Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:23]([NH:27][S:28]([C:31]1[S:32][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:35]=1)(=[O:30])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([NH:27][S:28]([C:31]1[S:32][C:33]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=4)[CH:11]=[C:10]([CH3:22])[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:34][CH:35]=1)(=[O:29])=[O:30])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(Cl)c2)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
5-{4-[4-(3,4-Dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butylamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-(3,4-dichlorophenyl)-6-methyl-pyrimidine (example E.63) (0.35 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.45 g, 1.3 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.22 g) which was subsequently deprotected.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2>CO.C(O)(=O)C.[Pd]>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH2:24])[CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: N#Cc1cccc(-c2ccc(C(=O)N[C@H]3CN4CCC3CC4)s2)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: NCc1cccc(-c2ccc(C(=O)N[C@H]3CN4CCC3CC4)s2)c1
Reaction time: 36 h
Yield: 7.3 %

Procedure:
To the solution of (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(3-cyanophenyl)thiophene-2-carboxamide) (311 mg) in methanol and acetic acid (1:1, 10 mL) a catalytic amount of 10% Pd—C was added and the mixture was hydrogenated at 50 p.s.i. for 36 hr. The mixture was filtered through a pad of celite. The residue was purified first by flash chromatography using 5-20% 3.5M methanolic ammonia/chloroform mixtures as the eluent and then by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The free base was prepared by basification of the product-containing fractions and extraction into chloroform followed by evaporation to gave the title compound (23 mg); MS (ES+) 342 (MH+).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][C@@H:8]([N:10]2[C:18]3[C:17]([F:19])=[CH:16][N:15]=[C:14](F)[C:13]=3[N:12]=[CH:11]2)[CH:7]=[CH:6]1)(=O)C.C([O:24][C@@H:25]1[CH2:29][C@@H:28]([N:30]2[C:34]3[C:35](F)=[N:36][CH:37]=[C:38]([F:39])[C:33]=3[N:32]=[CH:31]2)[CH:27]=[CH:26]1)(=O)C>N>[NH2:30][C:14]1[C:13]2[N:12]=[CH:11][N:10]([C@@H:8]3[CH2:9][C@@H:5]([OH:4])[CH:6]=[CH:7]3)[C:18]=2[C:17]([F:19])=[CH:16][N:15]=1.[NH2:10][C:35]1[C:34]2[N:30]([C@@H:28]3[CH2:29][C@@H:25]([OH:24])[CH:26]=[CH:27]3)[CH:31]=[N:32][C:33]=2[C:38]([F:39])=[CH:37][N:36]=1
Reactant: CC(=O)O[C@H]1C=C[C@H](n2cnc3c(F)cnc(F)c32)C1
Reactant: CC(=O)O[C@H]1C=C[C@H](n2cnc3c(F)ncc(F)c32)C1
Agent: N
Product: Nc1ncc(F)c2c1ncn2[C@H]1C=C[C@H](O)C1
Product: Nc1ncc(F)c2ncn([C@H]3C=C[C@H](O)C3)c12
Temperature: 100 °C

