(O)(C(F)(F)F)=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C)C.C1C=CC=CC=1>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C@H:3]([CH3:4])[CH2:2][CH:1]=[O:5])=[CH:8]1
Reactant: C/C=C/C=O
Reactant: Cn1ccc2ccccc21
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Solvent: ClCCl
Product: C[C@H](CC=O)c1cn(C)c2ccccc12
Yield: 82.5 %

Procedure:
Prepared according to the general procedure from (E)-crotonaldehyde (125 μL, 1.50 mmol), 1-methyl-1H-indole (64 μL, 0.50 mmol), TFA (7.7 μL, 0.10 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one (24.6 mg, 0.100 mmol) in CH2Cl2 (0.85 mL) and isopropanol (0.15 mL) at −83° C. for 19 h to provide, after silica gel chromatography (benzene), the title compound as a colorless oil (83 mg, 82% yield, 92% ee). IR (film) 3054, 2960, 2824, 2722, 1720, 1616, 1550, 1474, 1374, 1329, 1241, 740 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.75 (dd, J=2.1, 2.1 Hz, 1H, CHO), 7.63 (d, J=7.8 Hz, 1H, ArH), 7.32-7.21 (m, 2H, ArH), 7.12 (ddd, J=1.5, 7.4, 8.1 Hz, 1H, ArH), 6.84 (s, 1H, NCH), 3.75 (s, 3H, NCH3), 3.68 (dt, J=6.9, 13.8 Hz, 1H, ArCH), 2.88 (ddd, J=2.7, 6.9, 16.2 Hz, 1H, CH2CO); 2.71 (ddd, J=2.7, 6.9, 16.2 Hz, 1H, CH2CO); 1.44 (d, J=7.2 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) δ 202.8, 137.2, 126.6 125.2, 121.8, 119.1, 118.9, 118.8, 109.5, 51.2, 32.8, 26.0, 21.9; HRMS (CI) exact mass calcd for (C13H15NO) requires m/z 201.1154, found m/z 201.1152. [α]D−−4.2 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel AD and AD guard column (2:98 ethanol/hexanes, 1 mL/min); S isomer tr=25.2 min and R isomer tr=27.8 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7](Cl)=[O:8].C(N(CC)CC)C.[SH2:17]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:8])=[S:17]
Reactant: S
Reactant: COCCOCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOCC(O)=S
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
A solution of 2-methoxyethoxyacetyl chloride (700 mg.; 4.59 mmoles) in methylene chloride (10 ml.; dried over molecular sieves) was added dropwise at 0°-5° to a stirred solution of triethylamine (0.7 ml.; 508 mg.; 5.04 mmoles) in methylene chloride (20 ml.) which had been saturated at 0°-5° with H2S (ca. 30 min.). The light yellow mixture was stirred at 0°-5° for 30 min. and then at room temperature for 30 min. The mixture was washed with 1N HCl (10 ml.×2) and then brine. The CH2Cl2 layer was dried (Na2SO4) and evaporated yielding 2-methoxyethoxythioacetic acid (480 mg.; 3.20 mmoles; yield 69.7%) as a light yellow liquid: nmr (CDCl3): δppm 3.42 (3H, s, --OCH3), 3.4-3.9 (4H, m, --CH2CH2 -), 4.10 (2H, s, -OCCH2O), 5.0 (1H, br, -COSH); ir (neat): 2550 cm-1 (νS-H), 1770 (νc=o, thio acid).
