Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[O:26][CH3:27].Cl.Cl[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>>[CH3:27][O:26][C:5]1[CH:6]=[CH:7][C:8]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH2:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)[CH:18]=3)[CH2:13][CH2:12]2)=[CH:9][C:4]=1[C:3]([OH:2])=[O:28]
Reactant: ClCc1cccnc1
Reactant: COC(=O)c1cc(CN2CCC(c3c[nH]c4ccccc34)CC2)ccc1OC
Agent: Cl
Product: COc1ccc(CN2CCC(c3cn(Cc4cccnc4)c4ccccc34)CC2)cc1C(=O)O

Procedure:
This compound was prepared following the procedure described in example 1 (part E) starting with 0.054 g (0.13 mmol) of 5-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-2-methoxy-benzoic acid methyl ester and 0.029 mg (0.16 mmol) of 3-chloromethyl-pyridine hydrochloride. After the described purification, 0.007 g (11% of yield) of the expected acid was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]([CH3:14])([CH3:13])[CH2:9][C:10](=[O:12])[CH3:11])[CH:7]=1.[Br-:17].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl.CO>[Br:17][CH2:11][C:10](=[O:12])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:15][CH3:16])([CH3:13])[CH3:14]
Reactant: COc1ccc(F)cc1C(C)(C)CC(C)=O
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(F)cc1C(C)(C)CC(=O)CBr
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of the above ketone (1.34 g, 6 mmol) in methylene chloride (35 mL) and MeOH (5 mL), benzyltrimethylammonium tribromide (2.57 g, 6.6 mmol) was added at ambient temperature. After 30 minutes, TLC (hexanes-EtOAc (9:1)) showed complete disappearance of the starting material. The reaction mixture was diluted with methylene chloride (50 mL), washed with two 50 mL portions of water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 1-bromo-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one as a light brown liquid (80%) which was used for the next reaction without further purification.
Reaction SMILES: [CH2:1]([C:3]1([CH2:19][C:20]([O:22]C)=[O:21])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3/[CH:16]=[CH:17]\[CH3:18])[CH3:2]>C(O)C.[OH-].[Na+]>[CH2:1]([C:3]1([CH2:19][C:20]([OH:22])=[O:21])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3/[CH:16]=[CH:17]\[CH3:18])[CH3:2]
Reactant: C/C=C\c1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C/C=C\c1cccc2c3c([nH]c12)C(CC)(CC(=O)O)OCC3

Procedure:
(Z)-1-Ethyl-8-(1-propenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, methyl ester (1.01 g, 3.2 mmol) was dissolved in a mixture of 11.2 mL of ethanol and 11.2 mL of 10% aqueous sodium hydroxide, and the solution was heated under reflux for 3 hours. The reaction mixture was then concentrated to dryness, and a mixture of 13.4 mL of ether and 13.4 mL of 10% aqueous sodium hydroxide was added to the residue. The layers were separated, and the aqueous layer was acidified with concentrated hydrochloric acid and extracted with ether (2×25 mL). The combined ether extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give 897 mg of the crude product. This material was purified by flash chromatography (20% ethyl acetate/hexane, H3PO4 treated silica gel) to give the desired product as a colorless oil which partially solidified upon standing. Trituration with petroleum ether provided 440 mg of an off-white solid, m.p. 89.5°-93.5° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][CH:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[C:35]([O:37]C(C)(C)C)=[O:36].[ClH:45]>O1CCOCC1>[ClH:45].[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][CH:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]3=[O:24])[CH2:10][CH2:11]2)[N:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[C:35]([OH:37])=[O:36]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCC4C(=O)Nc5ccccc54)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCC4C(=O)Nc5ccccc54)CC3)C2=O)c1
Yield: 90 %

