Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].C(N(CC)CC)C.[F:12][C:13]1[C:14]([C:20](F)=[O:21])=[N:15][C:16]([F:19])=[CH:17][CH:18]=1>O>[F:12][C:13]1[C:14]([C:20]([O:4][CH:2]([CH3:3])[CH3:1])=[O:21])=[N:15][C:16]([F:19])=[CH:17][CH:18]=1
Reactant: CC(C)O
Reactant: O=C(F)c1nc(F)ccc1F
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)OC(=O)c1nc(F)ccc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 48 %

Procedure:
Anhydrous 2-propanol (0.361 g, 6 mmol) and anhydrous tri-ethylamine (0.405 g, 4 mmol) were added dropwise at room temperature to the 3,6-difluoropicolinoyl fluoride provided above. The mixture was stirred at room temperature for 6 hours, poured into a separatory funnel with water and extracted with ethyl ether. The organic phase was then washed with water and dried over MgSO4. The solvent was removed with a rotary evaporator. The concentrated crude product was purified using column chromatography (silica gel) with ethyl acetate/hexanes mixture (1/10) as eluent to give 0.39 g (48% yield, 99% GC purity, 98% LC purity) of desired product as a pale yellow liquid. GC/MS results were consistent with the chemical formula of isopropyl 3,6-difluoropicolinate: 70 eV EIMS (GC) m/z=160 (41%), 142 (100%), 115 (43%), 114 (66%), 64 (31%), 43 (51%). 1H NMR (400 MHz, CDCl3) δ 7.69 to 7.63 (m, 1H), 7.16 to 7.12 (m), 5.33 (hept, J=6.3 Hz, 1H), 1.41 (d, J=6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 161.41 (d, J=6.3 Hz), 158.80 (d, J=1.2 Hz), 158.26 (d, J=4.3 Hz), 156.41 (d, J=1.2 Hz), 155.62 (d, J=4.4 Hz), 134.05 (t, J=13.5 Hz), 131.06 (dd, J=23.9, 8.3 Hz), 114.86 (dd, J=41.7, 5.9 Hz), 70.34 (s), 21.71 (s). 19F NMR (376 MHz, CDCl3) δ−69.40 (d, J=26.9 Hz), −122.76 (d, J=27.4 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C@H:5]([CH2:7][N:8]2[C:12]([CH3:13])=[C:11](I)[C:10]([CH3:15])=[N:9]2)[CH2:4][O:3]1.C1COCC1.C([Mg]Cl)(C)C.CO[B:29]1[O:33][C:32]([CH3:35])([CH3:34])[C:31]([CH3:37])([CH3:36])[O:30]1>>[CH3:1][C:2]1([CH3:16])[O:6][C@H:5]([CH2:7][N:8]2[C:12]([CH3:13])=[C:11]([B:29]3[O:33][C:32]([CH3:35])([CH3:34])[C:31]([CH3:37])([CH3:36])[O:30]3)[C:10]([CH3:15])=[N:9]2)[CH2:4][O:3]1
Reactant: Cc1nn(C[C@@H]2COC(C)(C)O2)c(C)c1I
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1nn(C[C@@H]2COC(C)(C)O2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reaction time: 0.17 h

Procedure:
To a solution of 1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-4-iodo-3,5-dimethyl-1H-pyrazole (180.0 mg, 0.5354 mmol) in THF (5 mL, 60 mmol) was added 2 M isopropylmagnesium chloride in THF (0.5354 mL, 1.071 mmol) at rt, and the mixture was stirred for 10 min. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.2632 mL, 1.606 mmol) was added, and the mixture stirred at rt for 20 min. The reaction was quenched with sat. NH4Cl, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo to afford the title compound as a clear oil. The material was used in the next step without further purification.
Reaction SMILES: [Na].[C:2]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)#[N:3].[CH3:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][N:20]=1)[C:14]([NH:16][NH2:17])=O>CO>[N:7]1[CH:8]=[CH:9][C:4]([C:2]2[NH:17][N:16]=[C:14]([C:13]3[CH:18]=[CH:19][N:20]=[C:11]([CH3:10])[CH:12]=3)[N:3]=2)=[CH:5][CH:6]=1
Reactant: N#Cc1ccncc1
Reactant: Cc1cc(C(=O)NN)ccn1
Agent: [Na]
Solvent: CO
Product: Cc1cc(-c2n[nH]c(-c3ccncc3)n2)ccn1
Temperature: 260 °C
Reaction time: 0.5 h

