Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:34]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[C:36]([CH:42]([CH3:44])[CH3:43])[N:35]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:53][C:2]([F:1])([F:52])[C:3]1[CH:4]=[C:5]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][C:25]=1[C:34]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[C:36]([CH:42]([CH3:44])[CH3:43])[N:35]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2nc(C(C)C)ccc2OC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C(C)C)nc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-isopropyl-3-methoxy-pyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (70 mg) is dissolved in ethanol (2 ml), and thereto is added 1N-aqueous sodium hydroxide solution (0.5 ml) and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-isopropyl-3-methoxy-pyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (62 mg). The resulting carboxylic acid is dissolved in ethanol (1 ml), and thereto is added 1N-aqueous sodium hydroxide solution (85 μl) and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-isopropyl-3-methoxy-pyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (729 mg). MS (m/z): 729 [M−Na]−
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[C:15]([CH3:17])=[CH2:16])([CH3:4])([CH3:3])[CH3:2]>CCO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[CH:15]([CH3:17])[CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc(C(=O)OC)ccc1C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(C(C)(C)C)c(C(C)C)c1
Reaction time: 192 h
Yield: 85.9 %

Procedure:
To the ester 26.2 (167 mg, 0.72 mmol) in EtOH/EtOAc (1/1, v/v, 3.00 mL), was added Pd(OH)2/C (10 mg). The mixture was placed under an atmosphere of hydrogen and stirred for 8 days. The resulting mixture was filtered through Celite and concentrated in vacuo to give a clear oil (145 mg, 86%). The crude product (26.3) was used in the next step without further purification.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][NH:8]1)=[O:6])[CH3:3].[CH2:13](N(CC)CC)[CH3:14].C(I)C>C(Cl)(Cl)Cl>[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][N:8]1[CH2:13][CH3:14])=[O:6])[CH3:3]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)[C@@H]1C[C@H](O)CN1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCI
Product: CCOC(=O)[C@@H]1C[C@H](O)CN1CC

Procedure:
To a suspension of 12 g of (2S,4S)-2-ethoxycarbonyl-4-hydroxy pyrrolidine hydrochloride obtained in the preceeding para. (1) in 60 ml of chloroform, were added 12.42 g of triethylamine and the combined was added with 17.22 g of ethyl iodide and heat-refluxed for 4 hours. The reaction mixture was after-treated to obtain (2S,4S)2-ethoxycarbonyl-N-ethyl-4-hydroxy pyrrolidine as an oily (product Yield 9.55 g.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:12]([O-])=O)=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.CO>O1CCCC1>[NH2:12][C:3]1[C:2]([F:1])=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[O:9][C:5]=2[CH:4]=1
Reactant: Cc1nc2cc(F)c([N+](=O)[O-])cc2o1
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2cc(F)c(N)cc2o1
Reaction time: 1.5 h

