Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[CH2:15][O:14][C:13]2[CH:16]=[C:17]3[C:21](=[CH:22][C:12]1=2)[CH2:20][CH2:19][O:18]3.N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O.Br[CH2:45][C:46]1[O:47][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:49][CH:50]=1.ClCC1C=NC(OC)=NC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:45][C:46]1[O:47][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:49][CH:50]=1)[C:8](=[O:11])[C:7]12[C:12]2=[CH:22][C:21]3[CH2:20][CH2:19][O:18][C:17]=3[CH:16]=[C:13]2[O:14][CH2:15]1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: O=C1Nc2c(Cl)cccc2C12COc1cc3c(cc12)CCO3
Agent: COc1ncc(CCl)cn1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2c(Cl)cccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using 7′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 5-(chloromethyl)-2-methoxypyrimidine, 7′-chloro-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indolin]-2′-one was obtained (30%) as a colorless solid: mp 210-211° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ7.34-7.31 (m, 1H), 7.21-7.16 (m, 2H), 7.10-7.05 (m, 1H), 6.67-6.65 (m, 1H), 6.49 (s, 1H), 6.43 (s, 1H), 5.34 (s, 2H), 4.85 (d, J=9.6 Hz, 1H), 4.74 (d, J=9.6 Hz, 1H), 4.57-4.48 (m, 2H), 2.94 (t, J=3.0 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.4, 161.2, 160.4, 154.1, 139.4, 138.9, 137.2, 135.4, 130.5, 124.6, 122.8, 120.6, 120.1, 119.9, 118.7, 117.1, 114.3, 114.2, 108.7, 92.4, 79.8, 72.0, 56.6, 28.1.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:10]1([C:8]2[N:9]=[C:4]3[CH:3]=[C:2]([O:1][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:18]=[CH:17][N:5]3[C:6](=[O:16])[CH:7]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1
Reactant: OB(O)c1ccccc1
Reactant: O=c1cc(N2CCOCC2)nc2cc(O)ccn12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1cc(N2CCOCC2)nc2cc(Oc3ccccc3)ccn12
Temperature: 25 °C
Reaction time: 96 h
Yield: 9.9 %

Procedure:
8-Hydroxy-2-morpholinyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.2 g, 0.81 mmol), phenylboronic acid (0.29 g, 2.4 mmol), and copper acetate (0.20 g, 1.6 mmol) were suspended in dichloromethane and treated with triethylamine (0.23 ml, 1.6 mmol) and the mixture was stirred at RT for 4 days. The product was adsorbed onto silica and eluted through a silica column with ethyl acetate to yield a pale tan solid (0.026 g).
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([F:26])[CH:14]=1.[CH3:27][S:28]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:40]=1[NH:39][CH:38]=[CH:37]2)(=[O:30])=[O:29]>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:37]2[C:36]3[C:40](=[C:32]([CH2:31][S:28]([CH3:27])(=[O:30])=[O:29])[CH:33]=[CH:34][CH:35]=3)[NH:39][CH:38]=2)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([F:26])[CH:14]=1
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Reactant: N#CC1CC1C(O)c1ccc(Cl)cc1F
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Cc1cccc2c(C(c3ccc(Cl)cc3F)C3CC3C#N)c[nH]c12

Procedure:
1.76 g (7.98 mmol) of indium(III) chloride and 0.92 ml (12.0 mmol) of trifluoroacetic acid were added to 1.50 g (6.65 mmol) of the compound from Example 165A and 1.67 g (7.98 mmol) of the compound from Example 86A under argon in 69 ml of dichloromethane, and the mixture was heated under reflux for three days. It was concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) and another isocratic RP18 separation with acetonitrile/water 1:1 to result in 283 mg (10% of theory) of diastereomer 1 and 145 mg (5% of theory) of