Procedure:
Liquid ammonia (150 mL) was added to a mixture of (1R,4R)-4-(4,7-difluoro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopent-2-enyl acetate (4-1) (312 mg, 1.1 mmol, 1 equiv) and (1R,4R)-4-(4,7-difluoro-3H-imidazo[4,5-c]pyridin-3-yl)cyclopent-2-enyl acetate (4-2) (408 mg, 1.5 mmol, 1 equiv). The resulting solution was heated in a high pressure vessel to 100° C. for 2 days. The mixture was then concentrated and purified via reverse phase chromatography (5-95% CH3CN/water with 0.1% TFA modifier) to yield (1R,4R)-4-(4-amino-7-fluoro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopent-2-enol (4-3) as a white solid and (1R,4R)-4-(4-amino-7-fluoro-3H-imidazo[4,5-c]pyridin-3-yl)cyclopent-2-enol (4-4) as a white solid. 1H NMR (4-3) (500 MHz, CD3 OD): δ 8.03 (s, 1H); 7.61 (d, J=3.5 Hz, 1H); 6.31 (m, 1H); 6.20 (m, 1H); 5.93 (m, 1H); 5.09 (m, 1H); 2.40-2.50 (m, 1H); 2.27-2.37 (m, 1H). LRMS m/z (M+H) 235.0 found, 235.1 required. 1H NMR (4-4) (500 MHz, CD3 OD): δ 8.12 (s, 1H); 7.64 (d, J=2.5 Hz, 1H); 6.37 (m, 1H); 6.27 (m, 1H); 6.11 (m, 1H); 4.92 (m, 1H); 2.40-2.50 (m, 1H); 2.27-2.37 (m, 1H). LRMS m/z (M+H) 235.0 found, 235.1 required.
Reaction SMILES: [CH3:1][C:2]([CH2:9][N+:10]([O-])=O)=[CH:3][CH2:4][O:5][C:6](=[O:8])[CH3:7].N1C=CC=CC=1.P(Cl)(Cl)Cl.Cl>C(Cl)Cl>[CH3:1][C:2]([C:9]#[N:10])=[CH:3][CH2:4][O:5][C:6](=[O:8])[CH3:7]
Reactant: CC(=O)OCC=C(C)C[N+](=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: CC(=O)OCC=C(C)C#N
Reaction time: 1 h

Procedure:
To 500 mg. (0.003 m) of acetic acid(3-methyl-4-nitro-2-buten-1-yl)ester in 10 ml. of pyridine was added, under an atmosphere of nitrogen, 8 ml. of a 10% solution of phosphorous trichloride (0.008 m) in methylene chloride. After standing for 1 hour at room temperature the reaction mixture was poured, under cooling, into 3N HCl. The reaction mixture was then extracted with ether, washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was then evaporated after filtration of the drying agent. The acetic acid (3-methyl-3-cyano-2-propen-1-yl)-ester obtained as a yellow oily residue was purified via vacuum distillation, b.p. 63°/0.05 mmHg.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4]2([C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH2:8][C:7]2([CH3:15])[OH:14])[O:3]1.CN(C)C1C=CC=CC=1.[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>>[C:25]([O:14][C:7]1([CH3:15])[CH2:8][CH2:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:4]21[O:3][CH:2]([CH3:1])[CH2:6][CH2:5]2)(=[O:29])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C(=O)Cl
Reactant: CC1CCC2(O1)C(C)(C)CCCC2(C)O
Solvent: CN(C)c1ccccc1
Product: CC1CCC2(O1)C(C)(C)CCCC2(C)OC(=O)C(C)C
Yield: 10.6 %

Procedure:
2.12 g (0.01 M) of 2,6,10,10-tetramethyl-1-oxa-spiro[4.5]decan-6-ol--isomer A; see Example 1--were treated with a mixture of 12.1 g (0.1 M) of N,N-dimethylaniline and 5.3 g (0.05 M) of isobutyryl chloride as indicated in Example 5 to give 0.3 g (ca. 11%) of the desired ester, b.p. 110°/0.5 Torr.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O.[CH2:19]=[C:20]([CH3:22])[CH3:21].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]1[CH2:19][C:20]([CH3:22])([CH3:21])[C:9]2[C:2](=[CH:3][CH:4]=[C:5]([C:6]#[N:7])[CH:8]=2)[NH:1]1
Reactant: O=Cc1ccccc1Br
Reactant: N#Cc1ccc(N)cc1
Reactant: C=C(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2ccccc2Br)Nc2ccc(C#N)cc21
Temperature: 85 °C
Reaction time: 18 h
Yield: 40.1 %

