Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([NH2:15])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])O.[Na+].[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([NH:15][C:29]([O:28][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:30])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)SCCC2N
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)SCCC2NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 100 %

Procedure:
To an ethyl acetate (200 ml) solution of 4-aminothiochromane-7-carboxylic acid methyl ester (8.00 g) was added saturated aqueous sodium hydrogencarbonate solution (200 ml), and benzyloxycarbonyl chloride (6.75 g) was added at room temperature. The mixture was stirred at the same temperature for 2 hrs. The reaction mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography to give the objective 4-(benzyloxycarbonylamino)thiochromane-7-carboxylic acid methyl ester (12.8 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[O:26][C:5]2=[CH:6][C:7]3[S:8][C:9]4[C:14]([C:15]=3[C:16]([C:17]3[CH:22]=[C:21]([I:23])[C:20]([OH:24])=[C:19]([I:25])[CH:18]=3)=[C:4]2[C:3]=1[CH3:27])=[CH:13][CH:12]=[CH:11][CH:10]=4.O[C@@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([O:32]C)=[O:31]>>[CH3:1][C:2]1[O:26][C:5]2=[CH:6][C:7]3[S:8][C:9]4[C:14]([C:15]=3[C:16]([C:17]3[CH:18]=[C:19]([I:25])[C:20]([O:24][C@H:29]([CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:30]([OH:32])=[O:31])=[C:21]([I:23])[CH:22]=3)=[C:4]2[C:3]=1[CH3:27])=[CH:13][CH:12]=[CH:11][CH:10]=4
Reactant: Cc1oc2cc3sc4ccccc4c3c(-c3cc(I)c(O)c(I)c3)c2c1C
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Product: Cc1oc2cc3sc4ccccc4c3c(-c3cc(I)c(O[C@H](Cc4ccccc4)C(=O)O)c(I)c3)c2c1C

Procedure:
Prepared from 4-(2,3-dimethyl-1-oxa-9-thia-cyclopenta[b]fluoren-4-yl)-2,6 -diiodo-phenol and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester according to the procedure in Example 8 to provide the title compound as a white solid: mp 215-217: NMR (DMSO-d6): δ8.17 (s, 1H), 7.94 (d, J=8 Hz, 1H), 7.85 (d, J=4 Hz, 2H), 7.39-7.30 (m, 5H), 7.22 (dd, J=7 Hz, 1H), 7.16 (dd, J=7, 1 Hz, 1H), 6.87 (d, J=8 Hz, 1H), 5.41 (s, 1H), 3.43 (dd, J=6, 1 Hz, 2H), 2.36 (s, 3H), 1.56 (s, 3H); MS (+FAB): [M+H]+, 745; Anal. Calc. for C31H22I2O4S: C, 50.02; H, 2.98; N, 0.00. Found: C, 47.59; H, 2.98; N, 0.13.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=2[OH:15])[CH:5]=[C:4]([Cl:16])[N:3]=1.[CH2:17](O)[CH2:18][CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:17][CH2:18][CH3:19])=[C:8]([C:6]2[CH:5]=[C:4]([Cl:16])[N:3]=[C:2]([NH2:1])[N:7]=2)[CH:13]=1
Reactant: CCCO
Reactant: Nc1nc(Cl)cc(-c2cc(Br)ccc2O)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Reaction time: 16 h
Yield: 52.5 %

