Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13](O)(=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20].O=S(Cl)Cl>>[C:13]([O:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:2]([OH:5])(=[O:4])=[O:3])(=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: O=S(=O)(O)Cl
Reactant: Oc1ccccc1
Reactant: CC(C)CCCCCC(=O)O
Solvent: O=S(Cl)Cl
Product: CC(C)CCCCCC(=O)Oc1ccccc1S(=O)(=O)O

Procedure:
122 parts by weight of ClSO3H are added, at a temperature of 40° C., to 94 parts by weight of phenol in 158.5 parts by weight of isononanoic acid, and stirring is continued for a further hour at 40° C. 125 parts of SOCl2 are then metered in at such a rate that the evolution of gas takes place in a controlled manner, after which stirring is continued for a further hour. The Na salt of isononanoyloxybenzenesulfonic acid obtained after further working up as described in V1 has a D-content of 85% and an isomer ratio of 3.3 to 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH3:11][C@@H:12](O)[CH2:13][CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C@H:12]([CH2:13][CH3:14])[CH3:11])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: CC[C@@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@H](C)Oc1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 12.3 %

Procedure:
A solution of 750 mg (5.4 mmol) of 3-fluoro-4-hydroxybenzaldehyde, 403 mg (5.4 mmol) of (R)-(−)-2-butanol and 2 g (7.5 mmol) triphenylphosphine in 10 mL of THF was treated with 1.5 mL of diisopropylazodicarboxylate. The resulting solution was stirred at rt for 14 h, cooled to rt and concentrated. Chromatography on a Biotage 40M cartridge using 4:1 v/v hexanes/Et2O as the eluant afforded 130 mg of the title compound: 1H NMR (500 Mhz) δ 0.99 (t, J=7.6, 3H), 1.35 (d, J=6.2, 3H), 1.58–1.83 (m, 2H), 4.47 (m, 1H), 7.05 (t, J=8.2, 1H), 7.59 (d, J=8.2, 1H), 7.61 (s, 1H), 9.84 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.C(N(CC)CC)C.[F:21][C:22]([F:34])([F:33])[C:23]1[CH:28]=[CH:27][C:26]([S:29]([Cl:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>ClCCl>[ClH:32].[F:34][C:22]([F:21])([F:33])[C:23]1[CH:24]=[CH:25][C:26]([S:29]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)(=[O:31])=[O:30])=[CH:27][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cl
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.4 %

