Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:23]2[C:4](=[CH:5][C:6]3[S:12](=[O:13])[C:11]4[CH:14]=[C:15]([C:18]([O:20]C)=[O:19])[CH:16]=[CH:17][C:10]=4[CH2:9][CH2:8][C:7]=3[CH:22]=2)[CH2:3][CH2:2]1.[OH-].[K+]>O.C(O)C>[CH2:1]1[C:23]2[C:4](=[CH:5][C:6]3[S:12](=[O:13])[C:11]4[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=[CH:17][C:10]=4[CH2:9][CH2:8][C:7]=3[CH:22]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)S(=O)c1cc3c(cc1CC2)CCC3
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2c(c1)S(=O)c1cc3c(cc1CC2)CCC3
Reaction time: 1 h

Procedure:
Methyl 2,3,10,11-tetrahydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxylate 5-oxide (2.00 g; 6.13 mmole) was added to a solution of 85% potassium hydroxide (808 mg; 12.26 mmole) in a mixture of water (8 ml) and ethanol (40 ml) at room temperature. After 1 hour, the solution was filtered, evaporated to 15 ml and acidified to pH 2 with hydrochloric acid. The product was collected, washed with water and dried (finally at 105° C./0.005 Torr) to yield 1.55 g (81%) with a m.p. 290°-294° dec.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CO.FC(F)(F)C(O)=O.[CH2:16]([S:18]([C:21]1[CH:51]=[CH:50][C:24]([O:25][C:26]2[C:40]([CH2:41]NC(=O)/C=C\C(O)=O)=[CH:39][C:29]3[NH:30][C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[N:32][C:28]=3[CH:27]=2)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:17]>C(Cl)(Cl)Cl.[Cl-].[NH4+]>[CH2:16]([S:18]([C:21]1[CH:51]=[CH:50][C:24]([O:25][C:26]2[C:40]([CH2:41][CH2:1][OH:4])=[CH:39][C:29]3[NH:30][C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[N:32][C:28]=3[CH:27]=2)=[CH:23][CH:22]=1)(=[O:19])=[O:20])[CH3:17]
Reactant: O=C([O-])[O-]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2CNC(=O)/C=C\C(=O)O)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2CCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
9.0 mg of the obtained alcohol compound was dissolved in 1 ml of trifluoroacetic acid, and stirred at room temperature for 1.5 hours. The solvent was evaporated away, and the residue was diluted with chloroform and neutralized with aqueous saturated sodium hydrogencarbonate solution. This was extracted with chloroform, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, to obtain 9.0 mg of a trifluoroacetate. Potassium carbonate was added to a methanol (1 ml) solution of 9.0 mg of the trifluoroacetate, and stirred at room temperature for 30 minutes. This was diluted with chloroform, and aqueous saturated ammonium chloride solution was added to it, extracted with chloroform, and the organic layer was washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain 6.6 mg of the entitled compound as a colorless amorphous substance.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:37])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:27]=[CH:26][C:25]=2[CH3:36])[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:10][C:11]1([CH3:37])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:27]=[CH:26][C:25]=2[CH3:36])[CH2:12]1
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)O)ccc2N1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)NS(=O)(=O)C3CC3)ccc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.3 %