Procedure:
To the stirred solution of 2-(2-amino-6-chloro-pyrimidin-4-yl)-4-bromo-phenol (0.060 g, 0.20 mmol), 1-propanol (0.036 g, 0.60 mmol), and triphenylphosphine (0.157 g, 0.60 mmol) in tetrahydrofuran (5.0 ml) was added diethyl azodicarboxylate (0.104 g, 0.60 mmol). After stirring for 16 hours, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:6) to provide 4-(5-bromo-2-propoxy-phenyl)-6-chloro-pyrimidin-2-ylamine (0.036 g, 52% yield) as a white powder.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:20][CH2:21]/[CH:22]=[CH:23]/[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][N:28]=[C:27]2[NH:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C:42]2[CH:43]=[N:44][C:45]([CH3:48])=[CH:46][CH:47]=2)=[C:37]([Cl:49])[CH:36]=1>C(Cl)Cl>[Cl:49][C:37]1[CH:36]=[C:35]([NH:34][C:27]2[C:26]3[C:31](=[CH:32][CH:33]=[C:24](/[CH:23]=[CH:22]/[CH2:21][NH:20][C:1](=[O:4])[CH3:2])[CH:25]=3)[N:30]=[CH:29][N:28]=2)[CH:40]=[CH:39][C:38]=1[O:41][C:42]1[CH:43]=[N:44][C:45]([CH3:48])=[CH:46][CH:47]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(/C=C/CN)cc34)cc2Cl)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)NC/C=C/c1ccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(Cl)c3)c2c1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
A mixture of 14.4 μL (0.25 mmol) of acetic acid and 40.3 mg (0.33 mmol) of dicyclohexylcarbodiimide in 2 mL of methylene chloride were stirred for 10 minutes and treated with 100.3 mg of E-[6-(3-amino-propenyl)-quinazolin-4-yl]-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine. The reaction was allowed to stir at room temperature overnight. The precipitate which formed was filtered and chromatographed on silica gel, eluting with 6-10% methanol/chloroform to afford 106 mg of the title compound; mp 254-256° C.; 1H NMR (d6 DMSO): δ 9.88 (s, 1), 8.58 (s, 1), 8.48 (m, 1), 8.20 (m, 3), 7.95 (m, 1), 7.83 (m, 1), 7.71 (d, J=8.7 Hz, 1), 7.24 (m, 2), 7.19 (d, J=8.7 Hz, 1), 6.61 (d, J=16.2 Hz, 1), 6.48 (m, 1), 3.90 (m, 2).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[N:14]=[C:13](S(C)(=O)=O)[N:12]=1>ClCCl>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[N:14]=[C:13]([N:3]2[C:2]([CH3:1])=[CH:6][C:5]([CH3:7])=[N:4]2)[N:12]=1
Reactant: CS(=O)(=O)c1nc(Cl)cc(Cl)n1
Reactant: Cc1cc(C)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C)n(-c2nc(Cl)cc(Cl)n2)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
A suspension of 3,5-dimethylpyrazole (3.9 g, 40.7 mmol) and sodium hydride (60% in mineral oil, 1.7 g) in dichloromethane (50 mL) was added dropwise to a cooled (−78° C.) solution of 4,6-dichloro-2-methanesulfonyl-pyrimidine (10 g, 38.7 mmol) in dichloromethane (200 mL). The mixture was stirred at −78° C. for one hour. The reaction was carefully quenched at the same temperature by addition of water (150 mL). The mixture was allowed to warm to room-temperature. Brine (150 mL) was added and the phases were separated. The aqueous phase was extracted with dichloromethane (4×200 mL). The combined organic layers were washed with brine, dried over sodium sulphate, filtrated and concentrated in vacuo. The crude product was purified by flash chromatography (ethyl acetate/heptane as eluent) to give 4,6-dichloro-2-(3,5-dimethyl-pyrazol-1-yl)-pyrimidine (5.5 g, 59%) as a white crystalline compound.
Reaction SMILES: [C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][NH:33][CH:34](O)[CH3:35]>C(O)C>[C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][CH2:35][CH2:34][NH:33][CH3:32])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][CH2:35][CH2:34][NH:33][CH3:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OB(c1ccccc1)C(OC(B(O)c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CNC(C)O
Solvent: CCO
Product: CNCCOB(c1ccccc1)C(OC(B(OCCNC)c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
The entitled compound (8 mg) was obtained by allowing 20 mg of bis(4,4′-(phenylhydroxyboryl)benzyl) ether and 7.3 mg of N-methylaminoethanol to act in 0.7 mL of ethanol at room temperature.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Temperature: 64.5 °C
Reaction time: 10 h
Yield: 86.6 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 2.12 g (13.2 mmol) of 3-bromo-1-chloropropane (purity: 98 wt. %), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt. %), and 30 mL of methanol. The resulting mixture was under stirring at 62-67° C. in an argon gas atmosphere for 10 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 1.23 g (reaction yield: 86.5%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]([O:11]CC)=O.[CH3:14][CH2:15][Mg+].[Br-]>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1([OH:11])[CH2:15][CH2:14]1
Reactant: CC[Mg+]
Reactant: CCOC(=O)COC1CCCCO1
Agent: [Br-]
Solvent: C1CCOC1
Product: OC1(COC2CCCCO2)CC1
Reaction time: 2 h
Yield: 54.8 %