Procedure:
To a stirred solution of 4-aminobenzonitrile (10.0 g, 84.7 mmol) and 2-bromobenzaldehyde (10 mL, 84.7 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 85° C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 0-10% ethyl acetate in petroleum ether) to afford 2-(2-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (11.6 g, 40.0%) as a light yellow solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 341.0 & 343.0.
Reaction SMILES: [F:1][C:2]1[C:3]([C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:4]([NH:9][C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].F[C:28]1[C:37](F)=CC=C2[C:29]=1C(C1C=CC(F)=CC=1)(O)N(CC(F)(F)F)C(=O)N2.C(N(CC)CC)C.S(Cl)(Cl)=O.C([Mg]Br)C=C>C1COCC1>[CH2:37]([C:18]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:3]2[C:4](=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[NH:9][C:10](=[O:11])[N:12]1[CH2:13][C:14]([F:17])([F:16])[F:15])[CH:28]=[CH2:29]
Reactant: O=C(NCC(F)(F)F)Nc1ccc(F)c(F)c1C(=O)c1ccc(F)cc1
Reactant: O=C1Nc2ccc(F)c(F)c2C(O)(c2ccc(F)cc2)N1CC(F)(F)F
Agent: C=CC[Mg]Br
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCC1(c2ccc(F)cc2)c2c(ccc(F)c2F)NC(=O)N1CC(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5.0 g (13.289 mmol) N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (open form) and 5,6-difluoro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (closed form) in 25 ml THF was added 9.261 mL (66.443 mmol) triethylamine. After 1 h at 80° C., the reaction mixture was cooled to −78° C. To this solution was added 0.969 mL (13.289 mmol) thionyl chloride. After 30 mins at −78° C., 45 mL (41.195 mmol) allylmagnesium bromide (1.0M solution in dibutyl ether) was added dropwise. After 30 minutes at −78° C., the reaction mixture was quenched with saturated NH4Cl and warmed to room temperature. The reaction mixture was extracted three times with EtOAc and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 0-35% EtOAc:hexane) afforded 4-allyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. 1H NMR (CDCl3, 400 MHz) δ 7.46 (br s, 1H, ArNHC═O); 7.42-7.40 (m, 2H, ArH); 7.10-7.00 (m, 3H, ArH); 6.44 (m, 1H, ArH); 5.73-5.66 (m, 1H, CH2CH═CH2); 5.13-5.09 (m, 2H, CH2CH═CH2); 3.73 (m, 2H, NCH2CF3); 3.15 (m, 2H, CH2CH═CH2). HRMS (ES) exact mass calcd for C19H14F6N2O: 401.1083, Found: 401.1075.
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:2]([C:7]([NH:9][C@H:10]([C:15](O)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C[N:26]1CCOCC1.ClC(OCC(C)C)=O.N>C1COCC1>[NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH2:26])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CN1CCOCC1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(N)=O
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
Boc-Leu-Leu-OH (Bachem, 43.6 mmol) is dissolved in THF (250 ml) and N-methylmorpholine (43.6 mmol) is added. The mixture is cooled to −20° C. and isobutyl chloroformate (43.6 mmol) is added dropwise. The mixture is stirred for 10 min. and then a 25% aqueous solution of ammonia (52.3 mmol) is added at −20° C. The mixture is stirred for 3 hours at −20° C. to −10° C. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate and evaporated. The crude product is suspended in diethylether and the solid filtered of and dried (vacuum). 14.2 g of a white powder with mp. 155-156° C., Rf=0.5 (CH2Cl2/MeOH=9:1) is obtained.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:24]=[CH:23][C:11]([C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:25][SiH:26]([CH3:32])[O:27][Si:28]([CH3:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1.C1([Pt](Cl)(Cl)C2C=CC=C2)C=CC=C1>[CH3:25][Si:26]([CH3:32])([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:7][C:8]1[CH:24]=[CH:23][C:11]([C:12]([O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=2)=[O:13])=[CH:10][CH:9]=1)[O:27][Si:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: C[SiH](C)O[Si](C)(C)C
Reactant: C=CCCCCOc1ccc(C(=O)Oc2ccc(C#N)cc2)cc1
Agent: Cl[Pt](Cl)(C1C=CC=C1)C1C=CC=C1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)O[Si](C)(C)CCCCCCOc1ccc(C(=O)Oc2ccc(C#N)cc2)cc1