Procedure:
To a solution of N-tert-butyloxycarbonylpiperazine (1.00 g, 5.37 mmol) in dichloromethane were added triethylamine (1.05 eq, 0.78 ml) and 4-(trifluoromethyl)-benzenesulfonyl chloride (1.02 eq, 1.345 g). The mixture was stirred overnight at room temperature, diluted with dichloromethane, washed with aqueous sodium bicarbonate solution, water, dried over magnesium sulfate and evaporated. The resulting white solid was dissolved in ethyl acetate and a 5 M solution of hydrogen chloride in ethyl acetate added dropwise. The mixture was stirred 3 h at 50° C. The precipitated solid was filtered and dried to afford the title compound (558 mg, 31%) which was used without further purification. MS (m/z): 295.4 (M+H)+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[CH2:4][C:5](O)=[O:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:40][C:41]1([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:50]3[C:51]([CH3:56])=[N:52][O:53][C:54]=3[CH3:55])[CH:48]=2)[NH:43][C:42]1=[O:57]>C(Cl)Cl.O>[CH3:2][N:3]([CH3:8])[CH2:4][C:5]([NH:40][C:41]1([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:50]3[C:51]([CH3:56])=[N:52][O:53][C:54]=3[CH3:55])[CH:48]=2)[NH:43][C:42]1=[O:57])=[O:6]
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(N)(c1ccccc1)C(=O)N2
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(C)c1-c1ccc2c(c1)C(NC(=O)CN(C)C)(c1ccccc1)C(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
A mixture of 2-(dimethylamino)acetic acid hydrochloride (87 mg, 0.62 mmol), HATU (118 mg, 0.31 mmol), and Et3N (94 mg, 0.93 mmol) in CH2Cl2 (10 mL) was stirred at RT for 0.5 hours, and then 3-amino-5-(3,5-dimethylisoxazol-4-yl)-3-phenylindolin-2-one (100 mg, 0.31 mmol) was added and the mixture was stirred for another 12 h. And water (10 mL) was added, the mixture was extracted with CH2Cl2 (2×20 mL), combined organic phase, washed with brine (20 mL), dried with Na2SO4, concerned in vacuo, the mixture was purified with column chromatography to give product (50 mg, 40%) as a solid. 1H NMR (400 MHz, DMSO-d6): δH 10.70 (s, 1H), 9.74 (s, 1H), 7.26-7.40 (m, 7H), 6.99 (d, J=8.0 Hz, 1H), 4.07 (d, J=16.0 Hz, 1H), 3.93 (d, J=16.0 Hz, 1H), 2.78 (s, 3H), 2.71 (s, 3H), 2.38 (s, 3H), 2.20 (s, 3H). MS (ESI) m/e [M+1]+ 405.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16]Br)=[CH:12][CH:11]=2)[CH:3]=1.[CH3:18][C:19]([O-:21])=[O:20].[Na+].O.C(OCC)(=O)C>CN(C=O)C>[C:19]([O:21][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=2[Cl:8])=[CH:11][CH:12]=1)(=[O:20])[CH3:18]
Reactant: Clc1ccc(Br)cc1Cc1ccc(CBr)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of 4-bromo-2-(4-(bromomethyl)benzyl)-1-chlorobenzene (intermediate AI) (15.5 g) in DMF (70 mL), NaOAc (16.27 g) was added. The solution was heated to 70° C. After 3 h, H2O (100 mL) and ethyl acetate (200 mL) were added. The organic layer was separated, washed with brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography to obtain pure intermediate AJ (8.86 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2].[CH3:21][C:22]1[S:26][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH2:37][CH2:38]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:38][CH2:37][C:23]2[N:24]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=3)[S:26][C:22]=2[CH3:21])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2]
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)cc1OCC)OCC
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(C(F)(F)F)cc3)sc2C)cc1OCC)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(2-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl ester (example 58 c]) was reacted with 2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethanol [PCT Int. Appl. (2001), WO 01/00603 A1] in tetrahydrofuran in the presence of triphenylphosphine and DBAD (di-tert-butyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(2-ethoxy-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 1 e], to yield [rac]-2-ethoxy-3-(2-ethoxy-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid as colorless oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16].[CH3:25][C:26](=O)[CH2:27][C:28](=[O:30])[CH3:29]>C1COCC1>[C:28]([C:27]1[CH:21]([C:20]2[CH:23]=[CH:24][C:17]([C:15]#[N:16])=[CH:18][CH:19]=2)[NH:12][C:10](=[S:11])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=2)[C:26]=1[CH3:25])(=[O:30])[CH3:29]
Reactant: CC(=O)CC(C)=O
Reactant: NC(=S)Nc1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: C1CCOC1
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
3-Trifluoromethylphenyl thiourea (200 mg, 0.91 mol), 4-cyanobenzaldehyde (238.2 mg, 1.82 mmol) and 2,4-pentanedione (181.9 mg, 1.82 mmol) are dissolved in 5 ml THF. Ethyl polyphosphate (0.30 g) is added and the reaction mixture is stirred at reflux temperature overnight. After cooling to room temperature, the reaction is quenched with 10 ml of water and extracted with 10 ml ethyl acetate (2×). The combined organic layers are dried with sodium sulfate and the solvent is removed in vacuo. The product is purified via preparative HPLC (RP18-column; eluent: acetonitrile-water, gradient 10:90 to 90:10).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[CH:18]=[C:17]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[O:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2.[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=O>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[CH:18]=[C:17]([N:19]4[CH2:20][CH2:21][N:22]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][OH:26])[CH2:23][CH2:24]4)[O:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=CCCCCO
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cc(N4CCNCC4)on3)ccc21
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(N4CCN(CCCCCO)CC4)on3)ccc21

Procedure:
The preparation was carried out as already described via a reductive amination starting from 26 mg (0.05 mmol) of 1-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)isoxazol-5-yl]piperazine and 5 mg (0.05 mmol) of 5-hydroxypentanal. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:45][OH:46].CN(C)[CH:49]=[O:50]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[C:45]([O:50][CH3:49])=[O:46]
Reactant: CN(C)C=O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccnc2cc(OC)c(OC)cc12
Temperature: 85 °C

