Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1)[C:8](=[O:21])[C:7]2([C:24]1[C:32](O)=[CH:31][C:27]2[O:28][CH2:29][O:30][C:26]=2[CH:25]=1)[CH2:22][OH:23].C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1)[C:8](=[O:21])[C:7]12[C:24]2=[CH:25][C:26]3[O:30][CH2:29][O:28][C:27]=3[CH:31]=[C:32]2[O:23][CH2:22]1
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2c(F)cccc2C1(CO)c1cc2c(cc1O)OCO2
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2c(F)cccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 1, and making non-critical variations using 7-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (32%) as a white solid: mp 116-118° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.36-6.88 (m, 4H), 6.67 (s, 1H), 6.62 (d, 1H), 6.19 (s, 1H), 5.90 (d, 2H), 5.07 (q, 2H), 4.75 (dd, 2H); 13C NMR (75 MHz, DMSO-d6) δ176.9, 155.8, 154.1, 149.1, 148.8, 145.6, 142.4, 140.9, 140.3, 139.2, 139.2, 135.2, 135.2, 128.5, 128.4, 124.9, 128.4, 124.9, 124.8, 124.7, 121.2, 120.4, 120.4, 119.8, 117.6, 117.2, 117.0, 114.5, 114.5, 109.5, 103.2, 102.0, 93.8, 80.1, 58.3, 58.2, 39.0, 38.9; MS (ES+) m/z 448.3 (M+1).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH2:11][C@H:10]1[OH:24].[CH:26](Cl)(Cl)Cl.C(O)(=O)C.O>CO>[CH3:26][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH2:11][C@H:10]1[OH:24]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Reactant: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O

Procedure:
A mixture of heneicosa-8c, 11c,14c-trienoic acid (24 mg), glutathione (120 mg), hydroquinone (12 mg) and protein (600 mg) from the particulate enzyme fraction of the vesicular glands of sheep (obtained as described by Struyk et al., loc.cit.) suspended in aqueous 0.2 M tris(hydroxymethyl)aminomethane hydrochloride buffer solution, pH 8.0, to a total volume of 300 ml, was incubated aerobically by stirring the mixture in a large beaker open to the air at 30° for 20 minutes. The enzymic reaction was then terminated by acidification with citric acid to pH 4 and the mixture was extracted with two portions of ether (300 ml). The residue from evaporation of the extract was dissolved in chloroform and the solution chromatographed on a column of silica gel (25 g) using as successive eluants chloroform (150 ml), chloroform containing 3% methanol (150 ml), and chloroform containing 5% methanol (150 ml), and 10 ml fractions of eluate were collected. Small samples of the fractions (0.1 ml) were tested for the presence of a prostaglandin by treatment with 0.5 ml 3N potassium hydroxide in 75% aqueous methanol and examination for an ultraviolet absorption peak at 278 nm. The last fractions of the 3% methanol eluant and the first fractions of the 5% methanol eluant were found to contain the substance required: they were evaporated to give 12 mg of product. This was then purified further by RPPC using as support a diatomaceous earth (2.5 g) that had been made water-repellent by the action of a methylchlorosilane, as stationary phase a mixture (1.8 ml) of equal volumes of iso-octanol and chloroform, and as eluant aqueous methanol containing 9 volumes of methanol to 10 of water, and collecting 2 ml fractions. All those fractions shown to give the alkali reaction referred to above, except the first and the last, were combined and evaporated and the residue recrystallised from a mixture of ether and light petroleum to give 1α-(6-carboxyhexyl)-4α-hydroxy-5β-(3S-hydroxynon-1t-enyl)cyclopentan-2-one (ω-homo-PGE1, 7.2 mg), m.p. 92°-3°, showing an optical rotation in methanol (1 g/liter) at 20° of -69°. Comparison with PGE1 by TLC on silica gel using a mixture of chloroform, methanol, acetic acid and water in the respective proportions by volume 90:8:1:0.75, gave an Rf value for ω-homo-PGE1 of 0.34 as compared with 0.32 for PGE1, the two substances being just separated.
Reaction SMILES: CC(CCC=C(C)C)CCC(C)C(=O)C([O-])=O.CC(CCC=C(C)C)CCCC(=O)C([O-])=O.C[CH:35]([CH2:51][CH3:52])[C:36](=[O:50])[C:37]([O:39][CH2:40][CH2:41][CH:42]([CH3:49])[CH2:43][CH2:44][CH:45]=[C:46]([CH3:48])[CH3:47])=[O:38]>>[O:50]=[C:36]([CH2:35][CH2:51][CH3:52])[C:37]([O:39][CH2:40][CH2:41][CH:42]([CH3:49])[CH2:43][CH2:44][CH:45]=[C:46]([CH3:47])[CH3:48])=[O:38]
Reactant: CCC(C)C(=O)C(=O)OCCC(C)CCC=C(C)C
Agent: CC(C)=CCCC(C)CCC(C)C(=O)C(=O)[O-]
Agent: CC(C)=CCCC(C)CCCC(=O)C(=O)[O-]
Product: CCCC(=O)C(=O)OCCC(C)CCC=C(C)C

