Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:13])[N:4]([CH2:9][CH2:10][S:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([CH3:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([O:16][CH3:15])=[CH:25][C:24]=3[CH3:26])[CH2:20][CH2:21]2)[C:3](=[O:13])[N:4]([CH2:9][CH2:10][S:11][CH3:12])[CH:5]=1
Reactant: CSCCn1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(C)c2c(c1)CCN2
Agent: Cl
Product: COc1cc(C)c2c(c1)CCN2c1nc(Cl)cn(CCSC)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[2-(methylthio)ethyl]-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 111-113° C.; 1H NMR (300 MHz, CDCl3): δ 6.80 (s, 1 H), 6.68 (d, J=2.2 Hz, 1 H), 6.59 (d, J=2.2 Hz, 1 H), 4.40 (t, J=7.7 Hz, 2 H), 4.04 (t, J=7.1 Hz, 2 H), 3.79 (s, 3 H), 3.04 (t, J=7.7 Hz, 2 H), 2.89 (t, J=7.2 Hz, 2 H), 2.18 (s, 3 H), 2.06 (s, 3 H); HRMS (CI) calcd for C17H20N3O2SCl (M+): 365.0965; found m/z 365.0967.
Reaction SMILES: [OH:1][CH:2]([CH:43]([CH3:45])[CH3:44])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][C:34](=[O:36])[O:33][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:37][CH2:38][CH3:39])[N:13]3[N:40]=[CH:41][CH:42]=[C:12]23)[CH2:7][CH2:6]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH3:45][CH:43]([CH3:44])[C:2](=[O:1])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][C:34](=[O:36])[O:33][N:32]=4)=[CH:23][CH:24]=3)=[C:14]([CH2:37][CH2:38][CH3:39])[N:13]3[N:40]=[CH:41][CH:42]=[C:12]23)[CH2:7][CH2:6]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)C(C)C)CC2)c2ccnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)C(C)C)CC2)c2ccnn12
Reaction time: 2 h

Procedure:
To a solution of 4-[trans-4-(2-hydroxy-3-methylbutoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one (0.19 g) in methylene chloride (2 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.26 g), and the mixture was stirred for 2 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.047 g, 25%).
Reaction SMILES: [CH2:1]([Si:3]([CH2:17][CH3:18])([CH2:15][CH3:16])[O:4][C@@H:5]1[C@H:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[NH:7][C:6]1=[O:14])[CH3:2].C(N(C(C)C)CC)(C)C.[CH:28]([O:31][C:32](Cl)=[O:33])([CH3:30])[CH3:29]>ClCCl.CN(C1C=CN=CC=1)C>[CH2:17]([Si:3]([CH2:15][CH3:16])([CH2:1][CH3:2])[O:4][CH:5]1[CH:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:7]([C:32]([O:31][CH:28]([CH3:30])[CH3:29])=[O:33])[C:6]1=[O:14])[CH3:18]
Reactant: CC(C)OC(=O)Cl
Reactant: CC[Si](CC)(CC)O[C@H]1C(=O)N[C@H]1c1ccco1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC1C(=O)N(C(=O)OC(C)C)C1c1ccco1
Reaction time: 1 h
Yield: 96.1 %

Procedure:
(3R, 4R)-3-Triethylsilyloxy-4-(2-furyl)azetidin-2-one (0.51 g, 1.91 mmol) in 25 mL of dichloromethane was stirred with diisopropylethyl amine (0.78 mL, 4.4 mmol) and i-propylchloroformate (4.0 mL, 1.0M in toluene, 4.0 mmol) in addition to a catalytic amount of DMAP. The solution was stirred for 1 h and diluted with dichloromethane and washed with brine, dried over MgSO4 and concentrated. The residue was chromatographed over silica gel (eluted with 5:1 hexane/ethyl acetate) to give 649 mg of the title product (Y: 96%); IR(KBr) 1822, 1812, 1716, 1374, 1314, 1186, 1018, 1004, 746 cm-1 ; 1H NMR (CDCl3,300MHz) δ7.39 (m, 1H), 6.35 (m, 2H), 5.08 (ABq, J=15.6, 5.6 Hz, 2H), 4.96 (d, J=10.0 Hz, 1H), 1.25 (d, J=6.3 Hz, 3H), 1.17 (d, J= 6.3 Hz, 3H)), 0.83 (t, J=7.8, 9H), 0.50 (m, 6H); 13C NMR (CDCl3,75.5 Hz) δ165.5, 148.6, 147.8, 142.9, 110.5, 109.9, 77.6, 71.1, 55.9, 21.7, 21.6, 6.3, 4.4; DCIMS M+H calcd for C17H28NO5Si: 354, Found: 354.