Procedure:
5-Fluoro-2-methyl-6-nitrobenzoxazole (16 g, 81.57 mMole), was dissolved in tetrahydrofuran (150 mL), and methanol (50 mL). Raney-Nickel which had been pre-washed with water (×3) and tetrahydrofuran (×3), was added and the mixture was then hydrogenated at room temperature and 50 psi of hydrogen. The reaction is complete in approximately 1.5 hours. After this period, the catalyst is filtered off and the solution concentrated under reduced pressure. The residue is triturated with heptane, cooled and the solid filtered off. Yield 12 g.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH2:22][OH:23])[N:15]=1)[N:7]=3.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[N:7]1[C:8]([C:14]2[N:18]([CH:19]([CH3:20])[CH3:21])[N:17]=[C:16]([CH:22]=[O:23])[N:15]=2)=[CH:9][N:10]2[C:6]=1[C:5]1[CH:24]=[CH:25][CH:2]=[CH:3][C:4]=1[O:13][CH2:12][CH2:11]2
Reactant: CC(C)n1nc(CO)nc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)n1nc(C=O)nc1-c1cn2c(n1)-c1ccccc1OCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of [5-(8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-methanol 315 (166 mg, 0.51 mmol) in DCM (5 mL) was treated with Dess-Martin periodinane (DMP, 238 mg, 0.56 mmol) and resultant solution stirred at RT for 2 h under an atmosphere of nitrogen. The reaction was quenched by the addition of sodium thiosulphate (620 mg in 1 mL water) before the addition of further water and extracted twice with DCM. The combined organic extracts were washed with water then dried (Na2SO4), filtered and concentrated in vacuo to give 5-(4,5-Dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazole-3-carbaldehyde as a cream solid (170 mg, quantitative). LCMS: RT=4.30 min, [M+H]+ 324. 1H NMR 400 MHz (DMSO-d6) δ: 9.91 (1H, s), 8.43 (1H, dd, J=8.06, 1.78 Hz), 8.11 (1H, s), 7.34-7.34 (1H, m), 7.17-7.17 (1H, m), 7.07 (1H, dd, J=8.17, 1.23 Hz), 6.03 (1H, m), 4.57-4.48 (4H, m), 1.55 (6H, d, J=6.60 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH3:15])[C@H:10]([CH2:16][N:17]([CH:34]([CH3:36])[CH3:35])[C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37]1([CH2:43][C:44](Cl)=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH3:15])[C:44](=[O:45])[CH2:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:10]([CH2:16][N:17]([CH:34]([CH3:36])[CH3:35])[C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CNC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C)C(=O)Cc2ccccc2)C(C)C)ccc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3R,4R)-3-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-4-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 3.35 mmol) in CH2Cl2 (25 mL), phenylacetyl chloride (0.53 mL, 4.02 mmol) and triethylamine (0.56 mL, 4.02 mmol) are added under N2 atmosphere at 0° C. The mixture is stirred 30 min at 0° C., then allowed to reach RT and further stirred for 1 h. The reaction mixture is diluted with CH2Cl2 and poured into an aqueous saturated solution of NaHCO3. The organic layer is separated, and the aqueous one is extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography on silica gel (eluent: c-hexane/AcOEt 20:80 to 0:100) to give the title compound. TLC, Rf (CH2Cl2/MeOH 95:5)=0.4. MS (LC-MS): 526 [M-Boc+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.71 min.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[S:42][CH:43]=[CH:44][N:45]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:39]([C:41]2[S:42][CH:43]=[CH:44][N:45]=2)=[O:40])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1nccs1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(=O)c3nccs3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and N-methoxy-N-methylthiazole-2-carboxamide.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.O.[Cl-].[Ca+2].[Cl-]>C(O)C>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(Oc2ccc([N+](=O)[O-])nc2)cc1)OCc1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccc(NC(=O)OCc3ccccc3)cc2)cn1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
To a solution of benzyl {4-[(6-nitropyridin-3-yl)oxy]phenyl}carbamate (5.99 g, 16.4 mmol) in ethanol (80 mL)/water (16 mL) were added reduced iron (5.8 g, 98.4 mmol) and calcium chloride (1.42 g, 11.5 mmol), and the mixture was heated under reflux for 16 hr. The reaction mixture was cooled to room temperature, filtered through celite, and washed with ethanol. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (150 mL). The organic layer was washed with water and saturated brine in this order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, a solid was precipitated with hexane/ethyl acetate (=2/1, 30 mL) and collected by filtration to give the title compound (4.43 g, 81%). The solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (NH silica, hexane/ethyl acetate=3/1→1/3) to give the title compound (0.43 mg, 8%).
Reaction SMILES: N1C2C(=C([C:10]3[N:11]=[C:12]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:13]4[S:18][C:17](C=O)=[CH:16][C:14]=4[N:15]=3)C=CC=2)C=C1.C[O-].[Na+]>CO>[N:21]1([C:12]2[C:13]3[S:18][CH:17]=[CH:16][C:14]=3[N:15]=[CH:10][N:11]=2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: O=Cc1cc2nc(-c3cccc4[nH]ccc34)nc(N3CCOCC3)c2s1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: c1nc(N2CCOCC2)c2sccc2n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 91.5 %

Procedure:
To a suspension of 2-(1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (54 mg) in anhydrous methanol (8 ml) was added phosphorus sulphone (34 mg), followed by sodium methoxide (148u1). The reaction mixture was stirred at room temperature for 4.5 hours, then evaporated onto silica and purified by flash chromatography to give 2-(1H-indol-4-yl)-6-((E)-2-methanesulfonyl-vinyl))-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (30 mg).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH3:6])=[O:4].[S:7]([O-:10])([O-:9])=[O:8].[Na+:11].[Na+]>O>[CH3:6][O:5][C:3]([CH2:2][S:7]([O-:10])(=[O:9])=[O:8])=[O:4].[Na+:11]
Reactant: COC(=O)CCl
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CS(=O)(=O)[O-]
Reaction time: 56 h