Procedure:
MS (EI): 254 (M+, 1); 236 (2); 226 (1); 193 (1); 183 (6); 165 (1); 155 (7); 138 (15); 137 (10); 123 (26); 118 (3); 109 (17); 95 (41); 83 (15); 82 (32); 81 (54); 71 (87); 69 (100); 67 (23); 55 (34); 43 (66); 41 (72); 27 (14).
Reaction SMILES: [O:1]([C:8]1[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[O:1]([C:8]1[S:9][C:10]([CH:13]=[O:14])=[CH:11][N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cnc(Oc2ccccc2)s1
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: O=Cc1cnc(Oc2ccccc2)s1
Temperature: 40 °C
Reaction time: 5 h
Yield: 77.8 %

Procedure:
40 g of manganese dioxide were added to a solution of 10 g of (2-phenoxy-5-thiazolyl)-methanol in 250 ml of benzene and the mixture was stirred at 40° C. for 5 hours and was filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel.Elution with a 7-3 methylene chloride-ethyl acetate mixture yielded 7.7 g of (2-phenoxy-5-thiazolyl)-methanal melting at 50° C.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:39])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:38])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:38][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:39])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:36])([F:35])[F:37])(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)c3ccccc3C(F)(F)F)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)c2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
Lithium hydroxide monohydrate (0.013 g, 0.29 mmol) was added to a stirred solution of {6-chloro-3-methyl-4-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.039 g, 0.073 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes gave {6-chloro-3-methyl-4-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid (0.035 g, 92%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.49 (br. s, 1 H) 8.58 (d, J=6.85 Hz, 1 H) 7.93-8.13 (m, 6 H) 7.91 (s, 1 H) 7.53 (d, J=8.80 Hz, 2 H) 7.48 (d, J=8.80 Hz, 1 H) 6.93 (s, 1 H) 3.85 (s, 2 H) 2.03 (s, 3 H) MS calcd. for C26H17ClF3O4S [(M−H)−] 517, obsd. 517.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>>[OH:26][CH2:25][CH2:27][NH:28][C:21]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:24])=[N:19][C:18]=1[CH3:20])=[O:23]
Reactant: NCCO
Reactant: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Product: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NCCO
Yield: 79 %

Procedure:
As described for example 31b, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.20 mmol) was converted, using ethanolamine instead of 4-aminotetrahydropyran, to the title compound (62 mg, 79%) which was obtained as an off white solid. MS: m/e=391.2 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:13])[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([O:26][C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C(=O)N=C=O)(c1ccccc1)c1ccccc1
Reactant: OC1CCCCC1
Product: CC(C(=O)NC(=O)OC1CCCCC1)(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p.=126° C. and MS: m/e=351.4 (M+H+) was prepared in accordance with the general method of example 1 from 2,2-diphenylpropionyl isocyanate and cyclohexanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][C@@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH:6]=1)=[O:4]>CO.ClCCl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9]1)=[O:4]
Reactant: COC(=O)C1=CC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)C1
Reaction time: 62 h