Procedure:
Sodium (0.4 grams) is added to 4-cyanopyridine (8.3 grams, 0.08 mole) in methanol, and the solution is allowed to stand 30 minutes at room temperature. A suspension of 2-methylisonicotinic acid hydrazide (0.07 mole) in methanol (160 ml.) is added, and the resulting solution is heated at reflux for 30 minutes. After cooling, the intermediate acylamidrazone is collected by filtration. The acyclic intermediate is then heated at 260°C. for 15 minutes, after which the reaction is cooled to room temperature. Upon recrystallization from acetonitrile-water, 5-(4-pyridyl)-3-(2-methyl-4-pyridyl)-1,2,4-triazole is obtained, m.p. 245°-248°C.
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[OH:11]N1C(=O)C2=CC=CC=C2C1=O>C(#N)C1C=CC=CC=1>[C:4]1(=[O:11])[O:3][C:1](=[O:2])[C:10]2=[CH:9][CH:8]=[CH:7][CH:6]=[C:5]12
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C1OCc2ccccc21
Solvent: N#Cc1ccccc1
Product: O=C1OC(=O)c2ccccc21
Temperature: 100 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
A mixture of 2 mmole of phthalide, 2 mole % of N-hydroxyphthalimide relative to phthalide, and 5 ml of benzonitrile was stirred for 12 hours at 100° C. under an oxygen atmosphere. The products in the reaction mixture were analyzed by gas chromarography, and, as a result, phthalic anhydride (yield 46%) was formed.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]2[C:11]([O:33][CH3:34])=[N:12][N:13]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:43])=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([Cl:43])=[O:10])[C:5]2[C:11]([O:33][CH3:34])=[N:12][N:13]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:4]=2[CH:3]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)O)c12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)Cl)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carboxylic acid (Intermediate 36B, 440 mg, 0.936 mmol) was taken up in DCM (9.32 ml). DMF (93 n1) was added and the reaction was cooled to 0° C. Oxalyl chloride (164 μl, 1.873 mmol) was added and the mixture was allowed to stir for 1 hr eventually reaching room temperature. The mixture was concentrated in vacuo and then further dried under high vacuum. The residue was carried forward without further purification. MS: [M+H]+ m/z 484 (Methyl ester formed LCMS, sample prepared in MeOH).
Reaction SMILES: [C:1]12(CS(O)(=O)=O)C(C)(C)C([CH2:6][CH2:7]1)[CH2:4][C:2]2=O.[CH:16](OC)([O:19][CH3:20])[O:17][CH3:18].C(N(CC)CC)C>CO>[CH3:18][O:17][CH:16]([O:19][CH3:20])[CH2:6][CH2:7][CH2:1][CH:2]=[CH2:4]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: COC(OC)OC
Solvent: CO
Solvent: CCN(CC)CC
Product: C=CCCCC(OC)OC
Reaction time: 8 h
Yield: 1386.9 %

Procedure:
The crude product containing compound 5 was taken up in 30 mL of MeOH, and camphorsulfonic acid (596 mg, 2.5 mmol) and trimethyl orthoformate (5.46 mL, 50 mmol) were added. The mixture was heated at reflux for 3 h, then allowed to stand at room temperature overnight. The acid was neutralized by the addition of 0.70 mL of triethylamine, and most of the solvent was removed by distillation. The residue was partitioned between water and hexane, the hexane layer was dried over anhydrous Na2SO4, and the solution was filtered through a 3 in column of silica gel, eluting with additional hexane. The solvent was removed by distillation to leave 5.0 g of the product, compound 6, as a colorless liquid. 1H NMR (CDCl3) δ 1.39-1.49 (m, 2), 1.58-1.65 (m, 2), 2.03-2.11 (m, 2), 3.31 (s, 6, CH(OCH3)2), 4.37 (t, 1, J=5.7CH(OCH3)2), 4.93-5.05 (m, 2, CH═CH2), 5.80 (dddd, 1, J=6.6, 6.6, 10.3, 16.9, CH═CH2); 13C NMR (CDCl3) δ 23.79, 31.83, 33.42, 52.49, 104.33, 114.64, 138.38.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CBr
Reactant: COC(=O)c1c(O)cccc1O
Product: COC(=O)COc1cccc(O)c1C(=O)OC