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:31])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][C:15]=2[CH3:30])[C:8]2[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:7]1=2)=[O:4].Cl.[NH:38]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH3:39].[C:46](=[O:49])([O-:48])[O-].[K+].[K+].CN(C)C=O>O>[CH2:44]([O:43][C:41]([CH2:40][N:38]([CH3:39])[C:46]([O:48][CH2:2][C:3]([O:5][CH:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:31])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][C:15]=2[CH3:30])[C:8]2[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:7]1=2)=[O:4])=[O:49])=[O:42])[CH3:45]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CNC
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)CCl)c3cc(Cl)ccc32)c(C)c1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(C)C(=O)OCC(=O)OC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} chloroacetate (500 mg, 0.95 mmol), ethyl sarcosinate hydrochloride (230 mg, 1.5 mmol), and potassium carbonate (414 mg, 3.0 mmol) were added to dimethylformamide (DMF) (5 ml), and the mixture was stirred at 60° C. for 1 hour. Water was added to the reaction mixture, and the resulted precipitates were collected by filtration and washed with water. The precipitates were dissolved in ethyl acetate, dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (n-hexane:ethyl acetate=36:64→15:85). The purified product was concentrated under reduced pressure. Water was added the residue, and resulted precipitates were collected by filtration and dried to obtain 330 mg of {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} (ethoxycarbonylmethyl-methyl-carbamoyloxy)acetate as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([CH3:22])[C:11](=[O:21])[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[NH2:29].[C:35]1([CH3:45])[CH:40]=[CH:39][C:38]([S:41]([OH:44])(=[O:43])=[O:42])=[CH:37][CH:36]=1>ClC1C=CC=CC=1>[C:35]1([CH3:45])[CH:36]=[CH:37][C:38]([S:41]([OH:44])(=[O:42])=[O:43])=[CH:39][CH:40]=1.[CH3:34][O:33][C:31]1[CH:30]=[C:28]([N:29]2[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:12][C:11](=[O:21])[C:10]([CH3:22])=[C:9]2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:27]=[C:26]([O:25][CH3:24])[CH:32]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: COc1ccc(C(=O)C(C)C(=O)CC(=O)c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: COc1ccc(-c2c(C)c(=O)cc(-c3ccccc3)n2-c2cc(OC)cc(OC)c2)cc1

Procedure:
To 200 ml of chlorobenzene were added 3.1 g (0.01 mole) of 1-(4-methoxyphenyl)-2-methyl-5-phenyl-1,3,5-pentanetrione, 2.3 g (1.5 mole) of 3,5-dimethoxyaniline, 2.9 g (0.015 mole) of para-toluenesulfonic acid and 10 g of Molecular Sieves 5A, followed by refluxing the resulting mixture for 2 hours. After cooling the reaction mixture, solid matter was removed from the reaction mixture, followed by addition of 500 ml of chloroform thereto. The organic layer was washed first with 200 ml of 10% hydrochloric acid and then with water. The organic layer was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate by filtration, the solvent was distilled off and the residue was subjected to chromatography on a silica gel column (eluent: ethyl acetate). Upon washing the resultant crystals with ethyl acetate, 3.3 g of 1-(3,5-dimethoxyphenyl)-2-(4-methoxyphenyl)-3-methyl-6-phenyl-4(1H)-pyridinone p-toluenesulfonate having a melting point of 202°-204° C. was obtained.