Procedure:
0.94 g (0.024 mmol of Pt) of 0.5% strength dicyclopentadienylplatinum dichloride solution (dichloromethane) was added to a solution of 13.8 g (42.9 mmol) of 4-cyanophenyl 4-(5-hexenyloxy)benzoate and 6.48 g (43.7 mmol) of pentamethyldisiloxane in 50.0 g of toluene, and the mixture was refluxed for 3 hours. After complete hydrosilylation of the olefin, a further 0.94 g (0.024 mmol of Pt) of 0.5% strength dicyclopentadienylplatinum dichloride solution (dichloromethane) were added, and the mixture was refluxed for a further 2 hours. The reaction mixture was flushed with nitrogen, and the toluene was removed by vacuum distillation on a rotary evaporator. The crude product was purified by chromatography on silica gel. The 4-cyanophenyl 4-(6-pentamethyldisiloxanylhexyloxy)benzoate obtained was additionally recrystallized from petroleum ether (100° C.-140° C.) and exhibited the following phase behavior: c 54-55 (sA 53-55) i.
Reaction SMILES: C(SSCC)C.B(F)(F)F.CCOCC.[S:16]([C:26]1[C:31]([OH:32])=[C:30]([CH3:33])[CH:29]=[CH:28][CH:27]=1)[S:17][C:18]1C(O)=C(C)C=C[CH:19]=1>ClCCl>[CH2:18]([S:17][S:16][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([CH3:33])[C:31]=1[OH:32])[CH3:19]
Reactant: Cc1cccc(SSc2cccc(C)c2O)c1O
Agent: FB(F)F
Solvent: CCSSCC
Solvent: ClCCl
Solvent: CCOCC
Product: CCSSc1cccc(C)c1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 144.2 %

Procedure:
Diethyl disulfide (14.24 ml, 116 mmol) and BF3.OEt2 (14.66 mml, 16.42 mmol) were added to a solution of 6,6′-disulfanediylbis(2-methylphenol) (Compound 104) (1.61 g, 5.78 mmol) in dichloromethane (30 ml), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was then quenched by slowly adding a saturated NaHCO3 solution dropwise thereto at 0° C., after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→90/10) to afford 2-(ethyldisulfanyl)-6-methylphenol (Compound 105) (1.67 g, 72%).
Reaction SMILES: FC(S(O[C:9]1[C:26]([O:27][CH3:28])=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:29])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)(=O)=O)(F)F.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Si](C)(C)N[Si](C)(C)C.C[N:69](C)[CH:70]=[O:71]>[Pd](Cl)Cl>[CH3:28][O:27][C:26]1[C:9]([C:70]([NH2:69])=[O:71])=[CH:10][C:11]2[CH2:12][CH2:13][C@@H:14]3[C@@H:23]([C:24]=2[CH:25]=1)[CH2:22][CH2:21][C@@:19]1([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]1=[O:29]
Reactant: COc1cc2c(cc1OS(=O)(=O)C(F)(F)F)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(cc1C(N)=O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 44 %