diastereomer 2 of the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:8]2[C:16]3[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]([C:21]3[C:30]([OH:31])=[CH:29][C:24]4[O:25][CH2:26][CH2:27][O:28][C:23]=4[CH:22]=3)[C:9]2=[O:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:39]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:33]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[C:10]3([C:21]4[C:30](=[CH:29][C:24]5[O:25][CH2:26][CH2:27][O:28][C:23]=5[CH:22]=4)[O:31][CH2:39]3)[C:9]2=[O:32])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1cc(OC)c2c(c1)N(C(c1ccccc1)c1ccccc1)C(=O)C2c1cc2c(cc1O)OCCO2
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: COc1cc(OC)c2c(c1)N(C(c1ccccc1)c1ccccc1)C(=O)C21COc2cc3c(cc21)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,6-dimethoxy-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-4′,6′-dimethoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (96%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.41-7.24 (m, 10H), 6.97 (s, 1H), 6.42 (s, 1H), 6.19 (s, 1H), 6.04 (d, J=1.8 Hz, 1H), 5.69 (d, J=1.8 Hz, 1H), 4.81 (ABq, 2H), 4.21-4.06 (m, 4H), 3.62 (s, 3H), 3.47 (s, 3H); MS (ES+) m/z 522.1 (M+1).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[C:9](Cl)[C:8]=1[N+:18]([O-:20])=[O:19])[CH2:4][CH3:5].[NH3:21]>C(COC)OC>[CH3:1][CH2:2][CH:3]([NH:6][C:7]1[C:8]([N+:18]([O-:20])=[O:19])=[C:9]([NH2:21])[C:10]([CH3:16])=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH2:4][CH3:5]
Reactant: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(Cl)c1[N+](=O)[O-]
Reactant: N
Solvent: COCCOC
Product: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(N)c1[N+](=O)[O-]
Temperature: 94 °C

Procedure:
A mixture of 5.00 g. (0.0165 mole) of N-(3-pentyl)-3-chloro-2,6-dinitro-4-methylaniline and 30 ml. of dimethoxyethane was charged to a glass reaction tube. The tube was cooled, 5 ml. of anhydrous ammonia condensed into it, and the tube was then sealed. After heating for 5 hours at 94°C., the tube was opened and the reaction mixture was stripped of volatile material. The residue was taken up in 250 ml. of hot cyclohexane, the solution filtered while hot, then stripped to give an orange residue which was crystallized from 95% ethanol to give 1.02 g. of the desired product as orange needles, m.p. 157°-160.5°C. After recrystallization from 95% ethanol the product melts at 160°-161.5°C.
Reaction SMILES: [Br:1][C:2]1[C:3]([Br:18])=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.[Cl:19][CH2:20][C:21](Cl)=[O:22].C(N(CC)CC)C>O>[Cl:19][CH2:20][C:21]([N:11]1[C:5]2[CH:4]=[C:3]([Br:18])[C:2]([Br:1])=[CH:17][C:6]=2[NH:7][C:8](=[O:16])[C:9]2[CH:15]=[CH:14][CH:13]=[N:12][C:10]1=2)=[O:22]
Reactant: O=C1Nc2cc(Br)c(Br)cc2Nc2ncccc21
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1Nc2cc(Br)c(Br)cc2N(C(=O)CCl)c2ncccc21

Procedure:
6,11-Dihydro-8,9-dibromo-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one (0.1 mol) in 300 ml. of water-free dioxane is dissolved by heating to reflux. To the boiling solution is added, dropwise over 30 minutes, a solution of 15. g. (0.14 mol) of chloroacetyl chloride, dissolved in 40 ml. of water-free dioxane, and simultaneously 14.4 (0.14 mol) of triethylamine, dissolved in 30 ml. of water-free dioxane. The mixture is refluxed for 8 hours and then filtered while hot. The filtrate is evaporated in vacuo, and the resulting residue is recrystallized from acetonitrile to give 11-chloroacetyl-8,9-dibromo-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one.