Reaction SMILES: Cl.C([N:9]1[CH2:14][CH2:13][C:12]([NH:17][S:18]([C:21]2[S:22][C:23]([Cl:26])=[CH:24][CH:25]=2)(=[O:20])=[O:19])([CH2:15][OH:16])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.CCOC(C)=O.CCCCCC>CCOC(C)=O.C(OCC)C>[OH:16][CH2:15][C:12]1([NH:17][S:18]([C:21]2[S:22][C:23]([Cl:26])=[CH:24][CH:25]=2)(=[O:19])=[O:20])[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(NS(=O)(=O)c2ccc(Cl)s2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCOCC
Product: O=S(=O)(NC1(CO)CCNCC1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
4N HCl (5 mL) was added to a stirred solution of N-[1-Boc-4-(hydroxymethyl)piperidin-4-yl]-5-chlorothiophene-2-sulfonamide 5 (0.7 g, 1.7 mmol) in EtOAc (4 mL). The solution was allowed to stir at 25° C. After 30 min, a cloudy solution formed. After 2 h a precipitate formed. TLC (1: 1 EtOAc-hexane) indicated the reaction was complete. The solvent was reduced to ˜2-3 mL, diluted with diethyl ether (6 mL) and filtered through a filter funnel. The precipitate was washed with diethyl ether (3×5 mL) to obtain N-[4-(hydroxymethyl)piperidin-4-yl]-5-chlorothiophene-2-sulfonamide as an amorphous white solid (0.48 g, 90.7%). Mass Spectrum (+ESI): 311 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][OH:8].[H-].[Na+].[N+:11]([C:14]1[CH:15]=[N:16][CH:17]=[C:18]([N+]([O-])=O)[CH:19]=1)([O-:13])=[O:12].CCOCC>CN(C=O)C.O.[Cl-].[Na+].O>[N+:11]([C:14]1[CH:19]=[C:18]([O:8][CH2:7][C@@H:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])[CH:17]=[N:16][CH:15]=1)([O-:13])=[O:12]
Reactant: CN1CCCC1CO
Reactant: O=[N+]([O-])c1cncc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CN1CCC[C@H]1COc1cncc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.6 %

Procedure:
1-Methylpyrrolidinylmethanol (0.46 ml, 3.9 mmol) was added to a suspension of NaH in DMF at room temperature. After stirring at room temperature for 30 minutes, 3,5-dinitro-pyridine (0.34 g, 4 mmol) was added, and the mixture was allowed to stir at room temperature for 16 hours. The mixture was diluted with 1:1 water/brine, and the aqueous solution was extrated with ether. The combined ether layers were dried over MgSO4, filtered and concentrated. The residue was chromatographed, eluting with CH2Cl2 :methanol (10:0.5) to afford 70 mg of the title compound. MS (DCI/NH3) m/e: 238 (M+1). 1H NMR (CDCl3, 300MHz) δ: 9.06 (m, 1H), 8.62 (d, 1H), 7.97 (m, 1H), 4.07 (m, 2H), 3.50 (s, 3H), 3.13 (m, 1H), 2.73 (m, 1H), 2.35 (m, 1H), 2.05 (m, 1H), 1.82 (m, 3H).
Reaction SMILES: [OH:1][CH:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[C:5](=[O:17])[C:4]2[S:18][CH2:19][CH2:20][S:21][C:3]1=2.[H-].[Na+].Cl[C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)=[O:26].C>CN(C)C=O.C(#N)C>[CH3:33][N:30]1[CH2:31][CH2:32][N:27]([C:25]([O:17][CH:5]2[N:6]([C:7]3[CH:16]=[CH:15][C:14]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[N:8]=3)[C:2](=[O:1])[C:3]3[S:21][CH2:20][CH2:19][S:18][C:4]2=3)=[O:26])[CH2:28][CH2:29]1
Reactant: O=C1C2=C(SCCS2)C(O)N1c1ccc2cccnc2n1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccc3cccnc3n2)CC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 49.1 %

Procedure:
5-Hydroxy-6-(1,8-naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (8.45 g.) is added, at 0° C, to a suspension of sodium hydride (0.8 g.) in anhydrous dimethylformamide (125 cc.). The reaction mixture is stirred for half an hour at 0° C, and 1-chlorocarbonyl-4-methylpiperazine (8.45 g.) dissolved in anhydrous dimethylformamide (50 cc.) is then added. After stirring for 21/2 hours at 5° C., the reaction mixture is diluted with ice-water (500 cc.). The precipitate which has appeared is filtered off, washed four times with distilled water (total 200 cc.) and twice with diethyl ether (total 50 cc.) and then dissolved in methylene chloride (300 cc.). The organic solution is washed four times with distilled water (total 160 cc.), dried over anhydrous sodium sulphate, treated with decolourising charcoal (0.2 g.) and evaporated. When the residue liquid reaches a volume of 50 cc., boiling acetonitrile (200 cc.) is added. After cooling for 2 hours at 2° C., the crystals which have appeared are filtered off, washed three times with ice-cold acetonitrile (total 15 cc.) and dried under reduced pressure (20 mm. Hg). The crystals thus isolated (8.0 g.) are dissolved in boiling acetonitrile (270 cc.), decolourising charcoal (0.2 g.) is added to the boiling solution and the whole is filtered. After 24 hours at 2° C., the crystals which have appeared are filtered off, washed three times with ice-cold acetonitrile (total 10 cc.) and dried under reduced pressure (20 mm. Hg). 5-(4-Methylpiperazin-1-yl)carbonyloxy-6-(1,8-naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (5.8 g.), melting at 255° C., is thus obtained.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[Cl:8][C:9]1[C:18]([NH2:19])=[C:17]([NH:20][CH2:21][CH2:22][C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH:24]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.C(N(CC)CC)C>ClCCl>[Cl:8][C:9]1[C:18]([NH:19][C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2])=[C:17]([NH:20][CH2:21][CH2:22][C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH:24]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: CCOCC(=O)Cl
Reactant: Nc1c(Cl)nc2ccccc2c1NCCc1cc(-c2ccc(F)cc2)no1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCC(=O)Nc1c(Cl)nc2ccccc2c1NCCc1cc(-c2ccc(F)cc2)no1
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
Under a nitrogen atmosphere, ethoxyacetyl chloride (3.5 g, 28 mmol) was added dropwise to a solution of 2-chloro-N4-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}quinoline-3,4-diamine (9.0 g, 23.5 mmol) and anhydrous triethylamine (10.0 mL, 35.3 mmol) in anhydrous dichloromethane (75 mL) at 6° C. After the reaction was stirred for 30 minutes, an analysis by HPLC indicated the presence of starting material, and additional ethoxyacetyl chloride (2.0 g) was added. After the reaction was stirred for another 30 minutes, it was still incomplete, and additional ethoxyacetyl chloride (2.0 g) was added. The stirring was continued for an additional 30 minutes, and the work-up procedure described in Part A of Example 19 was followed to provide 11.12 g of N-[2-chloro-4-({2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}amino)quinolin-3-yl]-2-ethoxyacetamide as a white solid.
Reaction SMILES: [P:1](Cl)([Cl:6])([O:3][CH2:4][CH3:5])=[S:2].[O-:8][CH2:9][CH2:10][CH3:11].[Na+].C(O)CC>O1CCCC1>[P:1]([Cl:6])([O:8][CH2:9][CH2:10][CH3:11])([O:3][CH2:4][CH3:5])=[S:2]
Reactant: CCC[O-]
Reactant: CCOP(=S)(Cl)Cl
Agent: [Na+]
Solvent: CCCO
Solvent: C1CCOC1
Product: CCCOP(=S)(Cl)OCC
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To 30 g (167 mmole) of O-ethyl dichlorothiophosphate in 100 ml of tetrahydrofuran (THF) and cooled to -70° C. was added a solution of sodium propoxide (from 7.4 g of 60% NaH (184 mmole) and 11 g (176 mmole) of 1-propanol) in 50 ml of THF. After warming to room temperature over 2 hours, the THF was removed in vacuo and the residue was partitioned between 50 ml diethyl ether, 50 ml hexanes, and 25 ml cold water. The organic layer was dried over magnesium sulfate, concentrated in vacuo, and distilled (bp 45°-50° C. 1 torr) yielding 20 g of the title compound, an oil. nmr 1.0 t 3H, 1.4 t 3H, 1.8 sextet 2H, 4.4M 4H.