Procedure:
The subtitle compound was prepared from the product of step (i) (10 g) and methyl bromacetate (5.5 ml) by the method of example 11 step (i). Purified by chromatography eluting with 20% ethyl acetate in isohexane. Yield 3.68 g.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][O:11]2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[C:18]([OH:21])(=[S:20])[CH3:19]>C1(C)C=CC=CC=1>[C:18]([S:20][CH2:3][CH2:2][CH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[O:11][CH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][O:15]2)=[CH:8][CH:9]=1)(=[O:21])[CH3:19]
Reactant: C=CCc1ccc(C2OCC(C)(C)CO2)cc1
Reactant: CC(O)=S
Solvent: Cc1ccccc1
Product: CC(=O)SCCCc1ccc(C2OCC(C)(C)CO2)cc1
Temperature: 90 °C
Yield: 63.8 %

Procedure:
Following a general procedure (Lub et al. (1997) Liebigs Ann. Recueil, 2281–2288), 13 (845 mg, 3.60 mmol) and thioacetic acid (910 μL, 12.7 mmol) were dissolved in toluene (20 mL) and the solution was purged with argon for 15 min. Then AIBN (200 mg) was added and the mixture was heated to 90° C. Over a period of 23 h more AIBN (1.10 g) was added in several portions. Then aq NaHCO3 (10%, 50 mL) was added and the phases were separated. The aqueous phase was washed with ether and the combined organic phases were dried (Na2SO4). Purification by column chromatography (silica, ether/hexanes, 1:4) gave an orange oil, which solidified upon standing at −20° C. and was recrystallized from pentane to give 708 mg (63%) of colorless needles. mp 44° C. IR (neat): {tilde over (v)} 2951, 2850, 1692, 1620, 1518; 1H NMR δ 0.79 (s, 3H), 1.29 (s, 3H), 1.78–1.94 (m, 2H), 2.33 (s, 3H), 2.68 (t, 3J=7.3 Hz, 2H), 2.86 (t, 3J=7.3 Hz, 2H), 3.64 (d, 2J=1.0 Hz, 2H), 3.76 (d, 2J=11.0 Hz, 2H), 5.37 (s, 1H), 7.18, 7.42 (AA′BB′, 2×2H); 13C NMR (APT) δ 21.6 (−), 22.8 (−), 28.1 (+), 29.9 (+), 30.4 (−), 30.8 (+), 34.3 (+), 77.3 (+), 101.4 (−), 126.0 (−), 128.1 (−), 136.1 (+), 141.5 (+), 195.3 (+); GC-MS (EI) obsd 308, 307, 265, 232, 221, 204, 199, 180, 146, 133, 115, 91, 69, 43; Anal. Calcd for C17H24O3S: C, 66.20; H, 7.84; S, 10.40; Found: C, 66.19; H, 7.89; S, 10.54.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[S:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:27](O)(=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:3][C:2]1[CH2:4][S:5][C:6](=[O:7])[C:1]=1[C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)O
Reactant: O=C1CSC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)C1=C(O)CSC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a stirring solution of 695 mg (6.04 mmol) of thiotetronic acid in 10 mL of dimethylformamide is added 902 μL (6.47 mmol) of triethylamine and 240 mg (1.97 mmol) of 4-dimethylaminopyridine at 0° C. Next, 1.37 g (7.13 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 2.0 g (7.19 mmol) of γ-linolenic acid are added and the reaction mixture is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted three times with diethyl ether. The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was subjected to HPLC chromatography (2 inch Dynamax silica gel column, 25 mL/min) eluting with 100% ethyl acetate to give 1.8 g (79%) of 4-hydroxy-3-[(Z,Z,Z)-1-oxo-6,9,12-octadecatrienyl]-2(5H)-thiophenone as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:29]3[CH2:30][CH2:31][N:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:27][CH2:28]3)=[N:10][C:4]=2[CH:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)N=C(N1CCN(c3ccccc3)CC1)c1cccc3c1N2CC3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
A stirred mixture of 7.88 g (0.0250 mole) of 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine-6-one and 1200 ml of toluene was heated under nitrogen until a solution resulted. Then there was added 40.6 g (0.250 mole) of N-phenylpiperazine, followed by 14.2 g (0.075 mole) of titanium tetrachloride. The mixture was heated under reflux for three hours, cooled to room temperature and treated with 500 ml of 2N sodium hydroxide solution. After stirring vigorously for 15 minutes, the layers were separated. The aqueous phase was extracted with 300 ml of toluene. The toluene layers were combined, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, and concentrated to an oil. The oil was taken up in 80 ml of hot methanol, from which the product crystallized, affording 7.8 g (68%) of product. Recrystallization from a hot solution of dichloromethane (25 ml), to which methanol (25 ml) was added, provided the analytical sample, mp 171°-173° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:8]1([NH2:11])[CH2:10][CH2:9]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH:8]1([NH:11][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:10][CH2:9]1
Reactant: CCOC(=O)CBr
Reactant: NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
Ethyl bromoacetate (1 eq.) was added slowly to an ice-cold mixture of cyclopropylamine (17.5 mmol, 3 eq.) and K2CO3 (2 eq.) in DMF (25 ml) and the reaction mixture was then stirred at room temperature for 16 h. For working up, the mixture was diluted with water and extracted with 20% ethyl acetate/hexane solution. The organic phase was washed with water and sat. NaCl solution and dried over Na2SO4. After the solvent had been removed completely, the crude product was employed in the next stage without further purification. Yield: 52%
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([F:20])=[C:7]2[O:11][C:10]([CH:12]3[CH2:14][CH2:13]3)=[N:9][C:8]2=[C:15]([C:18]#[N:19])[C:16]=1[CH3:17])=O.C(=O)([O-])[O-].[Cs+].[Cs+].[C:27]([NH2:30])(=[S:29])[CH3:28]>C1(C)C=CC=CC=1>[CH:12]1([C:10]2[O:11][C:7]3[C:8](=[C:15]([C:18]#[N:19])[C:16]([CH3:17])=[C:5]([C:3]4[N:30]=[C:27]([CH3:28])[S:29][CH:2]=4)[C:6]=3[F:20])[N:9]=2)[CH2:14][CH2:13]1
Reactant: CC(N)=S
Reactant: Cc1c(C(=O)CBr)c(F)c2oc(C3CC3)nc2c1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Cc1nc(-c2c(C)c(C#N)c3nc(C4CC4)oc3c2F)cs1
Temperature: 100 °C
Reaction time: 6 h
Yield: 44.2 %