Procedure:
To a suspension of 60% sodium hydride (560 mg, 14 mmol) in N,N-dimethylformamide (5 mL) was added cyclopropanesulfonic acid amide (1.33 g, 14 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A24. A solution of 4,4-dimethyl-2-(2-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (800 mg, 2 mmol) and 1,1′-carbonyldiimidazole (690 mg, 4 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B24. Solution B24 was added to Solution A24 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [4,4-dimethyl-2-(2-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (90 mg, 9%) as a white solid: MS (ESI) M+1=484.1.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]1[CH3:13])(=[O:3])[CH3:2].CN(C)[CH:16]=[CH:17][CH:18]=[O:19].P(Cl)(Cl)(Cl)=O.C([O-])(=O)C.[Na+]>ClCCCl.O>[C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:8]([CH3:13])=[CH:9][C:10]([CH:16]=[CH:17][CH:18]=[O:19])=[C:11]1[CH3:12])(=[O:3])[CH3:2]
Reactant: CN(C)C=CC=O
Reactant: CC(=O)NCCn1c(C)ccc1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)NCCn1c(C)cc(C=CC=O)c1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
16.2 g (0.09 mol) of 1-(2-acetylaminoethyl)-2,5-dimethylpyrrole and 10 g (0.1 mol) of 3-dimethylaminoacrolein are dissolved in 80 ml of 1,2-dichloroethane. 9 ml (0.098 mol) of phosphorus oxychloride are added dropwise at -10° C. After 20 minutes, 41 g (0.5 mol) of sodium acetate in 150 ml of water are added, the mixture is stirred at room temperature for 18 hours and heated at 70° C. for 2 hours, the phases are separated, the organic phase is chromatographed over a silica gel column and the product is recrystallized from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=O)[C:12]([C:16]#[N:17])=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:13]1[C:12]([C:16]#[N:17])=[CH:11][C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Temperature: 100 °C

Procedure:
To 6-(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-nitrile (40.75g) was added POCl3 (20 mL). The reaction was heated to 100° C. for 13 hours. After cooling to room temperature the excess POCl3 was removed in vacuo before the residue was dissolved in CH2Cl2 and washed with saturated aqueous NaHCO3 solution. The solution was concentrated and purified via flash chromatography on silica gel with a gradient elution of 30% to 100% CH2Cl2 in hexane affording the title compound. HPLC/MS: 392.9 (M+1), 394.9 (M+3); Rt=4.45 min.
Reaction SMILES: C([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=O.[CH2:11]([N:13](CC)CC)C.ClC(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[N+:13]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])#[C-:11]
Reactant: CCN(CC)CC
Reactant: O=CCCCCCC(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: [C-]#[N+]CCCCCC(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of the above 6-formyl hexanoic acid Wang-resin ester (165 g, 0.16 mol) in dichloromethane (3.2 l) was added triethylamine (222 ml, 1.6 mol), tetrachloromethane (155 ml, 1.6 mol) and triphenylphosphine (168 g, 0.64 mol). The resulting mixture was stirred at room temperature for 16 h under an atmosphere of nitrogen. The resin was filtered off and washed with N,N-dimethylformamide, dichloromethane, methanol, dichloromethane and dried in a vacuum desiccator for 18 h which afforded 6-isocyano-hexanoic acid Wang-resin ester.
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([O:23]C)[CH:16]=2)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CO.C(Cl)(Cl)Cl>[CH2:1]([C:8]1[N:12]=[C:11]([CH:13]=[CH:14][C:15]2[CH:16]=[C:17]([OH:23])[C:18]([OH:21])=[CH:19][CH:20]=2)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C=Cc2nc(Cc3ccccc3)no2)cc1OC
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Oc1ccc(C=Cc2nc(Cc3ccccc3)no2)cc1O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
3-Benzyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl-]-[1,2,4]oxadiazole (compound of Example 4, Method A, Step 1; 0.180 g, 0.55 mmol) was dissolved in dichloromethane (7 mL) and cooled to −78° C. A solution of boron tribromide (0.41 mL, 4.40 mmol) in dichloromethane (4 mL), which was cooled to 0° C., was added slowly over a period of 15 min. After 3 h, the reaction mixture was warmed to room temperature and stirred for 3 h. After completion of the reaction, the mixture was quenched by dropwise addition of methanol (15 mL) at 0° C. and stirred for 20 min at room temperature. The solvent was evaporated and the residue obtained was redissolved in 10% methanol in chloroform at 0° C., followed by stirring with solid sodium carbonate to maintain pH ˜8. The solvent was evaporated and the crude product obtained was purified by column chromatography (silica gel, 0.5% methanol in chloroform) to afford the title compound.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:2][C:3]([O:5]N1C(=O)CCC1=O)=O.CCN(C(C)C)C(C)C.[NH2:32][C@H:33]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34][CH2:35][C:36](=[O:38])[OH:37].CCOC(C)=O>CN(C=O)C>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:2][C:3]([NH:32][C@H:33]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34][CH2:35][C:36](=[O:37])[OH:38])=[O:5]
Reactant: O=C(CNC(=O)OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H](CCC(=O)O)NC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.4 %