Procedure:
To a mixture of ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate (1 g, 5.3 mmol) and Ti(O-iPr)4 (1.06 mL, 3.5 mmol, Aldrich) in 18 mL of THF under N2 was added EtMgBr (4.5 mL, 13.25 mmol, 3M ether solution, Aldrich) dropwise over 2 hrs, and the temperature must be kept at 15-20° C. After stirring for 2 hrs, and the reaction mixture was quenched with saturated NH4Cl aqueous solution at 0° C. and extracted with EtOAc (30 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (20:1 (v/v) petroleum ether/EtOAc) to afford 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol as colorless oil (500 mg, 55%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[NH3:15]>CO.CCOC(C)=O>[NH2:15][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: N
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(SC)nc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a stirred solution of ethyl 4-chloro-2-methylsulfanyl-5-pyrimidinecarboxylate (4.50 g, 19.4 mmol) in MeOH is added 7 N NH3 (13.9 mL) in MeOH at 0° C. and the mixture is stirred for 2 h at room temperature. The reaction mixture is diluted with EtOAc and washed with saturated NaHCO3 solution. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is crystrallized from the mixed solvent of EtOAc and hexanes to give 2.90 g (66%) of ethyl 4-amino-2-methylsulfanyl-5-pyrimidinecarboxylate as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][NH2:8])[CH2:4][O:3]1.C(N(CC)CC)C.[CH3:17][Si:18]([CH3:26])([CH3:25])[CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22]>CN(C)C=O>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][NH:8][S:21]([CH2:20][CH2:19][Si:18]([CH3:26])([CH3:25])[CH3:17])(=[O:23])=[O:22])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CN)O1
Reactant: C[Si](C)(C)CCS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)OCC(CNS(=O)(=O)CC[Si](C)(C)C)O1
Reaction time: 15 h

Procedure:
A solution of 2,2-dimethyl-4-aminomethyl-1,3-dioxolane (10.0 g, 0.08 mol) and triethylamine (8.1 g, 11.1 mL, 0.08 mol) in 100 mL of N,N-dimethylformamide is cooled to 0 C. under argon atmosphere. Then β-trimethylsilylethanesulfonyl chloride (16.0 g, 0.08 mol) is added dropwise. The solution is allowed to reach 25 C. and is stirred for 15 hours. The solvents are removed under reduced pressure and the crude residue is partitioned between dichloromethane (100 mL) and 5% sodium bicarbonate solution (50 mL). The layers are separated and the organic layer is dried over anhydrous sodium sulfate and evaporated to give 2,2-dimethyl-4-[N-(β-trimethylsilylethanesulfonyl)-aminomethyl]-1,3-dioxolane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[CH2:7][CH2:8]O)([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[C:1]([O:5][C:6](=[O:10])[CH2:7][CH2:8][Br:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hydroxy-propionic acid tert-butyl ester is dissolved in acetonitrile and carbon tetrabromide and triphenylphosphine is added. The mixture is stirred at room temperature overnight. After this time the mixture is concentrated in vacuo. The gummy solid is triturated with hexanes and the liquid decanted, passed through pad of silica to remove any triphenylphosphine oxide, and concentrated in vacuo. 1H NMR (400 MHz, CHLOROFORM-d) ppm 1.3 (9H, s), 2.06-2.27 (2H, m), 4.07-4.25 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](C(OC)=O)([CH2:15][CH:16]=[CH2:17])[C:11]([O:13]C)=[O:12])=[CH:5][C:4]=1[O:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([CH2:15][CH:16]=[CH2:17])[C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[O:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C=CCC(Cc1ccc(OC)c(OCCc2ccccc2)c1)(C(=O)OC)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCC(Cc1ccc(OC)c(OCCc2ccccc2)c1)C(=O)O
Temperature: 25 °C
Yield: 100.3 %

Procedure:
To a solution of the methyl 3-[4-methoxy-3-(2-phenylethoxy) phenyl]-2-methoxycarbonyl-2-(2-propen-1-yl)propionate (7.50 g) in 75 ml of methanol, 0.73 g of sodium hydroxide in 1.1 ml of water was added and refluxed by heating for 30 hours under stirring. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 61 ml of aqueous solution of 3 N sodium hydroxide. The solution was refluxed by heating for 11 hours under stirring. The reaction solution cooled to room temperature was washed with diethyl ether. Then, concentrated hydrochloric acid was added thereto to make the solution acidic. The resultant solution was extracted with dichloromethane and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was stirred at 140-150° C. for 4 hours under heating to obtain 6.21 g of crude 3-[4-methoxy-3-(2-phenylethoxy)phenyl]-2-(2-propen-1-yl) propionic acid. This crude compound was used in the subsequent step without purification.
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.CSC.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=O)([CH3:21])[CH3:20])=[CH:14][CH:13]=1.C[O-].[Na+]>C(#N)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([C:19]([CH3:21])([CH3:20])[CH2:22][C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[CH2:7][O:6]2)=[CH:16][CH:17]=1
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(Cc1ccc(Cl)cc1)C(=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CSC
Solvent: CC#N
Product: CC(C)(Cc1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Reaction time: 12 h
Yield: 85.1 %