Procedure:
A 1-L 3 neck round-bottomed flask equipped with an overhead stirrer, reflux condenser, nitrogen inlet and thermocouple, was charged with 2-methoxy-17-oxoestra-1,3,5(10)-triene-3-yl(trifluoromethyl)sulfonate (Scheme 5, Compound 42) (15 g, 34.7 mmol), 1,3-bis(diphenylphosphino)propane (1.54 g, 3.73 mmol), palladium (II) chloride (0.33 g, 1.9 mmol), 1,1,1,3,3,3-hexamethyldisilazane (31 mL, 150 mmol) and anhydrous dimethylformamide (110 mL). Carbon monoxide was bubbled through the yellow solution while stirring for 5 minutes. The reaction was heated to 110° C. under an atmosphere of carbon monoxide (balloon) and allowed to stir for 15 h. During this period the reaction became dark. The reaction was quenched by treating with methanol (25 mL) and stirred for 10 min. The mixture was poured into ethyl acetate (1 L) and washed with 2N sulfuric acid (750 mL). The aqueous layer was extracted with ethyl acetate (2×500 mL) and the combined organic phases were washed with 2N sulfuric acid (250 mL) and saturated aqueous sodium bicarbonate (500 mL) then dried over 500 g of sodium sulfate. This mixture was suction-filtered through a bed of silica gel 60 (67 g) and concentrated to dryness affording crude product (11.2 g, 98% recovery). The crude material was purified by Flash column chromatography (360 g of silica gel 60, eluting with methylene chloride, then 1:5 ethyl acetate:methylene chloride). Concentration of the pure fractions (Rf=0.3, 1:5 ethyl acetete:methylene chloride, UV detection) and drying in a vacuum oven at 50° C., and removal of residual solvents afforded pure product (Scheme 5, Compound 54) (4.97 g, 44% yield) as an off-white to pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.82 (br s, 1H), 7.05 (s, 1H), 5.92 (br s, 1H), 4.02 (s, 3H), 3.05 (dd, 2H, J=5), 2.15 (m 2H,) 2.02-1.65 (m, 6H), 1.55-1.15 (m, 8H), 0.80 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 220.6, 167.2, 155.9, 145.5, 132.8, 129.4, 118.3, 108.4, 55.9, 50.5, 47.9, 44.9, 37.8, 35.8, 31.6, 28.26, 26.4, 25.8, 21.6, 13.8.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13](Cl)[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.C[C:18]([CH2:20][CH:21](C)C)=[O:19].C(=O)([O-])[O-].[Na+].[Na+].ClCCCO[CH:35]1[CH2:40][CH2:39][CH2:38][O:37][CH2:36]1>O>[O:37]1[CH2:36][CH2:35][CH2:40][CH2:39][CH:38]1[O:19][CH2:18][CH2:20][CH2:21][N:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: ClCCCOC1CCCOC1
Reactant: CC(=O)CC(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CCCOC2CCCCO2)C1
Reaction time: 24 h

Procedure:
A mixture of 11.6 g of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-5-chloro-1H-indole, 120 ml of isobutyl methyl ketone, 15.9 g of sodium carbonate and 22 ml of 3-(3-chloropropyloxy)-tetrahydro-2H-pyran was stirred at 100°-105° C. under an inert atmosphere for 24 hours and was cooled and poured into 500 ml of water. The mixture was stirred for one hour and was extracted with ethyl acetate. The organic phase was washed with water and with aqueous sodium chloride solution, dried and evaporated to dryness. The 29.6 g of crystalline residue were chromatographed over silica gel and eluted with a 6-3-1 chloroform-acetone-triethylamine mixture to obtain 13.1 g of 3-[1-(3-{2-tetrahydropyranyloxy}-propyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1H-indole in the form of crystals melting at 161° C.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[OH:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]([C@@H:27]2[CH2:31][C@H:30]([S:32]CC3C=CC(OC)=CC=3)[CH2:29][N:28]2[CH3:42])=[O:26])[CH2:21][CH2:20]1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:32][C@@H:30]1[CH2:29][N:28]([CH3:42])[C@H:27]([C:25]([N:22]2[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][OH:16])[CH2:24][CH2:23]2)=[O:26])[CH2:31]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCO)CC3)N(C)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN1C[C@@H](S)C[C@H]1C(=O)N1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 ml of trifluoroacetic acid and 520 μl of trifluoromethanesulfonic acid were added, whilst ice-cooling, to a solution of 1150 mg of (2S,4S)-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl)-4-(4-methoxybenzylthio)-1-methylpyrrolidine [prepared as described in step (i) above] in 3 ml of anisole, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, to give 1680 mg of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:36])[C:5]2[CH:11]=[C:10]([CH2:12][NH:13][C:14]3[CH:35]=[CH:34][C:17]([C:18]([NH:20][C@H:21]([C:29]([O:31]CC)=[O:30])[CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[O:19])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1.[OH-].[Na+]>CS(C)=O>[NH2:1][C:2]1[N:3]=[C:4]([NH2:36])[C:5]2[CH:11]=[C:10]([CH2:12][NH:13][C:14]3[CH:35]=[CH:34][C:17]([C:18]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:19])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCc2cnc3nc(N)nc(N)c3c2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1nc(N)c2cc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2n1
Reaction time: 6 h