Procedure:
((1,2-Bis(2R,5R)-2,5-dimethylphospholano)ethane)(cyclooctadiene)rhodium(I) trifluoromethanesulfonate (179 mg, 0.1 mol %) was added to a degassed solution of (4S)-4-tert-butoxycarbonylaminocyclopent-1-enecarboxylic acid methyl ester (70 g, 0.29 mol) in methanol (350 ml). The reaction mixture was transferred to a bomb and after purging with nitrogen and then hydrogen, a hydrogen pressure of 5 bar was applied and the reaction stirred for 62 h. The pressure was released and the bomb purged with nitrogen. Concentration of the reaction mixture gave a residue which was redissolved in dichloromethane (300 ml). Addition of silica (20 g) with stirring removed the catalyst from the reaction and filtration and concentration of the organic solution gave crude product as a yellow oil that solidified on standing (92% d.e.; measured by gc analysis). Crystallisation from tert-butylmethylether and heptane gave the title compound as colourless needles of 97% d.e. (63 g, 89%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]([C:7]([O-:9])=O)[C:2]=1[C:10]([O:12]C)=O.[NH:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17]>CCO>[OH:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][OH:20])[C:7]([C:3]1[C:2]([C:10]([N:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17])=[O:12])=[N:1][CH:6]=[CH:5][N:4]=1)=[O:9]
Reactant: OCCNCCO
Reactant: COC(=O)c1nccnc1C(=O)[O-]
Solvent: CCO
Product: O=C(c1nccnc1C(=O)N(CCO)CCO)N(CCO)CCO
Yield: 71.6 %

Procedure:
Methyl pyrazine-2,3-dicarboxylate (2 g, 10.2 mmol) was dissolved in EtOH (5 mL). Diethanolamine (2.14 g, 20.4 mmol) was added and the mixture was heated under reflux for 5 h. After cooling the solvent was evaporated and the residue was purified by silica gel chromatography (CHCl3 /MeOH, 8:2) to afford the title compound (2.5 g, 71.4%).
Reaction SMILES: N1([C:7]2[C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH:12]=2)CCOCC1.[CH:14]([C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:18]=1[NH2:19])([CH3:16])[CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:17]([CH:14]([CH3:16])[CH3:15])[C:18]=1[NH:19][C:7]1[C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH:12]=1)([CH3:26])[CH3:25]
Reactant: O=C1CCCC=C1N1CCOCC1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC1=CCCCC1=O
Temperature: 80 °C
Yield: 96.2 %