Procedure:
A slurry of 217 g (2 mols) methyl chloroacetate and 252 g (2 mols) sodium sulfite in 500 ml water was stirred and heated under reflux for about 2 hours. The resulting solution was allowed to stand at about 25° C. for 56 hours and then evaporated under reduced pressure to give solid residue. The residue was washed with acetone and dried under vacuum at 80°-90° C. to give crude sodium methoxycarbonylmethylsulfonate salt.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](OCC)(=[O:21])[CH2:17][C:18]([CH3:20])=O.[F:25][C:26]([F:36])([F:35])[C:27](=O)[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>[Cl-].[Zn+2].[Cl-].C(O)C>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]2[C:12]([C:18]([CH3:20])=[CH:17][C:16](=[O:21])[O:15]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([NH:8][C:9]1[CH:10]=[C:32]2[C:33]([C:27]([C:26]([F:36])([F:35])[F:25])=[CH:28][C:29](=[O:30])[O:31]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc(NCc2ccccc2)c1
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: Cc1cc(=O)oc2cc(NCc3ccccc3)ccc12
Product: O=c1cc(C(F)(F)F)c2ccc(NCc3ccccc3)cc2o1

Procedure:
According to this invention, water-soluble coumarins and azacoumarins having the structures: ##STR2## wherein R is CH3 or CF3 and wherein R1 is H or CH3 are prepared. The coumarins are prepared by means of a three step process involving (1) heating resorcinol and benzylamine to form 3-benzylaminophenol, (2) reacting the 3-benzylaminophenol with ethyl acetoacetate or ethyl trifluoroacetoacetate in the presence of anhydrous zinc chloride and absolute ethanol to form 7-benzylamino-4-methylcoumarin or 7-benzylamino-4-trifluoromethylcoumarin, (3) sulfonating the product of step (2) with oleum and (4) neutralizing the sulfonate formed in step (3) with sodium bicarbonate. The azacoumarins are prepared by a similar process except that 6-chloro-2-pyridinol and either benzylamine or benzylmethylamine are used as the starting compounds (the step (1) reactants).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.[C:28]([C:32]1[N:37]=[C:36]([N:38]2[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])[CH2:40][CH2:39]2)[CH:35]=[C:34]([CH:49]2[CH2:52][CH2:51][CH2:50]2)[N:33]=1)([CH3:31])([CH3:30])[CH3:29].[ClH:53].C(N=C=NCCCN(C)C)C>CN(C)C=O>[ClH:53].[C:28]([C:32]1[N:37]=[C:36]([N:38]2[CH2:39][CH2:40][N:41]([CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH2:42][CH2:43]2)[CH:35]=[C:34]([CH:49]2[CH2:52][CH2:51][CH2:50]2)[N:33]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3ccc(F)cc3)CC2)n1
Reaction time: 68 h
Yield: 74.2 %

Procedure:
0.45 g of 4-fluorobenzoic acid (3.21 mmol) and 0.98 g of triethylamine (9.7 mmol) were dissolved in 30 ml of dimethylformamide. At room temperature, 0.5 g of hydroxybenzotriazole (HOBt, 3.7 mmol), 1.2 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (3.47 mmol), and 0.7 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 3.65 mmol) were added and the mixture was stirred for 68 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (2%). The oily residue was re-dissolved in isopropanol and 1 N hydrochloric acid in diisopropyl ether was added. The resulting precipitate was filtered and dried to yield 1.2 g of the title compound.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]4([OH:35])[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[H-].[Na+].I[CH3:39]>CN(C=O)C>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]4([O:35][CH3:39])[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:24][CH2:23]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CCC(O)(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
To a 0° C. suspension of tert-butyl 4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-hydroxypiperidine-1-carboxylate (0.033 g, 0.069 mmol) in 2 mL DMF was added 60% NaH in mineral oil (0.0117 g, 0.486 mmol). The reaction mixture was warmed to ambient temperature and stirred 2 hours. Neat iodomethane (0.035 mL, 0.56 mmol) was added, and the reaction mixture was stirred for 21 hours. The reaction mixture was concentrated, and the residue was diluted with saturated NR4Cl and extracted with dichloromethane. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified by preparative TLC (0.5 mm plate, 9:1 dichloromethane:methanol) to give the title compound (0.016 g, 47.1% yield) as a yellow residue.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[CH2:27](O)[CH2:28][OH:29]>>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20]([O:22][CH2:27][CH2:28][OH:29])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: OCCO
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: C/C(=C\c1ccc(C(=O)OCCO)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
In a manner analogous to that described in Example 11, from p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid and ethyleneglycol there can be obtained 2-hydroxyethyl p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoate of melting point 138°-139° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]([N:17]=[C:18]=[O:19])([Cl:16])[Cl:15]>C(OCC)(=O)C>[Cl:13][C:14]([Cl:16])([Cl:15])[NH:17][C:18](=[O:19])[NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: O=C=NC(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1csc(NC(=O)NC(Cl)(Cl)Cl)n1
Yield: 49.7 %