Procedure:
tert-Butyl 3((4-oxo-8-(3-(2-oxoindolin-3-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.29 g, 0.488 mmol) and 4M hydrochloric acid/1% triethylsilane in 1,4-dioxane (6 mL) were stirred at room temperature for 4 hours. The reaction was evaporated and the residue purified by PTLC (10% methanol/dichloromethane). The product obtained from PTLC was redissolved in 4M hydrochloric acid in dioxane and evaporated. The residue was dissolved in acetonitrile (5 mL) and water (5 mL) and lyophilized to give product as a white solid (0.25 g, 90%); HPLC rt 9.32 min; NMR (DMSO-d6); δ1.82 (m, 4H); 1.89 (d, J=14 Hz, 2H); 2.94 (m, 2H); 3.16 (m, 2H); 3.44-3.54 (m, 5H); 4.64 (s, 4H); 6.79 (t, J=7.2 Hz, 1H); 6.84 (d, J=7.6 Hz, 1H); 6.97 (m, 1H); 7.01 (d, J=8.4 Hz, 2H); 7.17-7.23 (m, 3H); 7.32 (d, J=7.6 Hz, 1H); 7.49-7.58 (m, 2H); 7.87-7.89 (m, 2H); 10.38 (br s, 1H); 10.44 (s, 1H); 13.0 (br s, 1H); MS for C32H34N4O4 m/z 539 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[NH:16][N:15]=[N:14][N:13]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[CH:4]=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH:33]=[CH:34][C:35]=1[NH2:36])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)=[O:23].C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].CO>CS(C)=O.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2]>[CH3:32][C:27]1[CH:26]=[C:25]([NH:24][C:22]([C:21]2[CH:33]=[CH:34][C:35]3[N:36]=[C:4]([C:3]4[C:2]([CH3:1])=[CH:9][C:8]([O:10][CH2:11][C:12]5[NH:16][N:15]=[N:14][N:13]=5)=[CH:7][C:6]=4[CH3:17])[NH:18][C:19]=3[CH:20]=2)=[O:23])[CH:30]=[CH:29][C:28]=1[CH3:31]
Reactant: Cc1cc(OCc2nnn[nH]2)cc(C)c1C=O
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CS(C)=O
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cc(OCc5nnn[nH]5)cc4C)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6-dimethyl-4-(1H-tetrazol-5-yl-methoxy)-benzaldehyde (50 mg) in DMSO (1 mL) were added 3,4-diamino-N-(3,4-dimethyl-phenyl)-benzamide (55 mg), Yb(OTf)3 (13 mg), and Cu(OTf)2 (8 mg). The reaction mixture was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give 2-[2,6-dimethyl-4-(1H-tetrazol-5-yl-methoxy)-phenyl]-3H-benzoimidazole-5-carboxylic acid (3,4-dimethyl-phenyl)-amide: MS (m/z) 468.16 (M+1).
Reaction SMILES: [SiH](CC)(CC)CC.B(F)(F)F.CCOCC.[Br:17][C:18]1[CH:19]=[C:20]([CH:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=2)O)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=2)[CH:19]=1
Reactant: CCOc1ccc(C(O)c2cccc(Br)c2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCOc1ccc(Cc2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
Then, Et3SiH (4.09 mL, 0.0256 mol) and BF3.Et2O (1.47 mL, 0.0116 mol) were added sequentially to a chloroform (22 mL) solution of (3-bromophenyl)(4-ethoxyphenyl)methanol (3.92 g, 0.0128 mol) at −60° C. After stirred for one hour, the reaction solution was warmed to room temperature. After the reaction mixture was added with a saturated sodium carbonate aqueous solution and extracted with chloroform, the organic layer was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=50:1) to obtain a colorless oily title compound (2.84 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C(Cl)(=O)C(Cl)=O.[CH2:20]([O:22][C:23](=[O:37])[C:24]([C:27]1[CH:28]=[N:29][C:30]([NH2:36])=[C:31]([O:33][CH2:34][CH3:35])[CH:32]=1)([CH3:26])[CH3:25])[CH3:21]>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1>[CH2:20]([O:22][C:23](=[O:37])[C:24]([C:27]1[CH:28]=[N:29][C:30]([NH:36][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:13])=[C:31]([O:33][CH2:34][CH3:35])[CH:32]=1)([CH3:26])[CH3:25])[CH3:21]
Reactant: CCOC(=O)C(C)(C)c1cnc(N)c(OCC)c1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)c1cnc(NC(=O)c2cc3cc(Cl)ccc3[nH]2)c(OCC)c1
Reaction time: 0.75 h
Yield: 7 %

Procedure:
To a slurry of 0.31 mmol of 5-chloro-1H-indole-2-carboxylic acid in methylene chloride (1.5 mL) was added 0.4 mL of 1M oxalyl chloride solution in methylene chloride. A solution of DMF (0.031 mL) in methylene chloride (1 mL) was then added dropwise to the slurry. After shaking for 45 min., the acid chloride solution was added dropwise to a solution of 2-(6-amino-5-ethoxy-pyridin-3-yl)-2-methyl-propionic acid ethyl ester in DMF (0.5 mL) and pyridine (0.25 mL). The reaction mixture was then shaken overnight. The reaction mixture was partitioned between EtOAc and 1N aqueous hydrochloric acid, and the phases were separated. The organic phase was washed with 1N aqueous sodium hydroxide, brine, and dried over sodium sulfate. After filtration and evaporation, the residue was further purified on a 2 mm silica gel preparative plate, developing with 9:1 methylene chloride/methanol. The product band was extracted and evaporated to afford 22 mg (7% yield) of the title compound as an amorphous solid. AP/MS+=430, AP/MS−=428.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][N:16]([CH3:27])[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>CO>[ClH:1].[CH3:27][N:16]([CH2:15][CH:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1)[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=1
Reactant: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)c1ccnc(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Product: CN(CC1CCNCC1)c1ccnc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 100 %