Procedure:
4-Chloro-6,7-dimethoxyquinoline (3 g, 13.45 mmol), palladium acetate (605 mg, 2.69 mmol) and 1,3-bis(diphenylphosphino)propane (1.39 g, 3.36 mmol) were added to a pressure tube then dissolved in N,N-dimethylformamide (25 mL). Carbon monoxide gas was bubbled through the mixture for 10-15 minutes. The reaction mixture was heated at 85° C. overnight. Additional palladium acetate (303 mg, 1.35 mmol), 1,3-bis(diphenylphosphino)propane (277 mg, 0.671 mmol) and methanol (2 mL) were added to the reaction mixture then carbon monoxide was bubbled through the solution for 10 minutes. The reaction mixture was then heated at 85° C. overnight again. The mixture was concentrated under vacuum. The crude material was purified twice by silica gel chromatography (1% methanol/dichloromethane then 50%-67% ethyl acetate/hexane) to afford methyl 6,7-dimethoxyquinoline-4-carboxylate (2.07 g) as a light yellow solid. MS (ESI, pos. ion) m/z: 248.0 (M+1).
Reaction SMILES: [H-].[K+].[CH3:3][N:4]([CH3:12])[CH2:5][CH2:6][CH:7]([OH:11])[CH2:8][NH:9][CH3:10].C(C[CH2:17][C:18]1[CH:19]=[N:20][C:21]2[C:26]([C:27]=1Cl)=[CH:25][CH:24]=[CH:23][CH:22]=2)(O)=O.N.[O:30]1CCCC1>CO.C(OCC)(=O)C.O>[CH3:3][N:4]([CH3:12])[CH2:5][CH2:6][CH:7]1[CH2:8][N:9]([CH3:10])[C:17](=[O:30])[C:18]2[CH:19]=[N:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]=2[O:11]1
Reactant: O=C(O)CCc1cnc2ccccc2c1Cl
Reactant: C1CCOC1
Reactant: CNCC(O)CCN(C)C
Agent: N
Agent: [H-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CN(C)CCC1CN(C)C(=O)c2cnc3ccccc3c2O1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 19.4 g (35% in oil, 0.172 mole) of potassium hydride in 150 ml of tetrahydrofuran was added at a rapid drop, 12.4 g (0.086 mole) of 4-dimethylamino-1-methylamino-2-butanol. After 10 min., 20 g (0.086 mole) of 3-carboxyethyl-4-chloroquinoline was added via a powder dropping funnel over a period of 30 min. The mixture was stirred at room temperature overnight. Approximately 50 ml of water was added to quench the reaction and the mixture was partitioned between isopropanol ether and water. The aqueous layer was extracted again with two 70 ml portions of isopropyl ether. The aqueous layer was then continuously extracted for 15 hr with chloroform. The chloroform layer was collected, filtered and concentrated by rotary evaporation at 80°, 30 mm. The crude material (18 g) was purified by HPLC using silica gel as the stationary phase and 3% triethylamine/ethanol as the eluent. Approximately 4 g (b 15.6%) of product was obtained on evaporation of fractions having a similar thin layer chromatograph (TLC) using ethyl acetate, methanol and aqueous conc. ammonia (7:2:1 parts by volume respectively) on silica. TLC of the final product using the same solvent mix on silica was identical to that of the free base of the same compound prepared in Example 2. C.I. mass spec showed M+H of 300. The oxalate salt was also identical to that obtained in Example 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:12]([CH2:20][CH3:21])=[N+:13]([O-])[CH:14]=[C:15]([CH2:17][CH3:18])[N:16]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:14]1[C:15]([CH2:17][CH3:18])=[N:16][C:11]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])=[C:12]([CH2:20][CH3:21])[N:13]=1
Reactant: CCc1c[n+]([O-])c(CC)c(-c2ccc(OC)cc2OC)n1
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1nc(-c2ccc(OC)cc2OC)c(CC)nc1Cl
Temperature: 60 °C
Reaction time: 6 h