Procedure:
A 250-mL three-necked round-bottomed flask equipped with a condenser, gas inlet and septas is placed under N2 atmosphere. The flask is charged with 2-(morpholin-4-yl)-2-cyclohexen-1-one (7.0046 g, 38.65 mmol; Preparation 2), toluene (74.0 mL) and 2,6-diisopropylaniline (6.8521 g, 38.65 mmol). To the yellow solution is added p-toluenesulfonic acid monohydrate (7.3520 g, 38.65 mmol; p-TsOH.H2O). The reaction mixture became very thick with a lot of precipitate. The mixture is heated to 80° C. (oil bath temperature) and allowed to stir. Another 5.0 mL of toluene are added to facilitate stirring. The mixture is stirred for 2 hours. Reaction mixture is allowed to reach room temperature. The mixture is filtered. The filtrate is concentrated under high vacuum to afford 10.09 g of a yellow solid. The solid is dissolved in hot hexanes (about 30 mL) and filtered. The solution is allowed to cool to room temperature, seeded and place on the freezer. The solution is filtered while most of the solid is left behind on the flask. The flask is placed on an ice bath. The solid is rinsed with two about 6 mL portions of cold hexanes. The yellow solid is allowed to dry, transfer to a vial and left to dry overnight under vacuum (first crop: 4.0550 g). Mother liquor is concentrated and recrystallization is repeated two more times. The second crop is left in the freezer for 5 hours (second crop: 1.0785 g) and third crop is left overnight (third crop: 0.6919 g). The combined yield of title compound of Preparation 3 is 5.8254 g (55.54%).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:76][CH2:75][N:74]([C:77](=[O:80])[CH2:78][OH:79])[CH2:73][CH2:72]5)=[N:69][CH:70]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:72][CH2:73][N:74]([C:77](=[O:80])[CH2:78][OH:79])[CH2:75][CH2:76]5)=[N:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)CO)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(CO)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Yield: 13 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 1-(4-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-1-yl)-2-hydroxy ethanone (70 mg, 0.105 mmol) was hydrolyzed with lithium hydroxide (9 mg, 0.210 mmol) in THF/methanol/water (5/1/1 mL) to yield 7 mg (10.7% yield) of the titled compound. 1H NMR CD3OD, 400 MHz): δ 8.497-8.493 (d, 1H), 8.44-8.43 (d, 1H), 8.39-8.38 (d, 1H), 8.32-8.29 (dd, 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.71 (s, 1H), 7.42-7.31 (m, 2H), 7.13-7.12 (d, 1H), 7.07-7.01 (m, 2H), 5.45 (s, 2H), 4.33 (s, 2H), 3.84-3.70 (m, 8H). MS: m/z=512.55 (M+1), HPLC: 96.01% in method A.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([OH:8])=[C:4]2[S:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:3]=12.[C:16]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[S:9][C:4]=2[C:5](=[O:8])[N:6]([CH3:16])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc2c(Br)cnc(O)c2s1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc2c(Br)cn(C)c(=O)c2s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.4 %

Procedure:
To a solution of methyl 4-bromo-7-hydroxythieno[2,3-c]pyridine-2-carboxylate (300 mg, 1.04 mmol) stirred at 0° C. in DMF (6.6 mL) under an atmosphere of nitrogen was added K2CO3 (358 mg, 2.6 mmol). After stirring at 0° C. for 15 min, methyl iodide (177 mg, 1.3 mmol) was added dropwise. The ice bath was removed, and mixture was stirred at rt for 20 min, 50° C. for 2 h, and rt for 10 h. The reaction mixture was treated with water (8 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of EtOAc (10 to 100%) in DCM to afford the title compound (284 mg, 90%) as a white solid. LCMS (M+H)+=303.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][N:7]=1)=[O:5])[CH3:2].[Cl-].[Li+].N1C=CC=CC=1.C1(C)C=CC(S([Cl:34])(=O)=O)=CC=1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:15]=1[Cl:34])=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1n[nH]c2c(c1=O)CCCC2
Agent: [Cl-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1nnc2c(c1Cl)CCCC2
Yield: 60.6 %