Procedure:
Hydrogen chloride gas is passed through a methanol (500 mL) solution of 1-t-butoxycarbonyl-4-{[(methyl)(2-trifluoromethylpyridin-4-yl)amino]methyl}piperidine maintaining <20° C., for 5 minutes. The mixture is kept at this temperature for 1 hour before it is concentrated in vacuo providing 4-{[(methyl)(2-trifluoromethylpyridin-4-yl)amino]methyl}piperidine hydrochloride (430 mg, 100%).
Reaction SMILES: [OH2:1].[CH3:2][C:3]([OH:5])=[O:4]>>[C:3]([OH:5])(=[O:4])[CH2:2][C:2]([CH2:2][C:3]([OH:5])=[O:4])([C:3]([OH:5])=[O:4])[OH:1]
Reactant: CC(=O)O
Reactant: O
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O

Procedure:
A first mixture of water, mustard, vinegar and citric acid was produced as well as a second mixture of the remaining ingredients except for the oil. The two mixtures were then mixed in a heatable “Stephan Cutter UMC 5 electronic” at 600 rpm for approximately 3 minutes (the mayonnaise at a temperature of 60° C. and the dressing at 25° C.). The oil was then added and mixed in for a further minute in the same conditions.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH2:22]([O:24][CH:25]([O:28][CH2:29][CH3:30])[CH2:26][NH2:27])[CH3:23]>N1C=CC=CC=1>[CH2:22]([O:24][CH:25]([O:28][CH2:29][CH3:30])[CH2:26][NH:27][C:13]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:11][CH:10]=1)=[O:21])[CH3:23]
Reactant: O=C(Nc1ccc(-n2cncn2)cc1)Oc1ccccc1
Reactant: CCOC(CN)OCC
Solvent: c1ccncc1
Product: CCOC(CNC(=O)Nc1ccc(-n2cncn2)cc1)OCC
Temperature: 50 °C
Yield: 97.9 %

Procedure:
A mixture of phenyl 4-(1H-1,2,4-triazol-1-yl)phenylcarbamate (13 g), 2,2-diethoxyethyl amine (7.4 g) and pyridine (3.67 g) was heated at 50° C. for 3 hours. The resultant was cooled and the precipitated crystals were washed with a mixture of diisopropyl ether and petroleum ether (1:1, 100 ml×2) to give 1-(2,2-diethoxyethyl)-3-[4-(1H-1,2,4-triazol-1-yl)phenyl]urea (14.5 g) as a colorless crystalline
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[C:19]3[CH2:20][CH2:21][CH2:22][CH:23]([OH:24])[C:18]=3[O:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[H-].[Na+].Br[CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1.O>CN(C=O)C.C(OCC)(=O)C>[F:35][C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([F:36])[CH:32]=1)[CH2:28][O:24][CH:23]1[C:18]2[O:17][N:16]=[C:15]([C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[C:19]=2[CH2:20][CH2:21][CH2:22]1
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: COc1cc(-c2noc3c2CCCC3O)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2noc3c2CCCC3OCc2cc(F)cc(F)c2)ccc1-n1cnc(C)c1

Procedure:
To the 3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4,5,6,7-tetrahydrobenzo[d]isoxazol-7-ol (48 mg, 0.15 mmol) in DMF (2 ml) at 0° C., was added NaH (7 mg, 0.18 mmol). The mixture was stirred for 10 min before addition of 1-(bromomethyl)-3,5-difluorobenzene. Stirring was continued for 1 hr before addition of water (3 mL) and extraction with ethyl acetate. The organic phase was washed with water, brine, dried over MgSO4 and concentrated. The crude product was purified by preparative TLC using 5% of MeOH in DCM as solvent to afford the title product. 1H NMR (CDCl3) δ: 7.82 (br. s., 1H), 7.53 (s, 1H), 7.30-7.40 (m, 214), 6.89-7.03 (m, 2H), 6.73 (t, J=9.0 Hz, 1H), 4.84 (d, J=12.9 Hz, 1H), 4.76 (d, J=13.7 Hz, 1H), 4.64 (t, J 3.7 Hz, 1H), 3.93 (s, 3H), 2.73-2.82 (m, 1H), 2.57-2.68 (m, 1H), 2.33 (br. s., 314), 2.17-2.26 (m, 1H), 1.87-2.07 (m, 3H). MS(M+H)+=452.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:33]C(=O)OC(C)(C)C)[C:10](=[O:32])[NH:11][C:12]2[CH:13]=[C:14]3[C:30](=[O:31])[NH:29][N:28]=[CH:27][C:16]4=[C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[NH:18][C:19]([CH:20]=2)=[C:15]34)=[CH:4][CH:3]=1.[ClH:41].C(N(CC)CC)C>O1CCOCC1>[ClH:41].[NH2:33][C@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:10]([NH:11][C:12]1[CH:13]=[C:14]2[C:30](=[O:31])[NH:29][N:28]=[CH:27][C:16]3=[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[NH:18][C:19]([CH:20]=1)=[C:15]23)=[O:32]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(F)cc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N[C@H](Cc1ccc(F)cc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 49 %