Reaction SMILES: Cl[C:2](=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:9][C:10]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13]>N1C=CC=CC=1>[Cl:19][C:16]1[CH:15]=[C:11]2[C:10](=[CH:18][CH:17]=1)[NH:9][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:14][C:12]2=[O:13]
Reactant: NC(=O)c1cc(Cl)ccc1N
Reactant: CCOC(=O)C(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(=O)c2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl chlorooxoacetate (2.0 mL) was added to a solution of 2-amino-5-chlorobenzamide (2.50 g) in pyridine (15 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the resultant residue was dissolved in acetic acid (50 mL). Acetic anhydride (5.0 mL) was added to the solution, and the mixture was heated under reflux for 16 hours. The solvent was distilled away under reduced pressure, and ethanol was added to the residue. Crystals precipitated were collected by filtration and washed, to thereby give the title compound (2.71 g).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:10].Br[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:4]1([CH3:10])[CH:5]=[CH:6][CH:7]=[C:8]([O:9][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:3]=1
Reactant: COc1ccc(Br)cc1
Reactant: Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(Oc2cccc(C)c2)cc1
Temperature: 170 °C
Reaction time: 2 h

Procedure:
21.8 g of sodium hydride (55% in oil) are placed in 100 ml of absolute pyridine and treated dropwise during 1 hour with 54.1 g of m-cresol in 200 ml of pyridine. After completion of the reaction, 1.2 g of cuprous chloride are added and subsequently 93.5 g of 4-bromoanisole are added dropwise during 1 hour at reflux temperature. After refluxing for 4 hours, the pyridine is distilled off, the mixture being heated at the end up to 170° C. (internal temperature). After 2 hours, 350 ml of water are added dropwise with ice-cooling, followed by 500 ml of diethyl ether and a further 150 ml of water. The mixture is filtered with suction over Celite and the phases are separated. The organic phase is washed in sequence with 200 ml of 2N hydrochloric acid, three times with 100 ml of 2N sodium hydroxide each time, with 200 ml of water and with 200 ml of saturated sodium chloride solution. After drying over sodium sulfate and evaporation, there is obtained a brown-red oil which is filtered over a five-fold amount of silica gel with n-hexane/diethyl ether and then distilled to yield pure p-(m-tolyloxy)anisole; b.p. 106°-108° C./0.04 Torr; nD20 =1.5738.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH2:13])=[CH:11][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=2[F:31])[N:24]=[C:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:22]=1[CH3:39].Cl.O1CCOCC1>CN1C(=O)CCC1>[N:4]1([C:7]2[C:12]([NH:13][C:21]3[C:30]4[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=4[F:31])[N:24]=[C:23]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[C:22]=3[CH3:39])=[CH:11][C:10]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:9][N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure K, method 2 using 2,5-dimorpholinopyridin-3-amine (118 mg, 0.45 mmol; described herein), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (130 mg, 0.45 mmol; described herein), 4.0M hydrogen chloride in 1,4-dioxane (110 μL, 0.45 mmol), and NMP (450 μL). Purification afforded N-(2,5-di-4-morpholinyl-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (500 MHz, chloroform-d) δ ppm 8.66-8.74 (1H, m), 7.85-7.94 (2H, m), 7.73 (1H, d, J=11.0 Hz), 7.57-7.66 (2H, m), 7.38 (1H, ddd, J=6.0, 4.9, 2.8 Hz), 7.02 (1H, ddd, J=13.4, 8.5, 2.6 Hz), 6.44 (1H, d, J=2.9 Hz), 3.86-3.98 (4H, m), 3.76-3.85 (4H, m), 2.91-3.47 (8H, m), 2.21 (3H, s). Mass Spectrum (ESI) m/e=519.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][OH:9].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:9][CH2:8][CH2:7][C:6]2[S:5][CH:4]=[N:3][C:2]=2[CH3:1])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ncsc1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2scnc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.3 %

Procedure:
To a solution of 4-methyl-5-thiazoleethanol (2 mL, 16.7 mmol) in CH2Cl2 (10 mL) and pyridine (10 mL) was added p-toluenesulfonyl chloride (3.5 g, 18.4 mmol) portionwise over 15 min. This mixture was stirred at ambient temperature for 18 h then was quenched with 5% aqueous HCl (15 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organics were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via column chromatography (SiO2, 50% hexanes/ethyl acetate) to give 2-(4-methylthiazol-5-yl)ethyl 4-methylbenzenesulfonate (3.24 g, 10.9 mmol, 65% yield). MS (DCI/NH3) m/z 298 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH:2]=1.[Cl-].[NH4+]>O.O1CCCC1.CO.[Fe]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:2]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cccnc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1ccc(Oc2cccnc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