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[N:4]([CH3:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][N:7]=1.S(=O)(=O)(O)[OH:14].[OH-].[Na+]>>[CH:2]([C:3]1[N:4]([CH3:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][N:7]=1)=[O:14]
Reactant: Cn1c([N+](=O)[O-])cnc1C(Cl)Cl
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cn1c([N+](=O)[O-])cnc1C=O

Procedure:
210 parts of 2-dichloromethyl-1-methyl-5-nitroimidazole are stirred in 800 parts by volume of 10 percent strength by weight sulfuric acid for 2 hours at 100° C. The mixture is then neutralized with 550 parts of 6 N sodium hydroxide solution, with intense cooling, and the resulting solution is extracted with 4 times 500 parts by volume of methylene chloride. The combined extracts are dried. 126 parts (82% of theory) of 2-formyl-1-methyl-5-nitroimidazole of melting point 93° C. (after recrystallization from toluene) are obtained.
Reaction SMILES: CS[C:3]([N:7]1[CH2:11][C:10]([CH3:13])([CH3:12])[CH:9]=[N:8]1)=[N:4][CH2:5][CH3:6].[Br:14][C:15]1[CH:20]=[C:19]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:18]=[CH:17][C:16]=1[NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28]>C(#N)C>[Br:14][C:15]1[CH:20]=[C:19]([S:21](=[O:24])(=[O:23])[N:22]=[C:3]([N:7]2[CH2:11][C:10]([CH3:12])([CH3:13])[CH:9]=[N:8]2)[NH:4][CH2:5][CH3:6])[CH:18]=[CH:17][C:16]=1[NH:25][C:26](=[O:31])[C:27]([F:29])([F:30])[F:28]
Reactant: CCN=C(SC)N1CC(C)(C)C=N1
Reactant: NS(=O)(=O)c1ccc(NC(=O)C(F)(F)F)c(Br)c1
Solvent: CC#N
Product: CCNC(=NS(=O)(=O)c1ccc(NC(=O)C(F)(F)F)c(Br)c1)N1CC(C)(C)C=N1
Yield: 1.4 %

Procedure:
3.41 g (1 mol equiv.) N-Ethyl-4,4-dimethyl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester and 6.24 g (1.05 mol equiv.) N-(2-Bromo-4-sulfamoyl-phenyl)-2,2,2-trifluoro-acetamide were added to 100 mL acetonitrile. The reaction mixture was refluxed overnight, and subsequently volatiles were removed under reduced pressure. The residue was taken up in ethyl acetate and extracted with 2N NaOH, and the organic layer was dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (Et2O) afforded 7.1 g (83%) N-(2-bromo-4-{[(4,4-dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-sulfamoyl}-phenyl)-2,2,2-trifluoro-acetamide. 1H NMR (400 MHz, CDCl3) δ 1.18 (t, J=7.3 Hz, 3H), 1.24 (s, 6H), 3.43-3.51 (m, 2H), 3.79 (br.s., 2H), 6.78 (s, 1H), 7.93 (dd, J=8.6, 2.0 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.39 (d, J=8.6 Hz, 1H), 8.61 (br.s., 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[F:20])=[C:9](/[C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]2)\[F:10])=[CH:4][CH:3]=1.Cl.[CH2:22]1[CH2:26]OC[CH2:23]1>>[CH2:23]([C@H:2]1[CH2:7][CH2:6][C@H:5](/[C:8](/[F:20])=[C:9](/[C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]2)\[F:10])[CH2:4][CH2:3]1)[CH2:22][CH3:26]
Reactant: C1CCOC1
Reactant: CCC[C@H]1CC[C@H](/C(F)=C(\F)c2ccc(F)cc2)CC1
Agent: Cl
Product: CCC[C@H]1CC[C@H](/C(F)=C(\F)[C@H]2CC[C@H](CCC)CC2)CC1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
Then, a mixed solution containing 1.3 g (6.31 mmol) of 2-(trans-4-n-propylcyclohexyl)-1,1,2-trifluoroethylene obtained in Example 1 and 10 ml of dry THF, was dropwise added thereto at the same temperature over a period of 15 minutes. The mixture was reacted at the same temperature for one hour and then the temperature was raised to -10° C. Then, 100 ml of 1N hydrochloric acid was added thereto. The organic layer was separated. The aqueous layer was extracted with n-hexane, and the extract was combined with the organic layer. The combined organic layer was washed with water and dried. Then, the solvent was distilled off, and the obtained crude solution was purified by silica gel column chromatography. The obtained solid was further recrystallized from ethanol to obtain 1.18 g (yield: 60%) of (E)-1,2-bis(trans-4-n-propylcyclohexyl)-1,2-difluoroethylene.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9](CO)[OH:10])[OH:8])[OH:6])[OH:4].O=C[C@@H]([C@H]([C@@H](CO)O)O)O>C(O)C>[CH2:2]([OH:1])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Solvent: CCO