Procedure:
Preparation of example 168 from the title compound of Example 152 (49 mg, 0.091 mmol) and 4M HCl in dioxane (10 mL) was carried out analogously to Example 91. Isolation, also in an analogous manner, included freebasing with triethylamine and subsequent silica gel chromatography eluting with 3:1:1 hexane:ethyl acetate:ethanol. With ice bath cooling, the purified freebase in CH2Cl2 (10 mL) was treated with 4M HCl in dioxane (0.1 mL). After removal of the volatile components, the title compound (21 mg, 0.044 mmol) was obtained as an orange/yellow powder in 49% yield.
Reaction SMILES: [O:1]1CCC[CH2:2]1.[C:6]1([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([Li])CCC.C(OCC)=O.C(O)(=O)C>CCCCCC>[C:6]1([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH:2]=[O:1])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(-n2ccnc2)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCOC=O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: O=Cc1nccn1-c1ccccc1
Reaction time: 1 h

Procedure:
To 50 ml of dry tetrahydrofuran containing 5.0 g (3.5 mmoles) of 1-phenylimidazole and cooled to -78° C. was added 13.8 ml (3.5 mmoles) of a 2.5M solution of n-butyllithium in hexane and the mixture stirred in the cold for one hour. Ethyl formate (2.8 ml, 3.5 mmoles) was then added and the mixture stirred for 80 minutes. Acetic acid (1.99 ml, 3.5 mmoles) was added and the cooling bath was removed. After stirring for 5 minutes the mixture was poured into water and the product extracted with ethyl acetate. The extracts were combined, dried over magnesium sulfate and concentrated to give 6.58 g of a pale yellow oil which solidified when triturated with a small amount of cold ether, 4.02 g.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:35])[CH:6]1[CH:11]=[C:10]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)[C:9]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7]1=[S:32](=[O:34])=[O:33].Cl>O.C(O)C>[CH2:25]([NH:24][C:8]1[C:7](=[S:32](=[O:34])=[O:33])[CH:6]([CH:11]=[C:10]([N:12]2[CH:13]=[CH:14][CH:15]=[CH:16]2)[C:9]=1[S:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:5]([OH:35])=[O:4])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)C1C=C(n2cccc2)C(Sc2ccccc2)=C(NCc2ccccc2)C1=S(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1C=C(n2cccc2)C(Sc2ccccc2)=C(NCc2ccccc2)C1=S(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
A solution of 0.083 g of NaOH in 30 ml of water is added to a solution of 1.0 g of 3-benzylamino-4-phenylthio-5-pyrrol-1-yl-sulfonyl-benzoic acid methyl ester in 70 ml of ethanol, and the mixture is stirred first for 4 hours at room temperature and then for 1 hour at 40° C. to complete the reaction. After stripping off the ethanol under reduced pressure, the aqueous phase is acidified with dilute hydrochloric acid and the product is filtered off and recrystallized from ethyl acetate. 3-Benzylamino-4-phenylthio-5-pyrrol-1-yl-sulfonylbenzoic acid of melting point 218°-220° C. is obtained. Yield: 60%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:10](=O)[O:9][CH2:8]2.COC1C=C(C=CC=1)C=O.C1(P(=[CH:42][C:43]([O:45][CH3:46])=[O:44])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[OH:9][CH2:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:12]=1/[CH:10]=[CH:42]/[C:43]([O:45][CH3:46])=[O:44]
Reactant: COc1cccc2c1C(=O)OC2
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COc1cccc(C=O)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C/c1c(CO)cccc1OC
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
1-Hydroxy-7-methoxy-1,3-dihgydrobenzo[c]furan (1.08 g), which was prepared with using 7-methoxyphthalide which was synthesized with using 3-methoxybenzaldehyde by the method described in Journal of Organic Chemistry, 1980, 45, 1835-1838, was dissolved in chloroform (20 ml). Methyl (triphenylphosphoranylidene)acetate (2.68 g) was added to the solution. The mixture was stirred for 40 min. at 50° C. A temperature of the reaction mixture was down to room temperature. The reaction solution was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (1.25 g) having the following physical data.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH3:12])[CH2:5]/[CH:6]=[CH:7]/[C:8]([O:10]C)=[O:9].[ClH:13]>CO>[ClH:13].[CH3:3][N:4]([CH3:12])[CH2:5]/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9]
Reactant: COC(=O)/C=C/CN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)C/C=C/C(=O)O
Temperature: 25 °C
Yield: 50 %