Procedure:
Z-Gly-OSu (1.3 g, 4.25 mmol) was dissolved in DMF (15 ml) and DIEA (1.82 ml, 10.6 mmol) and H-Glu-OtBu (0.949 g, 4.67 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. AcOEt (100 ml) was added and the mixture was washed with 0.2N hydrochloric acid (100 ml) and water (2×100 ml). The organic phase was dried (Na2SO4) and concentrated in vacuo to afford 1.7 g (quant.) of Z-Gly-Glu-OtBu as an oil.
Reaction SMILES: [CH2:1]([C:13]1[S:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+].[O-:22][Mn](=O)(=O)=O.[K+].Cl>O>[CH2:1]([C:13]1[S:17][C:16]([C:18]([OH:22])=[O:19])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCCCCCCCCCCc1ccc(C=O)s1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCc1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 38.1 %

Procedure:
In a 2 liter-four-necked flask, 30.0 g(1.07×10-1 mol) of 5-dodecylthiophene-2-carbaldehyde, 6.0 g of NaOH, 21.3 g of KMnO4 and 900 ml of water were placed and stirred for 17 hours at room temperature. After the reaction, the reaction mixture was acidified with conc. hydrochloric acid, followed by four times of extraction with 300 ml of ethyl acetate, three times of washing with 500 ml of water, drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain 29.9 g of a crude product. The crude product was purified by silica gel column chromatography with the use of an hexane/ethyl acetate (=2/1) mixture solvent and recrystallized from ethyl acetate to obtain 12.1 g of a pure product (yield: 38.2%).
Reaction SMILES: [Na].[O-]CC.[Na+].Cl.[C:7]([NH2:10])(=[NH:9])[CH3:8].[C:11]([OH:19])(=[O:18])/[C:12](=[C:14](\[CH:16]=O)/[Br:15])/Br>C(O)C>[Br:15][C:14]1[C:12]([C:11]([OH:19])=[O:18])=[N:9][C:7]([CH3:8])=[N:10][CH:16]=1
Reactant: CC(=N)N
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ncc(Br)c(C(=O)O)n1
Temperature: 50 °C
Yield: 41.7 %