Procedure:
To a solution of ethyl 2-aminothiazol-4-ylacetate (1.86 g.) in dried ethyl acetate (37 ml.) was dropwise added trichloromethylisocyanate (1.6 g.) with stirring under ice-cooling. The mixture was stirred for 2 hours at room temperature, and trichloromethylisocyanate (0.32 g.) was further added thereto, and then the mixture was further stirred for 1 hour at room temperature. After the reaction, the reaction mixture was filtered. The filtrate was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate, and then the solvent was distilled off therefrom. The residue was pulverized in diethyl ether to give colorless crystals of ethyl 2-(3-trichloromethylureido)thiazol-4-ylacetate (1.72 g.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]2[CH2:28][C:27]([CH3:30])([CH3:29])[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:31]#[N:32])[CH:25]=3)[NH:20]2)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>ClCCl>[C:31]([C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]([C:15]1[CH:14]=[C:13]([NH:12][S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:10])=[O:9])[CH:18]=[CH:17][CH:16]=1)[CH2:28][C:27]2([CH3:30])[CH3:29])#[N:32]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)Nc2ccc(C#N)cc21
Reaction time: 8 h
Yield: 43.4 %

Procedure:
3-Fluoro-benzenesulfonyl chloride (116 mg, 0.59 mmol) was added dropwise to a mixture of 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (150 mg, 0.54 mmol) and pyridine (65 mg, 0.81 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir overnight. The reaction mixture was washed by water, dried over magnesium sulfate. It was filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to afford N-[3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-3-fluoro-benzenesulfonamide as off-white solid (102 mg, yield: 42.5%). MS (ESI+APCI) M+1=436.1.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[C:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)[C:3]=1[C:4](O)=[O:5].CN(C)C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[Cl:1][C:2]1[C:3]2[C:4](=[O:5])[C:19]3[C:18](=[CH:23][CH:22]=[C:21]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[CH:20]=3)[NH:17][C:7]=2[C:8]([N+:14]([O-:16])=[O:15])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1ccc(COc2ccc(Nc3c([N+](=O)[O-])cc([N+](=O)[O-])c(Cl)c3C(=O)O)cc2)cc1
Solvent: CN(C)c1ccccc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(COc2ccc3[nH]c4c([N+](=O)[O-])cc([N+](=O)[O-])c(Cl)c4c(=O)c3c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred, ice-cold mixture of 2.67 g of 2-chloro-6-[[4-[(4-methoxyphenyl)methoxy]phenyl]amino]-3,5-dinitrobenzoic acid, 18 ml of 1,2-dichloroethane, and 4.4 ml of N,N-dimethylaniline, was added 0.70 ml of phosphorus oxychloride. After 2.5 hours, the ice bath was removed and the mixture stirred 24 hours at room temperature. The precipitate was collected, washed with water, then with methanol, and dried to provide the title compound, melting above 240° C. with decomposition.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:29]=[C:28]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:27]=[C:26]2[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=1[C:25]2=[N:38]O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Ni].C(O)C.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:29]=[C:28]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:27]=[C:26]2[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=1[CH:25]2[NH2:38])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc2c(c(-c3nc4ccccc4n3C(=O)OC(C)(C)C)c1)-c1ccccc1C2=NO
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(-c2nc3ccccc3n2C(=O)OC(C)(C)C)c2c(c1)C(N)c1ccccc1-2
Yield: 102.7 %

Procedure:
The procedure used in Example 6 is followed, but starting from 250 mg of 5-[1-(tert-butoxycarbonyl)benzimidazol-2-yl]-7-( tert-butoxycarbonyl-amino)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, and 29 mg of Raney nickel in 4 ml of ethanol and 4 ml of tetrahydrofuran for 10 hours at 60° C. under an initial hydrogen pressure of one bar. After filtration of the catalyst, and purification by formation of a paste in diisopropyl ether, in this way we obtain 250 mg of 5-[1-(tert-butoxycarbonyl)benzimidazol-2-yl]-7-(tert-butoxycarbonylamino)-9H-fluoren-9(R,S)-ylamine, in the form of an orange powder which is used as it is in the following stage.