Procedure:
A solution of 59.2 g (0.47 mol) of dimethyl sulphate and 32 g (0.517 mol) of dimethyl sulphide in 270 ml of acetonitrile is stirred at room temperature for 5 days. A solution of 81.5 g (0.2655 mol) of 4-chlorophenyl 4-chlorophenyl-tert.-butyl ketone in 80 ml of acetonitrile is then added dropwise at 20° to 25° C. in the course of about 2 hours. 28.7 g (0.53 mol) of sodium methylate are added at the same temperature. The entire reaction mixture is subsequently stirred for 12 hours and is then concentrated in vacuo. The residue is stirred overnight with a mixture of 200 ml of ethyl acetate and 150 ml of water. The organic phase is separated off, dried over sodium sulphate and concentrated in vacuo. 72.6 g (85.2% of theory) of crude 2-(4-chlorophenyl)-2-(4-chlorophenyl-tert.-butyl)-oxirane are obtained and are further reacted directly. ##STR156##
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24](=O)C)=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].II.[N:29]1C=CC=CC=1>>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:29])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc([C@H]2CC[C@H](c3ccc(C(C)=O)cc3)CC2)cc1
Reactant: c1ccncc1
Agent: II
Product: CCCCCc1ccc([C@H]2CC[C@H](c3ccc(C#N)cc3)CC2)cc1
Reaction time: 2.5 h

Procedure:
14.0 g of trans-4-(4-n-pentylphenyl)-1-(4-acetylphenyl)-cyclohexane are heated for 2 hours on a steambath, together with 30 g of iodine and 100 ml of pyridine. After the evaporation of the pyridine under reduced pressure, the residue is dissolved in chloroform and purified over a short silica gel column. The eluate is evaporated and the 4-[trans-4-(4-n-pentylphenyl)-cyclohexyl]-benzoic acid remaining behind is brought to the boil for 2.5 hours with 30 ml of thionyl chloride. After distilling off the excess thionyl chloride, the 4-[trans-4-(4-n-pentylphenyl)-cyclohexyl]-benzoyl chloride is dissolved in 250 ml of dioxane and this solution mixed with 100 ml of 25% aqueous ammonia solution. The reaction mixture is poured into 1.5 liters of ice water and the precipitated 4-[trans-4-(4-n-pentylphenyl)-cyclohexyl]-benzamide filtered off and dried. The dry amide is dissolved at 40° in 170 ml of dimethyl formamide. To this solution are added dropwise at 50° , in the course of 30 minutes, 26 g of phosphorus oxide trichloride. After 1 hour the reaction mixture is poured into 300 ml of icewater. After extracting several times with 100 ml amounts of dichloromethane, washing of the extracts with 5% sodium bicarbonate solution and then with water, drying over sodium sulphate and evaporation, there is obtained trans-4-(4-n-pentylphenyl)-1-(4-cyanophenyl)-cyclohexane which is purified by recrystallisation from ethanol; m.p. 80°, c.p. 160°.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([CH2:15]O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O.C1COCC1>N1C=CC=CC=1>[Cl:19][CH2:15][CH:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: OCC1c2ccccc2Oc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: ClCC1c2ccccc2Oc2ccccc21
Temperature: 50 °C
Yield: 95.7 %