Procedure:
To a slurry of 4-oxo-1,4,5,6,7,8-hexahydrocinnoline-3-carboxylic acid ethyl ester (1 g), lithium chloride (0.19 g) and pyridine (0.36 ml) in dichloromethane (30 ml) was added p-toluenesulphonyl chloride (0.85 g). The reaction mixture was heated at reflux for 20 h. The solid was collected by filtration, and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography using a gradient elution: CH2Cl2 (500 ml), CH2Cl2/MeOH 99:1 (500 ml), CH2Cl2/MeOH 98:2 (1 liter). The appropriate fractions were combined and evaporated under reduced pressure to give a solid (0.65 g, 61%). δH (360 MHz; CDCl3) 1.44 (3H, t, J=7 Hz, CH3), 1.89 (4H, m, CH2), 2.85 (2H, t, J=5.7 Hz, CH2), 2.62 (2H, t, J=5.7 Hz, CH2), 4.51 (2H, t, J=7 Hz, CH2), m/z (ESP+) 241/243 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[O:20][CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[S:42][C:36]3[C:37](=[O:41])[O:38][CH2:39][CH2:40][C:35]=3[CH:34]=2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:37]([C:36]3[S:42][C:33]([C:30]4[CH:29]=[CH:28][C:27]([Cl:26])=[CH:32][CH:31]=4)=[CH:34][C:35]=3[CH2:40][CH2:39][OH:38])=[O:41])=[CH:15][C:14]=2[O:20][CH3:21])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1OCCc2cc(-c3ccc(Cl)cc3)sc21
Reactant: COc1cc(N)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)cc2CCO)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
Dissolve 3-(4-amino-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (2.27 mmol, 667 mg) in toluene (35 mL) and add 2M trimethylaluminum in toluene (2.27 mmol 1.13 mL). Add to this solution 2-(4-chloro-phenyl)-4,5-dihydro-thieno[2,3-c]pyran-7-one (1.51 mmol 400 mg) and heat the reaction at 80° C. for 5 h. Cool the reaction to room temperature and slowly quench with 10 mL of saturated Rochelle's salt. Stir the mixture for 10 min and dilute with 40 mL of water. Separate the organic portion and extract the aqueous portion with EtOAc (2×25 mL). Dry the combined organics over Na2SO4, filter, and concentrate to dryness. Purify by chromatography (hexane to 70% ethyl acetate/hexane) to afford 840 mg (99%) of the title compound. MS/ES m/z (35Cl) 557.0 [M−H]−.
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.[O:26]=[S:27]1(=[O:35])[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[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:32]([CH:29]5[CH2:30][CH2:31][S:27](=[O:35])(=[O:26])[CH2:28]5)=[O:33])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)C1CCS(=O)(=O)C1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C1CCS(=O)(=O)C1

Procedure:
The title compound, white solid (21.1 mg, 54.1%), MS (ISP) m/z=477.2 [(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 1,1-Dioxo-tetrahydro-thiophene-3-carboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][CH:13]=[CH:14][N:15]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]2[O:12][CH:13]=[CH:14][N:15]=2)[CH2:19][CH2:18]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(-c2ncco2)c1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2-c2ncco2)CC1
Yield: 70 %

Procedure:
2-(2-Chloro-5-nitrophenyl)-oxazole (0.366 g, 1.63 mmol) was heated in N-methylpiperazine (15 mL) at reflux for 5 hrs. The mixture was allowed to cool and excess N-methylpiperazine was distilled under high vacuum. The residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with water then brine, dried over sodium sulfate, filtered and concentrated. Drying under high vacuum gave 1-methyl-4-(4-nitro-2-oxazol-2-yl-phenyl)-piperazine (0.328 g, 70%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:11][OH:12])[C:9]#[N:10])=[CH:4][C:3]=1[CH2:13][NH:14][C:15]([O:17][CH3:18])=[O:16].[CH3:19]I>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:11][O:12][CH3:19])[C:9]#[N:10])=[CH:4][C:3]=1[CH2:13][NH:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: CI
Reactant: COC(=O)NCc1cc(C(C#N)=NO)ccc1Cl
Solvent: CO
Product: CON=C(C#N)c1ccc(Cl)c(CNC(=O)OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.5 %

Procedure:
0.36 g of 2-[4-chloro-3-(methoxycarbonylaminomethyl)phenyl]-2-hydroxyiminoacetonitrile and 0.54 g of a 28% sodium methylate methanol solution were added to 5 ml of methanol, and 0.49 g of methyl iodide was added thereto, followed by stirring at room temperature for 24 hours. The reaction solution was vacuum concentrated, the solvent was distilled off, water was added to the residue, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Wakogel C-200, eluent: hexane/ethyl acetate=4/1-5/1) to obtain 0.18 g of 2-[4-chloro-3-(methoxycarbonylaminomethyl)phenyl]-2-methoxyiminoacetonitrile as colorless crystals (m.p. 104-107° C.)