Procedure:
6-(2-Bromoacetyl)-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-79) (39.98 g, 28.6 mmol) was dissolved in toluene (270 ml), then cesium carbonate (13.02 g, 39.90 mmol) and thioacetamide (2.58 g, 34.28 mmol) were added, followed by stirring at 100° C. for 6 hours under nitrogen atmosphere. The reaction liquid was cooled, the insoluble matter was separated by filtration through Celite, ethyl acetate was added to the filtrate, followed by washing with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was recrystallized and purified with n-hexane/ethyl acetate to obtain the entitled compound (3.96 g, 44%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[O:19][CH2:20][CH3:21])[C:9](=[O:22])[C:8]=2[CH:7]=[C:6]([C:23]([O:25]CC)=[O:24])[CH:5]=1)[CH3:2].[OH-].[K+]>O.O1CCOCC1>[CH2:1]([O:3][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[O:19][CH2:20][CH3:21])[C:9](=[O:22])[C:8]=2[CH:7]=[C:6]([C:23]([OH:25])=[O:24])[CH:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(OCC)c2c(c1)C(=O)c1cccc(OCC)c1C2=O
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cccc2c1C(=O)c1c(OCC)cc(C(=O)O)cc1C2=O
Reaction time: 0.25 h

Procedure:
4,5-Diethoxy-9,10-dihydro-9,10-dioxoanthracene-2-carboxylic acid, ethyl ester (2.67 g) and crushed potassium hydroxide (1.22 g) were dissolved by magnetically stirring in water (13 ml) and dioxan (26 ml). Within 15 minutes a mustard coloured solid began to separate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])=[C:7]1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[Mn]([O-])(=O)(=O)=[O:33].[K+]>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S:15]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)(=[O:33])=[O:16])=[C:7]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1c(S(=O)N2CCOCC2)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1c(S(=O)(=O)N2CCOCC2)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 18 h
Yield: 82.1 %

Procedure:
To a suspension of ethyl N-(3,4-dichlorobenzyl)-3-morpholinosulphinylindole-2-carboxylate (803 mg) in acetone (40 ml) was added a solution of potassium permanganate (528 mg) in water (15 ml). The resulting mixture was stirred for 18 hours. The mixture was poured into water (20 ml) and extracted with diethyl ether, dried (MgSO4) and concentrated to a gum which was purified by column chromatography using iso-hexane:ethyl acetate (3:1) as eluent to give the desired product (681 mg, 82%); NMR d (CDCl3) 1.3 (t, 3H), 3.2-3.2 (m, 4H), 3.7-3.8 (m, 4H), 5.4 (s, 2H), 6.95 (d, 1H), 7.3-7.4 (m, 5H), 8.05 (d, 1H); M/z (+) 499.2 (MH+), 497.3.
Reaction SMILES: S(=O)(O)[O-].[Na+].[C:6]([NH:16][C@H:17]([CH:22]=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[C-:24]#[N:25].[K+]>O.C(OCC)(=O)C>[C:6]([NH:16][CH:17]([CH2:18][CH:19]([CH3:20])[CH3:21])[CH:22]([OH:23])[C:24]#[N:25])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: CC(C)C[C@@H](C=O)NC(=O)OCc1ccccc1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CC(NC(=O)OCc1ccccc1)C(O)C#N