4-(Pyridin-3-yl)oxy-1-nitrobenzene prepared in Step A was dissolved in the mixture of water (100 mL), tetrahydrofuran (100 mL) and methanol (100 mL). Iron powder (103 g, 1.84 mol) and ammonium chloride (99 g, 1.84 mol) were added thereto, and the mixture was stirred for 3 h at 80° C. using a mechanical stirrer. After completion of the reaction, the reaction mixture was filtered through a cellite, washed with methanol, and concentrated under reduced pressure. The solid thus obtained was filtered, washed with ether, and dried to give the title compound (17 g, Yield 36%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][C@H:11]([CH2:15][OH:16])[CH:12]([CH3:14])[CH3:13].[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]1[O:26][C:25](=[O:27])[C:24]2([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[N:23]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([NH:23][C:24]1([C:25]([NH:10][C@H:11]([CH2:15][OH:16])[CH:12]([CH3:14])[CH3:13])=[O:27])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26]
Reactant: O=C1OC(c2ccco2)=NC12CCCCC2
Reactant: CC(C)[C@H](N)CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](CO)NC(=O)C1(NC(=O)c2ccco2)CCCCC1
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A solution of 8.81 ml (50.6 mmol) of N,N-diisopropylethylamine, and 2.09 g (20.2 mmol) of L-valinol in 10 mL of methylene chloride was added to a solution of 3.71 g (16.9 mmol) of 2-(2-furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in 100 ml of toluene, and the mixture was heated under reflux for 14 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the mixture was stirred overnight. The obtained crystal was collected by filtration to obtain 4.06 g (74.7%) of the title compound.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH3:5][O:6][C:7](=[O:40])[CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][C@H:14]1[C:18](=[O:19])[CH:17]=[CH:16][C@@H:15]1/[CH:20]=[CH:21]/[C@@H:22]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:23][CH2:24][C:25]1[S:26][C:27]([CH3:31])=[C:28]([Br:30])[CH:29]=1>C1COCC1.[Cu]I>[CH3:5][O:6][C:7](=[O:40])[CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][C@H:14]1[C:18](=[O:19])[CH2:17][CH:16]([CH:1]=[CH2:2])[C@@H:15]1/[CH:20]=[CH:21]/[C@@H:22]([O:32][Si:33]([C:36]([CH3:37])([CH3:39])[CH3:38])([CH3:34])[CH3:35])[CH2:23][CH2:24][C:25]1[S:26][C:27]([CH3:31])=[C:28]([Br:30])[CH:29]=1
Reactant: C=C[Mg]Br
Reactant: COC(=O)CCC/C=C\C[C@H]1C(=O)C=C[C@@H]1/C=C/[C@H](CCc1cc(Br)c(C)s1)O[Si](C)(C)C(C)(C)C
Agent: [Cu]I
Solvent: C1CCOC1
Product: C=CC1CC(=O)[C@H](C/C=C\CCCC(=O)OC)[C@H]1/C=C/[C@H](CCc1cc(Br)c(C)s1)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
Vinylmagnesium bromide (1.25 mL, 1.25 mmol, 1 M/THF) was added to a 0° C. mixture of CuI (158 mg, 0.83 mmol) in 2 mL THF. The dark mixture was stirred for 5 min. and then was cooled to −78° C. A solution of Enone 7 (169 mg, 0.28 mmol) in 1 mL THF was added by cannula, rinsing with 0.25 mL THF. The mixture was stirred for 1.5 h and then 20 mL saturated NH4Cl was added. The resulting mixture was stirred for 20 min. and then was extracted with ethyl acetate (3×20 mL). The combined ethyl acetate solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (7.5% ethyl acetate/hexanes) gave the title ketone (138 mg, 0.22 mmol, 79%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.O.C(O)(=O)C.O>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1NS(=O)(=O)c1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(Cl)cccc1NS(=O)(=O)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.8 %

Procedure:
652 mg of 4-{[(3-chloro-2-methylphenyl)amino]sulfonyl}benzoic acid was dissolved in 10.0 mL of THF, and 6.00 mL of a 1 M borane-THF complex was added thereto under an argon atmosphere, followed by stirring at room temperature for 4 hours. To the reaction liquid was added 1.00 mL of a mixed solution of water-acetic acid (1:1) and added water, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 467 mg of N-(3-chloro-2-methylphenyl)-4-(hydroxymethyl)benzenesulfonamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:23])=[C:15]([N+:20]([O-])=O)[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[OH-].[Na+]>CO.[Zn]>[NH2:20][C:15]1[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]2[O:3][C:2]([CH3:24])([CH3:1])[CH:6]([C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=3)[C:5]=2[C:14]=1[CH3:23]
Reactant: Cc1ccc(C2c3c(C)c([N+](=O)[O-])c(C)c(C)c3OC2(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CO
Product: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Yield: 61.6 %

Procedure:
2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-5-nitro-2,3-dihydrobenzofuran (1.26 g, 3.9 mmol) was dissolved in methanol (30 ml). Zinc powder (1.3 g) and 1N sodium hydroxide (15 ml) were added to the solution and the mixture was heated under reflux for 3 hours. Insoluble materials were filtered off and water was added. The mixture was extracted with ethyl acetate. The extract was washed with water, dried and then the solvent was distilled off. The residue was purified by column chromatography on silica gel (hexane-isopropyl ether, 95:5) and crystallized from hexane to obtain the desired compound (710 mg, yield: 53.7%), m.p. 119°-120° C.