Procedure:
The product from step 2 (3.3 g) is dissolved in POCl3 (25 mL) and the resulting solution stirred at 60° C. for 6 hours. The reaction mixture is cooled, and the volatiles are removed under reduced pressure. Flash chromatography (1-4% ethyl acetate in hexanes) affords 2-chloro-5-(2,4-dimethoxy-phenyl)-3,6-diethyl-pyrazine as a clear oil. MS: 307. H-1 NMR (400 MHz, CDCl3): 1.16 (t, 3H), 1.31 (t, 3H), 2.60 (q, 2H), 3.00 (q, 2H), 3.75 (s, 3H), 3.76 (s, 3H), 6.53 (d, 1H), 6.59 (dd, 1H), 7.19 (d, 1H).
Reaction SMILES: COC1C=C(S)C=C(C)C=1.C(OC(=O)CC(=O)CCl)C.C([O:23][C:24](=[O:54])[CH2:25][C:26]1[C:27]2[C:34]([CH3:35])=[CH:33][C:32]([O:36][CH2:37][C:38]3[S:42][C:41]([C:43]4[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=4)=[N:40][C:39]=3[CH3:53])=[CH:31][C:28]=2[S:29][CH:30]=1)C>>[CH3:35][C:34]1[C:27]2[C:26]([CH2:25][C:24]([OH:54])=[O:23])=[CH:30][S:29][C:28]=2[CH:31]=[C:32]([O:36][CH2:37][C:38]2[S:42][C:41]([C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:50])[F:51])=[CH:45][CH:44]=3)=[N:40][C:39]=2[CH3:53])[CH:33]=1
Reactant: CCOC(=O)Cc1csc2cc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)cc(C)c12
Agent: CCOC(=O)CC(=O)CCl
Agent: COc1cc(C)cc(S)c1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1cc(C)c2c(CC(=O)O)csc2c1

Procedure:
The title compound was prepared in the manner analogous to example 5C starting with 3 3-methoxy-5-methyl-benzenethiol and the 4-chloro-3-oxo-butyric acid ethyl ester. MS m/z 251 (M+1). Step 2. Preparation of {4-Methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzo[b]thiophen-3-yl}-acetic acid ethyl ester (Compound 17B)
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([F:11])[CH:4]=1)#[N:2].[CH2:12](O)[CH2:13][CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[O:8]1[CH2:12][CH2:13][CH2:14][O:15][CH:7]1[C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[F:11]
Reactant: OCCCO
Reactant: N#Cc1ccc(C=O)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(C2OCCCO2)c(F)c1
Reaction time: 6 h

Procedure:
4-Cyano-2-fluorobenzaldehyde (65 g, 436 mmol) and 1,3-propanediol (36.5 g, 479 mmol; 1.1 eq.) were, together with 4-toluenesulfonic acid monohydrate (1.66 g, 8.72 mmol; 0.02 eq.), initially charged in toluene (1000 ml) and stirred at boiling point on a water separator for 6 h. The reaction mixture was then washed with saturated sodium bicarbonate solution (3×300 ml) and saturated sodium chloride solution (3×300 ml). The organic phase was dried over sodium sulfate and concentrated. The title compound was obtained as a solid (92 g, quant.).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])C)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH:20]3[CH2:21][CH2:23][CH2:13][CH:12]([CH3:17])[CH2:4]3)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1CCCC(Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.060 g, 0.13 mmol) in tetrahydrofuran (4 mL) and methanol (0.011 mL, 0.26 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.1 mL, 0.20 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid a pH of approximately 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 98:2 dichloromethane/methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.86 (m, 4 H) 1.08 (m, 1 H) 1.29 (m, 3 H) 1.60 (m, 3 H) 1.93 (m, 1 H) 3.04 (m, 1 H) 5.76 (d, J=3.31 Hz, 1 H) 7.14 (d, J=5.52 Hz, 1 H) 7.19 (d, J=8.46 Hz, 1 H) 7.26 (t, J=7.54 Hz, 1 H) 7.52 (dt, J=8.46, 1.47 Hz, 1 H) 7.65 (d, J=8.09 Hz, 1 H) 7.73 (t, J=5.15 Hz, 1 H) 15.93 (s, 1 H). MS (ESI−) m/z 457 (M−H)−.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([CH3:7])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:7][C@H:6]1[C@H:2]([O:1][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:3][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5]1
Reactant: C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(+/−)-(trans)-benzyl 3-hydroxy-4-methylpyrrolidine-1-carboxylate (9.2 g, 39.1 mmol) in pyridine (50 mL) at 5° C. was added tosyl chloride (9.69 g, 50.8 mmol) in one portion and the resulting mixture was allowed to warm to rt and stir overnight. The reaction mixture was concentrated and the residue was taken up in dichloromethane (400 mL) and washed with water (50 mL×2), 0.5 N HCl (50 mL×2), water, sat aq. sodium bicarbonate (50 mL×2), brine, then dried over magnesium sulfate, filtered and concentrated to give a dark oil as the crude title compound which was used directly without any further purification. HPLC (method B) retention time=3.60 min. LCMS (m+1)=390.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34](O)=[O:35])[CH2:29][CH2:28]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:34](=[O:35])[CH2:33][N:30]5[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CN1CCN(CC(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4OCO5)CC3)CC2)CC1