Procedure:
Sodium (356 mg, 15.5 mmol) was carefully added to ethanol (5.9 mL) to prepare sodium ethoxide solution in ethanol. The above freshly prepared sodium ethoxide in ethanol solution (3.5 mL) was added to a stirred suspension of acetamidine hydrochloride (0.91 g, 9.69 mmol). The mixture was warmed to 50° C., then the heating bath was removed and a solution of mucobromic acid (1 g, 3.87 mmol) in ethanol was added dropwise at a rate which maintained a constant temperature, followed by a further sodium ethoxide in ethanol solution (2 mL). After cooling, the mixture was filtered and evaporated to a residue which was shaken vigorously with hydrochloric acid (2 M×2.4 mL). The brown precipitate was filtered and washed with cold water, then freeze-dried to give 5-bromo-2-methylpyrimidine-4-carboxylic acid (350 mg, 42%) as a brown solid. LCMS: 218 [M+1]+, 1H NMR (400 MHz, DMSO-d6): δ 2.62 (s, 3H), 9.03 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=1.[CH3:17][O:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=2)[N:23]([NH2:31])[CH:22]=1)=[O:20].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[CH3:17][O:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=2)[N:23]([NH:31][C:14]([C:10]2[C:11]([CH3:13])=[N:12][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][CH:9]=2)=[O:16])[CH:22]=1)=[O:20]
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Reactant: COC(=O)c1cn(N)c2ccc(F)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(NC(=O)c2cnc(-c3ccccn3)nc2C)c2ccc(F)cc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 2-(2-pyridyl)-4-methyl-pyrimidine-5-carboxylic acid (559 mg, 2.6 mmol) and 1-amino-5-fluoro-1H-indole-3-carboxylic acid methyl ester (540 mg, 2.6 mmol) in DMF (25 mL) is stirred at 50° C. for 0.5 h. The mixture is treated with DMTMM (718 mg, 2.6 mmol) and stirred at 50° C. for 1 h. The mixture is diluted with saturated aqueous Na2CO3 (50 mL), and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 1%-10% MeOH in DCM to afford 5-fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H-indole-3-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-])=O)[C:3]=1[C:12]([F:15])([F:14])[F:13].C(OCC)(=O)C.C(O)(=O)C>[Fe].O>[NH2:9][C:4]1[C:3]([C:12]([F:13])([F:14])[F:15])=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: O=[N+]([O-])c1c(O)ccc(Cl)c1C(F)(F)F
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(O)ccc(Cl)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A mixture of 1.57 g of 4-chloro-2-nitro-3-trifluoromethylphenol and 5 ml of ethyl acetate was added dropwise to a mixture, which was heated to 80° C., of 1.8 g of electrolytic iron, 7 ml of acetic acid and 7 ml of water, which was stirred for 30 minutes. The mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.1 g of 2-amino-4-chloro-3-trifluoromethylphenol.
Reaction SMILES: Br.[CH2:2]([N:4]([CH2:19][CH3:20])[CH2:5][CH2:6][O:7][C:8]1[C:13](C)=[CH:12][C:11]([N+:15]([O-])=O)=[CH:10][C:9]=1C)[CH3:3].O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[CH2:19]([N:4]([CH2:2][CH3:3])[CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=1)[CH3:20]
Reactant: CCN(CC)CCOc1c(C)cc([N+](=O)[O-])cc1C
Agent: Br
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN(CC)CCOc1ccc(N)cc1
Reaction time: 1.5 h

Procedure:
To 8.0 g (23 mmol) of N,N-diethyl-2-(2,6-dimethyl-4-nitrophenoxy)ethanamine hydrobromide in 90 mL of ethanol add 26.0 g (115 mmol) of tin(II) chloride dihydrate. Heat the mixture to reflux with stirring for 1.5 h. Cool the mixture and pour it onto ice-water. Adjust the pH to 12 by the addition of dilute sodium hydroxide. Add ethyl acetate and filter the mixture through celite. Extract the filtrate twice with ethyl acetate. Wash the extract with saturated sodium chloride solution and dry over anhydrous sodium sulfate. Remove the drying agent by filtration and emove the solvent in vacuo to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[BH4-].[Na+]>CC(O)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CCOC)CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)C1(CCOC)CCC(O)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-(2-Methoxy-ethyl)-4-oxo-cyclohexanecarboxylic acid ethyl ester (1.60 g) was dissolved in 2-propanol (25 mL) The mixture was cooled to 0° C. and sodium borohydride (331 mg) was added in 3 portions over 10 minutes. Stirring was continued for 2 hours at 0° C. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The title compound was obtained as an inseparable mixture of cis and trans diastereomeres (ratio: 3/1) as a light yellow liquid (1.58 g, 98%). This mixture was used without further purification. MS (EI)=230.0 [MH+].
Reaction SMILES: C[C@H:2]1[C@@H:11]2[N:6]([C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH:5]=[CH:4][C:3]1=[O:16].Cl[C:18]1C=CC2N3C(=C(C)C(=O)CC3)CCC=2C=1>>[CH3:18][C:13]1[CH:14]=[CH:15][C:7]2[N:6]3[CH:11]([CH2:2][C:3](=[O:16])[CH:4]=[CH:5]3)[CH2:10][CH2:9][C:8]=2[CH:12]=1
Reactant: C[C@@H]1C(=O)C=CN2c3ccccc3CC[C@H]12
Reactant: CC1=C2CCc3cc(Cl)ccc3N2CCC1=O
Product: Cc1ccc2c(c1)CCC1CC(=O)C=CN21