Procedure:
To a mixture of 4.0 g of 9-xanthenemethanol and 3.0 mL of freshly distilled thionyl chloride in 30 mL of freshly distilled THF was added dropwise 1.7 mL of pyridine over a period of 15 minutes. The mixture was heated in an oil bath at 50° C. for 12 hours, cooled to room temperature, and washed with half sat'd brine (30 mL), sat'd NaHCO3 (30 mL) and water (2×30 mL). The organic layer was dried over MgSO4 and the solvent was evaporated in vacuo to give 4.16 g (95.7%) of the crude 9-chloromethylxanthene as an off-white solid. Recrystallization from CH3OH--CH2Cl2 (4:1) gave 3.53g (81.35%) of the pure 9-chloromethylxanthene as white needles, m.p. 104.5°-106° C.; 1H NMR (CDCl3 ):δ 3.67 (d, 2H, CH2), 4.32 (t, 1H, CH), 7.04-7.46 (m, 8H, aryl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[N:15]1([C:21]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:22]=2[C:23](Cl)=[O:24])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([C:23]([C:22]2[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=[CH:29][C:21]=2[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:24])[CH2:13][CH2:14]1
Reactant: Cc1ccc(N2CCNCC2)c(F)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Product: Cc1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCOCC3)CC2)c(F)c1
Yield: 70 %

Procedure:
Title compound was prepared according to procedure described in example 46 from 1-(2-Fluoro-4-methyl-phenyl)-piperazine and 2-morpholin-4-yl-5-nitro-benzoyl chloride (70% yield, yellow oil, MS (m/e): 429.2 (M+H+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:43][NH:44][NH:45][C:46](=[O:48])[CH3:47].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([N:44]([CH3:43])[NH:45][C:46](=[O:48])[CH3:47])=[O:13])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)O
Reactant: CNNC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NN(C)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 104.3 %

Procedure:
To a solution of (2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-phenylpropionic acid (0.27 g, 0.96 mmol) in methylene chloride (10 ml) was added 1-hydroxy-7-azabenzotriazole (0.13 g, 0.96 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.18 g, 0.96 mmol) and the mixture was cooled to 0° C. Then acetic acid N'-methylhydrazide (0.19 g, 0.96 mmol) and diisopropylethylamine (0.41 ml, 2.40 mmol) were added and the mixture was stirred at room temperature overnight. Then methylene chloride (50 ml) was added and the mixture was washed with water (10 ml), saturated sodium bicarbonate (10 ml), brine (10 ml), dried (MgSO4), filtered and concentrated in vacuo to give 0.35 g (125%) of crude N-[(1R)-2-(N'-acetyl-N-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methylcarbamic acid tert-butyl ester as a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)[CH3:2].[Cl:21][CH2:22][C:23](Cl)=[O:24].O>CN(C)C(=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1[N:7]=[C:8]([NH:11][C:23](=[O:24])[CH2:22][Cl:21])[S:9][CH:10]=1)[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)c1csc(N)n1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(NC(=O)OC(C)(C)C)c1csc(NC(=O)CCl)n1
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of 1.26 g of α-t-butyloxycarbonylamino-α-(2-aminothiazol-4-yl)acetic acid ethyl ester in 5 ml of N,N-dimethylacetamide is added 708 mg of chloroacetyl chloride under stirring. After the stirring for further 1 hour at room temperature, the reaction solution is poured into water and extracted with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate aq. solution and then water and dried over anhydrous magnesium sulfate. The distillation of the solvent gives 1.435 g of α-t-butyloxycarbonylamino-α-[2-(chloroacetamido)thiazol-4-yl]acetic acid ethyl ester as crystals (yield, 90.8%). Melting point: 192°-193° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH3:10][N:11]1[C:15](=[O:16])[C:14]([CH2:17][Cl:18])=[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:12]1>>[CH3:10][N:11]1[C:15](=[O:16])[C:14]([CH2:17][Cl:18])=[C:13]([C:19]2[CH:24]=[CH:23][C:22]([N+:1]([O-:4])=[O:2])=[CH:21][CH:20]=2)[O:12]1
Reactant: O=[N+]([O-])O
Reactant: Cn1oc(-c2ccccc2)c(CCl)c1=O
Agent: O=S(=O)(O)O
Product: Cn1oc(-c2ccc([N+](=O)[O-])cc2)c(CCl)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
After cooling 76 ml of concentrated nitric acid (specific gravity 1.42) to 0° C., 80 ml of concentrated sulfuric acid was gradually added thereto and further 9 g of 2-methyl-4 chloromethyl-5-phenyl-3-isooxazolone was added thereto as crystals thereof while keeping the temperature thereof below 5° C. The resultant mixture was stirred for 30 minutes at 5° C. and poured into 2 liters of ice water followed by stirring for one hour to deposit crystals, which were collected by filtration and dried to provide 9.4 g of the desired product. The yield was 87%.