Procedure:
The title compound, white solid (13.5 mg, 35.1%), MS (ISP) m/z=471.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and 2-(4-methylpiperazin-1-yl)acetic acid.
Reaction SMILES: [Mg].[CH2:2](Br)[CH:3]([CH3:5])[CH3:4].[N:7]1([C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH:15]=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>CCOCC>[CH3:4][CH:3]([CH3:5])[CH2:2][CH:15]([OH:16])[C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)CBr
Reactant: O=Cc1ccccc1N1CCCCC1
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)CC(O)c1ccccc1N1CCCCC1
Reaction time: 0.33 h
Yield: 54.2 %

Procedure:
In a 3 necked round bottom flask (25 ml), equipped with a dropping funnel, reflux condenser and thermometer pocket, placed magnesium turnings (0.254 gm, 10.47 mmol) and flame dried the apparatus. Dry diethyl ether (10 ml.) was added to Mg. Turning, Isobutyl bromide (1.13 ml, 1.45 gm, 10.58 mmol) was taken in 2 ml of dry ether and added drop wise to the Mg turnings. As soon as ether starts boiling (in a few minutes) the reaction was cooled using ice-salt and continued the addition of isobutyl bromide. After complete addition of isobutyl bromide continued for another 20 minutes. o-piperidino benzaldehyde 8 (1.0 gm, 5.29 mmol) in 2 ml of ether was added drop wise at −10° C. After the completion of addition of 8 continued the stirring for 1 hr and the reaction was quenched with ice-cooled saturated ammonium chloride solution (5 ml), the solid separated is filtered off, the filtrate is extracted with ethyl acetate (10×2 ml) dried over sodium sulphate and concentrated to yield 1.36 gm of crude product. The crude product was chromatographed and obtained pure 9 (54.2%).
Reaction SMILES: C([O:3][C:4](=[O:22])/[C:5](/[CH3:21])=[CH:6]/[CH:7]=[C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.[OH-].[K+]>CO.O>[C:9]1([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7]/[CH:6]=[C:5](\[CH3:21])/[C:4]([OH:22])=[O:3])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)/C(C)=C/C=C(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C/C(=C\C=C(c1ccccc1)c1ccccc1)C(=O)O
Reaction time: 8 h
Yield: 82.2 %

Procedure:
As in the Example 99. a solution of 3,3-diphenyl-2-propenal (2.08 g) in ethanol (25 mL) was reacted with (carbethoxyethylidene)triphenylphosphorane (4.0 g) for 30 minutes at room temperature. The reaction was worked up in the usual manner to give 2.8 g of (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid ethyl ester as the sole product. The crude ester (2.8 g) in methanol (25 mL) was treated with 2N potassium hydroxide (10 mL) and the mixture was heated at reflux until the oil dissolved, then it was cooled and left at ambident temperature overnight. The reaction was diluted with water (20 mL) and most of the methanol was removed under reduced pressure. The solution was acidified with 2N hydrochloric acid (12 mL) and the resulting solid was recovered by filtration, washed with water and dried. The crude acid was triturated with hot hexane to furnish 2.08 g of (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid, mp 184°-186° C. A sample was crystallized from 2-propanol to afford the analytical specimen, mp 185°-186.5° C.