Yield: 81.6 %

Procedure:
A solution of 3.43 g of sodium bisulfite in 20 ml of water was added to 2.81 g of N-carbobenzoxy-L-leucinal, and the mixture was stirred under ice-cooling for 14 hours. To the reaction mixture were added a solution of 1.41 g of potassium cyanide in 50 ml of water and 200 ml of ethyl acetate, and the mixture was stirred at room temperature for 4 hours. The ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 2.54 g of 3-carbobenzoxyamino-2-hydroxy-5-methylhexanenitrile as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:21]([O:23]CC)=[O:22])[C:6](=[O:20])[N:7]2[C:12]=1[CH:11]=[C:10]([N:13]1[CH2:18][CH2:17][NH:16][CH:15]([CH3:19])[CH2:14]1)[CH:9]=[CH:8]2)[CH3:2].[OH-].[Na+].[ClH:28]>C1COCC1>[ClH:28].[CH2:1]([C:3]1[CH:4]=[C:5]([C:21]([OH:23])=[O:22])[C:6](=[O:20])[N:7]2[C:12]=1[CH:11]=[C:10]([N:13]1[CH2:18][CH2:17][NH:16][CH:15]([CH3:19])[CH2:14]1)[CH:9]=[CH:8]2)[CH3:2]
Reactant: CCOC(=O)c1cc(CC)c2cc(N3CCNC(C)C3)ccn2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1cc(C(=O)O)c(=O)n2ccc(N3CCNC(C)C3)cc12
Temperature: 65 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a suspension of 0.686 g (2 mmol) of ethyl 1-ethyl-8-(3-methyl-1-piperazinyl)-4H-quinolizin-4-one-3-carboxylate, from Step 1, in 8 mL of THF was added 8.0 mL of a 1.0N aqueous sodium hydroxide solution and the reaction mixture was heated, with stirring, at 65° C. for 3 hours. The THF was removed from the reaction mixture by distillation during the reaction. The concentrated reaction mixture was cooled to ambient temperature and adjusted to pH 1-2 with 16 mL of 1N aqueous hydrochloric acid solution. The aqueous solution was concentrated in vacuo to remove the water and the residue was suspended in 10 mL of water. The solid was collected by filtration and dried in vacuo to afford the 385 mg (55% yield) of the title compound, m.p.>295° C.; MS DCI-NH3 : 316 (M-Cl)+ ; IR (KBr): 3420 (OH), 1720 (C=O) cm-1 ; 1H NMR (TFA) d 1.50 (t, 3H, J=7.5 Hz), 1.70 (d, 3H, J=6 Hz), 3.00 (q, 2H, J=7.5 Hz), 3.70-4.10 (m, 6H), 4.55 (m, 1H), 4.60 (m, 1H), 7.40 (d, 1H, J=3.0 Hz), 7.68 (dd, 1H, J=3.0 Hz, 8.4 Hz), 8.18 (s, 1H), 9.19 (d, 1H, J=8.4 Hz). Analysis calculated for C17H22ClN3O3 +H2O: C, 55.21; H, 6.54; N, 11.36. Found: C, 55.19; H, 6.07; N, 11.34.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9][C:10]2[C:20]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][C:11]=2[Cl:28])=[N:6][CH:7]=1.[NH:29]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[ClH:28].[N:29]1([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][S:9][C:10]3[C:20]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15][C:14]=4[CH:13]=[CH:12][C:11]=3[Cl:28])=[N:6][CH:7]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Br)cn3)c2CC1
Reactant: C1CCCNCC1
Product: Cl
Product: Clc1ccc2c(c1SCc1ccc(N3CCCCCC3)cn1)CCNCC2