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
After 25 hours, strain CD804 (Ex. 4D) had consumed 15 g/L D-xylose and produced about 4.7 g/L of xylitol and 1 g/L of ethanol from the flask containing the glucose isomerase. In contrast, strains CD805 (Ex. 6C) and CD806 (Ex. 6B) had each consumed 25 g/L D-xylose in the presence of glucose isomerase. Strain CD805 produced in this time about 1.9 g/L of xylitol and 7.1 g/L of ethanol. Strain CD806 produced in this time about 1.8 g/L of xylitol and 6.8 g/L of ethanol. Xylulose seems to be consumed by the strains at very high rates, something which is not observed in S. cerevisiae. The non-oxidative pentose phosphate pathway controls the fermentation rate of xylulose but not of xylose in S. cerevisiae TMB3001. FEM Yeast Res. 2002 August; 2(3):277-82. Johansson B, Hahn-Hagerdal B). Without added glucose isomerase, each of strains CD804, CD805 and CD806 consumed xylose very slowly.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17](O)=[O:18])=[C:12]([CH2:15][OH:16])[CH2:13][S:14][C@H:9]12)=[O:6].Cl>CC(C)=O.O>[CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[CH:9]2[S:14][CH2:13][C:12]3[CH2:15][O:16][C:17](=[O:18])[C:11]=3[N:10]2[C:20]1=[O:21])=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1csc(N)n1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C3=C(COC3=O)CSC12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
A solution of 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.3 g) in a mixture of acetone (3 ml) and water (1.5 ml) was adjusted to pH 2 with 6 N hydrochloric acid and stirred for 4 hours at ambient temperature. After the acetone was distilled off, to the residue was added water (1 ml). The mixture was adjusted to pH 7 with a saturated aqueous solution of sodium bicarbonate and ice-cooled for 1 hour. Precipitating crystals were collected by filtration, washed with water and dried to give 6-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]-thiazine-1,7(4H)-dione (syn isomer) (0.23 g), mp 210° to 215° C. (dec.).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[Cl:8][C:9]([Cl:13])([Cl:12])[CH2:10]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:10][C:9]([Cl:13])([Cl:12])[Cl:8])=[O:6]
Reactant: OCC(Cl)(Cl)Cl
Reactant: O=C(O)CCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(CCCBr)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.9 %

Procedure:
A stirred solution of 4-bromobutyric acid (3.34 g, 20.0 mmol) in toluene (50 ml) was added 2,2,2-trichloroethanol (14.94 g, 0.10 mol) and p-toluenesulfonic acid monohydrate (7.60 g, 40.0 mmol) and refluxed with a Dean-Stark trap attached for 6 h. Water was removed continuously. The reaction mixture was cooled to room temperature and concentrated in vacuo. The mixture was added CH2Cl2 (75 ml) and washed with H2O (3×25 ml). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to leave an oil. The residue was distilled to leave the title compound as a colourless oil (4.77 g, 79.9%) (bp 100° C. at 0.5 mmHg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CN(C)C=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]=[O:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)nc3N21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C=O)nc3N21
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
A solution of 2.0 g (5.43 mmol) (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b) in 15 ml tetrahydrofuran was cooled to −75 deg C. and treated with 4.40 ml (0.65 mmol) tert-butyllithium (1.5 M solution in n-pentane). After 30 min, 0.60 ml (0.63 g, 8.15 mmol) N,N-dimethylformamide was added dropwise. After 2.5 h the reaction mixture was poured onto 10% aqueous citric acid solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash-chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:3) as eluant to afford the desired compound as a yellow oil (40.1%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[C:36]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52](Cl)=[O:53])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:36]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1)=[O:53])(=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(OCc1ccccc1C(=O)Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOC(=O)c3ccccc3COC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with 2-chlorocarbonyl-benzyl benzoate there was obtained tert-butyl (3RS,4RS)-4-[4-[2-(2-benzoyloxymethyl-benzoyloxy)-ethoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 716 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][N:31]([C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[C:38](=[O:40])[CH3:39])=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: COC[C@H](C)NCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Reactant: CC(=O)OC(C)=O
Product: COC[C@H](C)N(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(C)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
A suspension of urea 334 (66 mg, 0.127 mmol) in acetic anhydride (2 ml) was stirred at rt for 2 days. The reaction mixture was quenched by addition of methanol and water, and partitioned with AcOEt. After separation, the organic layer was collected, washed with water, 1N NaOH (×4), water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude solid was purified by flash column chromatography on silica gel (eluent 2% of ammonium hydroxyde in MeOH/DCM: 05/90 to 10/90) to afford the compound 335 (46 mg, 0.08 mmol, 64% yield) as an off-white fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): mixture of rotamers, 8.70 (s, 1H), 8.58-8.48 (m, 2H), 8.34 and 8.30 (2s, 1H), 8.27 and 8.19 (2d, J=8.3 Hz, 1H), 7.85-7.69 (m, 2H), 7.38 (t, J=9.0 Hz, 1H), 7.20 (bd, J=9.0 Hz, 1H), 6.67-6.54 (m, 2H), 4.74-4.16 (m, 3H), 3.41-3.22 (m, 2H), 3.15 and 3.13 (2s, 3H), 2.59-2.52 (m, 1H), 2.16 and 1.96 (2s, 3H), 1.09 and 1.04 (2d, J=6.9 Hz, 3H), 0.72-0.58 (m, 2H), 0.50-0.36 (m, 2H). MS (m/z): 564.4 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=3)[CH2:35][CH2:34]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4cc(C)ccc4nc3OC)CC2)c1
Yield: 94 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 94%). MS(ESI) m/z 438 (M+1).
Reaction SMILES: [CH2:1]1[C:6](=O)[N:5](Br)[C:3](=[O:4])[CH2:2]1.[NH2:9][C:10](N)=[S:11]>O>[NH2:9][C:10]1[S:11][C:1]([CH2:2][CH2:3][OH:4])=[CH:6][N:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: NC(N)=S
Solvent: O
Product: Nc1ncc(CCO)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 117.5 %

Procedure:
To an ice cold suspension of NBS (1.182 g, 6.72 mmol) in water (8 mL) was added 2,3-dihyofuran (0.75 mL, 9.92 mmol) slowly. The resulting solution was stirred at 0° C. for 1 h, followed by addition of thiourea (0.505 g, 6.63 mmol). The mixture was heated under reflux under nitrogen atmosphere overnight to form a yellow clear solution. The mixture was extracted with EtOAc (3×5 mL) and the aqueous solution was treated with ammonium hydroxide to pH 12. The solution was extracted with CH2Cl2 (2×5 mL), followed by extraction with EtOAc (8×10 mL). The CH2Cl2 layer contains small amount of product and large amount of impurities, which was discarded. The EtOAc layers were combined, dried, and concentrated to give 1.123 g 2-(2-amino-thiazol-5-yl)-ethanol
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:8][C:7]1[C:2]([O:22][C:19]2[CH:20]=[CH:21][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
2,3-Dichloro-5-trifluoromethylpyridine (2.16 g, 0.01M) and 4-nitrophenol (1.53 g, 0.011M) were mixed in methyl ethyl ketone (10 ml) containing anhydrous potassium carbonate (2.0 g) and heated at the reflux temperature for 10 hours. The cooled mixture was filtered to remove the solid matter and the filtrate concentrated by evaporation of the solvent under reduced pressure. The residue was triturated with diethyl ether and 3-chloro-5-trifluoromethyl-2-(4-nitrophenoxy)pyridine collected as a buff coloured solid (0.75 g), m.p. 98°-100° C.