Procedure:
A solution of the product obtained in Example 3, VII (R=H, R1 =C2H5) (359 mg, 0.724 mmol) in dimethyl sulfoxide (10 ml) under N2 was treated with 1N NaOH (1.81 ml, 1.81 mmol), stirred in a stoppered flask under N2 for 6 hours, and evaporated to dryness in vacuo at <30° C. A solution of the residue in water (18 ml) was filtered and acidified to pH 3.6 with 1N HCl. The precipitate was collected by filtration, washed with water at pH 3.6 and dried in vacuo (P2O5); yield 297 mg (87%), mp indefinite (softens above 200° C.); mass spectrum, m/e 440 (M+1)+ ; λmax nm (εx 10-3): 0.1N HCl-218 (40.5), 280 sh (16.9), 300 (18.8); pH 7-218 (38.5), 245 (19.2), 280 (23.9), 296 sh (22.7); 0.1N NaOH-248 (22.0), 280 (24.4), 296 sh (22.7), 345 (7.75); 1H-NMR (DMSO-d6, 6% w/v), δ2.00 m (CH2CH2CO), 2.29 t (CH2CO), 4.36 m (CHN, CH2N), 6.66 d, 7.68 d (C6H4), 7.41 (NH2), 8.04 m (NH2, NH, CO2H), 8.52 d, 8.70 d (5-CH, 7-CH).
Reaction SMILES: I[CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[OH:13][CH:14]([C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[Na+].O>CS(C)=O.C1COCC1>[OH:13][CH:14]([C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: ICC1CCc2ccccc2C1
Reactant: CCCCCC(O)c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: CCCCCC(O)c1cccc(OCC2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 21.3 %

Procedure:
A mixture of 4.0 g (0.018 mol) 2-(iodomethyl)-1,2,3,4-tetrahydronaphthalene, 3.4 g (0.018 mol) 3-(1-hydroxyhexyl)phenol and 3.4 ml NaOH (5N) in 50 ml DMSO and 20 ml THF was stirred at room temperature for a period of 48 hours. The reaction mixture was concentrated under reduced pressure. The concentrated reaction mixture was poured into water and extracted with ether. The ether extract was washed with water, dried over MgSO4 and concentrated to dryness under reduced pressure. The residue was passed through a silica gel comumn using hexane/ethyl acetate (3:1) as eluent. Evaporation of eluent gave an oily product (1.3 g).
Reaction SMILES: ClS([C:5]1[CH:9]=[CH:8][S:7][C:6]=1C)(=O)=O.S1C=CC=C1.[Cl:16][S:17](O)(=[O:19])=[O:18].P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:16][S:17]([C:6]1[S:7][CH:8]=[CH:9][CH:5]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1sccc1S(=O)(=O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccsc1
Product: O=S(=O)(Cl)c1cccs1
Yield: 70 %

Procedure:
This compound was produced as described for chlorosulfonyl-methylthiophene in J. org. Chem. 33, 1357 (1968) from thiophene, chlorosulfonic acid and PCl5. The yield was 70%. The substance was a low melting solid.