Procedure:
Use a method similar to the Example 369, using 6-(5-bromopyridin-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H benzo[d]azepine and homopiperidine to give the title compound as a yellow solid. MS (ES+) m/z 402 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[N:11][CH:10]=1.OO.CC[O:32]CC.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:18][CH2:19]2)=[O:16])=[N:11][CH:10]=1)=[O:32]
Reactant: CCOCC
Reactant: COc1ccc(C2(C(=O)Nc3ncc(Sc4ccccc4Cl)s3)CC2)cc1
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C2(C(=O)Nc3ncc(S(=O)c4ccccc4Cl)s3)CC2)cc1
Temperature: 85 °C
Yield: 36.6 %

Procedure:
1-(4-Methoxy-phenyl)-cyclopropanecarboxylic acid [5-(2-chloro-phenylsulfanyl)-thiazol-2-yl]-amide (50.0 mg, 0.120 mmol) was dissolved in 3 mL of acetic acid containing hydrogen peroxide (30% aqueous solution, 40.8 mg, 0.360 mmol). The mixture was warmed to 85° C. for 1 hour. Ether (1.5 mL) and water (1.5 mL) was added and the layers were separated. the organic layer was dried over sodium sulfate, filtered, and evaporated to dryness. The crude reaction mixture was then separated by reverse-phase preparative liquid chromatography to yield the pure product (19.7 mg, 0.0439 mmol, 36.6%). ESI-MS m/z calc. 448.0. found; 449.1 (M+1)+ Retention time 3.53 minutes. 1H NMR (400 MHz, CD3CN) δ 1.23-1.35 (m, 2H), 1.61-1.68 (m, 2H), 3.80 (s, 3H), 6.90-7.00 (m, 2H), 7.34-7.41 (m, 2H), 7.54-7.68 (m, 3H), 8.03-8.10 (m, 1H), 8.22-8.30 (m, 1H), 9.32 (s, 1H).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])=N1)[CH2:2][CH2:3][CH3:4].[CH2:19](N(CC)CC)C.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:1]([N:5]1[CH:19]=[C:7]2[N:8]([C:27](=[O:29])[O:18][C:13]3[C:12]2=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][C:10]1=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Reactant: CCCCN1N=C(c2ccccc2O)NCC1=O
Solvent: ClCCl
Product: CCCCN1C=C2c3ccccc3OC(=O)N2CC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38.9 %

Procedure:
To a solution of Compound 83 (0.21 g, 0.85 mmol) dissolved in 5 mL dichloromethane, was added triethylamine (0.13 mL, 0.94 mmol). The solution was cooled to 0° C. in an ice bath, and triphosgene (0.28 g, 0.94 mmol) was added. After 15 min, the cooling bath was removed. After the reaction stirred for 45 minutes at room temperature, the reaction was complete by TLC. The reaction was quenched with saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash column chromatography (15-20% ethyl acetate/hexanes), afforded 90 mg (39% yield) of Compound 25 as a yellow oil.