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:6])([OH:5])[OH:4].O.[C:8]([OH:12])(=[O:11])[CH:9]=O.[CH:13](O)=[O:14]>>[CH:13]([N:1]([CH2:2][P:3]([OH:5])([OH:4])=[O:6])[CH2:9][C:8]([OH:12])=[O:11])=[O:14]
Reactant: NCP(=O)(O)O
Reactant: O=CO
Reactant: O=CC(=O)O
Solvent: O
Product: O=CN(CC(=O)O)CP(=O)(O)O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Aminomethylphosphonic acid (3.12 g, 0.028 mol) was dissolved in 30 ml of stirred 98% formic acid maintained at 80° C. with an oil bath. Glyoxylic acid hydrate (5.60 g, 0.061 mol) was added to the solution in several portions, resulting in vigorous gas evolution. After one hour, the reaction flask was removed from the oil bath and the solvent removed on a rotary evaporator to afford crude N-formyl-N-phosphonomethylglycine as a viscous yellow oil.
Reaction SMILES: [OH:1][C@@H:2]([CH2:25][OH:26])[CH2:3][C:4]1[CH:5]=[C:6]([F:24])[C:7]([C:10]2([F:23])[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[N:8][CH:9]=1.Cl.C(OCC)C>ClCCl.O1CCOCC1>[F:24][C:6]1[CH:5]=[C:4]([CH2:3][C@@H:2]([OH:1])[CH2:25][OH:26])[CH:9]=[N:8][C:7]=1[C:10]1([F:23])[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2ncc(C[C@@H](O)CO)cc2F)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: OC[C@H](O)Cc1cnc(C2(F)CCNCC2)c(F)c1
Yield: 113.4 %

Procedure:
A solution of 25 (1.70 g, 4.6 mmol) in dichloromethane (10 mL) was stirred with 4 mol/L HCl in dioxane (15 mL) in a closed vessel overnight at room temperature. The resulting suspension was stirred for 1 h with ethyl ether. The solid precipitated was collected by filtration and washed several times with ethyl ether to afford 1.42 g (100%) of 26 as a pale yellow foam (HCl salt). The identity of compound 26 was confirmed by LC/MS and was used directly for the next step. LC/MS (M+1) 310.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.O.OC1C2N=NNC=2C=CC=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][CH2:30][C:31](O)=[O:32].C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:31](=[O:32])[CH2:30][CH2:29][C:25]1[S:24][CH:28]=[CH:27][CH:26]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC2
Reactant: O=C(O)CCc1cccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)CCN(C(=O)CCc1cccs1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-6-methoxyisoquinoline (3.29 g), hydroxybenzotriazole monohydrate (5.72 g) and 3-(2-thienyl)propanoic acid (3.31 g) in 280 ml of dry tetrahydrofuran (THF) at 0° C. was added DCC (4.37 g) in one portion. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was filtered and concentrated. The residue was taken up into 200 ml of ethyl acetate (EtOAc) refiltered, washed with 5% aq. HCl (50 ml), 5% aq. NaCl (50 ml), 10% aq. KOH (50 ml), dried (MgSO4), filtered, and concentrated. Chromatography on silica gel (elution with 20% EtOAc:hexanes) afforded 4.54 g of the desired product.