Procedure:
(cis) and (trans) 4-methyl4,4a,5,6-tetrahydro-( 11H)-benzo[c]quinolizin-3-one; 8-chloro4-methyl-1 ,2,5,6-tetrahydro-(11H)-benzo[c] quinolizin-3-one;
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@@:6]1([C:26]([OH:28])=[O:27])[C@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:25])[C:22]([OH:24])=[O:23].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]O)=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][O:23][C:22]([C@:8]2([F:25])[C@@H:7]3[C@H:9]2[CH2:10][C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[C@@:6]3([NH2:5])[C:26]([OH:28])=[O:27])=[O:24])=[CH:32][CH:31]=1
Reactant: OCc1ccc(F)cc1
Reactant: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)O
Solvent: O=S(Cl)Cl
Product: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
23 μL of thionyl chloride was added to 30 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid suspended in 0.3 mL of 4-fluorobenzyl alcohol at room temperature, and the mixture was stirred for 3 days at 60° C. After standing to cool, the reaction solution was purified by reverse phase chromatography (Wako gel 50C18 (made by Wako Pure Chemical Industries Ltd.) eluent:water, a 70% aqueous solution of acetonitrile), thereby yielding 5 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-(4-fluorobenzyl)ester.
Reaction SMILES: O1C=CC=C1.[CH3:6][O:7][CH:8]1[CH2:12][CH:11]=[C:10]([O:13][CH3:14])[O:9]1>>[CH3:6][O:7][CH:8]1[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[O:9]1
Reactant: COC1=CCC(OC)O1
Solvent: c1ccoc1
Product: COC1CCC(OC)O1
Yield: 3.3 %

Procedure:
After 1 F/mol of furan, the GC-percentage by area of furan had been reduced from 22.7 to 16.9%, and the GC-percentage by area of 2,5-dimethoxydihydrofuran remained at 30%. At the same time, 3.3% of 2,5-dimethoxytetrahydrofuran were formed.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:24](=[O:27])(=[O:26])[NH2:25])[C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:7]([OH:9])=[O:8])([O-])=O.N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:24](=[O:26])(=[O:27])[NH2:25])[C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:15]=1)[C:7]([OH:9])=[O:8]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1cccc(C(F)(F)F)c1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Nc1cccc(C(F)(F)F)c1

Procedure:
By substituting 3-nitro-5-sulphamyl-4-(m-trifluoromethylanilino)-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the above compound was obtained with a melting point of 273°-274° C.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH2:8][CH2:9][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[OH:11])[CH:2]=1.C(N(CC)CC)C.[C:26](=O)(OC(Cl)(Cl)Cl)[O:27]C(Cl)(Cl)Cl>C(Cl)Cl>[C:12]1([C@H:10]2[O:11][C:26](=[O:27])[N:7]([C:3]3[CH:2]=[C:1]([CH3:18])[CH:6]=[CH:5][CH:4]=3)[CH2:8][CH2:9]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(NCC[C@H](O)c2ccccc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(N2CC[C@@H](c3ccccc3)OC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of (S)-3-(m-tolylamino)-1-phenylpropan-1-ol (40 mg, 0.17 mmol) in dry CH2Cl2 (1 mL) was added triethylamine (50 mg, 0.51 mmol) and bis(trichloromethyl) carbonate (20 mg, 0.067 mmol) at 0° C., and the reaction mixture was stirred overnight at room temperature. When the reaction was over, the mixture was concentrated to give the crude product, which was purified by preparative TLC (3:1 Petroleum ether/EtOAc) to give (S)-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one (12 mg, 26%). 1H NMR: (400 MHz, CDCl3): δ=2.24-2.37 (m, 5H), 3.52-3.63 (m, 1H), 3.70-3.79 (m, 1H), 5.42 (dd, 1H), 7.01-7.10 (m, 3H), 7.18-7.23 (m, 2H), 7.32-7.39 (m, 4H).