Procedure:
A sodium hydroxide solution (3.35 g in 25 ml of water, 0.084 moles) is added dropwise to a solution of 12 g methyl 4-dimethylaminocrotonate (0.084 moles) in 100 ml methyl alcohol at room temperature. The reaction mixture is heated to 40–45° C. for 1 hour then cooled to room temperature. The pH is adjusted to about 1˜2 with 5 N HCl. The mixture was concentrated to a thick oil, which is triturated with dehydrated alcohol to form a solid. The solid by-product is filtered and the filtrate is evaporated to an oil, which is triturated with isopropyl alcohol to afford 7.0 g of white solid product. Yield is 50% with the purity 86.3% by GC-MS.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]3[NH:9][CH:10]([C:16]4[N:17]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:19][CH:20]=4)[CH2:11][C:12](=[O:15])[C:13]=3[O:14][C:6]=2[CH:5]=[CH:4][C:3]=1[O:24][CH3:25].O1CCOCC1>O>[OH:15][C:12]1[CH:11]=[C:10]([C:16]2[N:17]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:19][CH:20]=2)[N:9]=[C:8]2[C:7]3[C:2]([Cl:1])=[C:3]([O:24][CH3:25])[CH:4]=[CH:5][C:6]=3[O:14][C:13]=12
Reactant: COc1ccc2oc3c(c2c1Cl)NC(c1csc(C(C)C)n1)CC3=O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2oc3c(O)cc(-c4csc(C(C)C)n4)nc3c2c1Cl
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A mixture of 10B (10.3 g, 27.33 mmol, crude) and FeCl3.6H2O (33.04 g, 164.0 mmol, 6 eq) was added to 1,4-dioxane (300 mL) The mixture was refluxed for 16 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (300 mL), extracted with ethyl acetate and concentrated to give a crude product 10C (8.75 g), which was used for the next step directly.
Reaction SMILES: [C:1]1([C:7]2[C:11](=O)[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:31]([NH2:35])[CH:32]([CH3:34])[CH3:33].CCOCC>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[CH2:31]([N:35]=[C:11]1[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:32]([CH3:34])[CH3:33]
Reactant: O=C1C(c2ccccc2)=C(c2ccccc2)C(c2ccccc2)=C1c1ccccc1
Reactant: CC(C)CN
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)CN=C1C(c2ccccc2)=C(c2ccccc2)C(c2ccccc2)=C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
3 g (7.8 mmol) of tetraphenylcyclopentadienone and 3.49 ml (35.1 mmol) of isobutylamine were dissolved in 50 ml of toluene and 0.7 ml(5.85 mmol) of TiCl4 was added thereto at 0° C. The resulting mixture was agitated for 30 minutes at room temperature and then refluxed for 12 hours. The reaction mixture was cooled and ether was added thereto to induce solid precipitation. The resultant solid was filtered and dried to obtain 2.3 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([P:12]([CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])(=[O:16])[O:13][CH2:14][CH3:15])[CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:11][CH2:10][CH2:9][CH:8]([P:12]([CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])(=[O:16])[O:13][CH2:14][CH3:15])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: CCOC(OCC)P(=O)(OCC)C(CC#N)c1ccc(Cl)cc1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(OCC)C(CCN)c1ccc(Cl)cc1

Procedure:
A solution of 20 g of ethyl 1-(4-chlorophenyl)-2-cyanoethyl(diethoxymethyl)phosphinate in 85 ml of ethanol is added to 131 g of an 8% solution of ammonia in ethanol. To this are added 8.5 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered, the filtrate is concentrated under reduced pressure and the crude product is distilled under reduced pressure to give ethyl 3-amino-1-(4-chlorophenyl)propyl(diethoxymethyl)phosphinate, b.p. 190° C./0.02 mbar, 31P=+41.5 and +41.3 ppm (CDCl3).