Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:27][CH3:28]>CN(C)C=O>[CH2:27]([C:9]1[O:10][C:6]2[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:7]=2[C:8]=1[C:11]([OH:13])=[O:12])[CH3:28]
Reactant: O=C(O)c1coc2c1C(=O)CCC2
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1oc2c(c1C(=O)O)C(=O)CCC2
Temperature: 60 °C
Yield: 86.9 %

Procedure:
To a stirred mixture of 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (640 g, 3.55 mol), potassium carbonate (1.7 kg, 10.65 mol) and cesium carbonate (100 g, 0.32 mol) in N,N-dimethylformamide (9.0 L) is added iodoethane (1250 g, 8.01 mol). The mixture is heated at 60° C. for 2 h. After cooling to ambient temperature, the mixture is filtered, the solid is rinsed with ethyl acetate, and the filtrate concentrated in vacuo. Water (2 L) is added then extracted with ethyl acetate (2×2 L); the combined organic extracts are washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give ethyl 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (642 g). A mixture of this ester (640 g, 3.07 mol) and ammonium acetate (426 g, 5.53 mol) in N,N-dimethylformamide (320 mL) is heated to 100° C. for 2 h. The reaction mixture is concentrated in vacuo , ice water (2.5 L) is added, and extracted with dichloromethane (2×3 L); the combined organic extracts are washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give ethyl 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate (357 g). A mixture of this ester (170 g, 0.82 mol) in ethyl alcohol (250 mL) and a solution of sodium hydroxide (165 g, 4.1 mol) in water (1 L) is heated at reflux for 1 h, then cooled in an ice water bath. Concentrated hydrochloric acid (350 mL) is added dropwise, the precipitate collected by filtration, rinsed with ice water (3 ×), and dried in a vacuum oven at 75° C. to afford 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate (125 g). m.p. 269-270° C.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[CH:22][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3].[Cl:31]C1C2C=CC=CC=2C2C(=C3C(=C(C=O)C=2)C=CC=C3)C=1.NC(C)(CO)CO>>[CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[C:22]([Cl:31])[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3]
Reactant: CC(CO)(COS(C)(=O)=O)NCc1cc2c3ccccc3ccc2c2ccccc12
Reactant: O=Cc1cc2c3ccccc3c(Cl)cc2c2ccccc12
Agent: CC(N)(CO)CO
Product: CC(CO)(COS(C)(=O)=O)NCc1cc2c3ccccc3c(Cl)cc2c2ccccc12

Procedure:
Using the reductive amination procedure outlined in 1C, 12-chloro-6-chrysenecarbaldehyde (4A) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-(((12-chloro-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediol methanesulfonate.1/3H2O mp 233°-233.5° (dec), (EtOH/Et2O), (C,H,Cl,N,S).
Reaction SMILES: OC1C2N=NNC=2C=CC=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[O:42]1[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][NH2:50])[CH2:44][CH2:43]1.[CH2:51]1[CH:55]([CH2:56][CH2:57][CH2:58][CH2:59][C:60](O)=[O:61])[S:54][S:53][CH2:52]1>O1CCCC1>[S:53]1[CH2:52][CH2:51][CH:55]([CH2:56][CH2:57][CH2:58][CH2:59][C:60]([NH:50][CH2:49][CH2:48][N:45]2[CH2:46][CH2:47][O:42][CH2:43][CH2:44]2)=[O:61])[S:54]1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)CCCCC1CCSS1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCCC1CCSS1)NCCN1CCOCC1
Reaction time: 20 h
Yield: 88 %

Procedure:
4.5 g of hydroxybenzotriazole, 10.5 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 7.8 g of diisopropylethylamine and 3.9 g of 2-morpholino-1-ethylamine are added at room temperature to a solution of 6.2 g of thioctic acid in 180 ml of tetrahydrofuran. After 20 hours, the reaction mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate, washed and then dried over Na2SO4. Concentration under reduced pressure yields 8.4 g of the expected product.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][CH:6]=[CH2:7])[CH2:3][OH:4].[H-].[Na+].IC.[CH2:13](OCC)C>CN(C)C=O.O>[CH3:1][C:2]([CH3:8])([CH2:3][O:4][CH3:13])[CH2:5][CH:6]=[CH2:7]
Reactant: CCOCC
Reactant: C=CCC(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCC(C)(C)COC
Reaction time: 1 h

Procedure:
2,2-Dimethylpent-4-en-1-ol (4.0 g.) was added dropwise to a suspension of sodium hydride (1.13 g. 80% dispersion in oil, washed with hexane) in dry dimethylformamide (80 ml.) under nitrogen. After stirring for 1 hour, iodomethane (5.3 g.) was added dropwise and the mixture stirred for a further hour. Diethyl ether (100 ml.) was added and was followed by slow addition of water (100 ml.). The ethereal extracts were evaporated in vacuo and the residue was dissolved in hexane (50 ml.). The hexane solution was washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and 4,4-dimethyl-5-methoxypent-1-ene was obtained as a colourless oil (1.9 g.).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.[CH3:36][NH:37][C:38](=[O:50])[C@H:39]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[NH2:40]>C(Cl)Cl.CN(C=O)C>[CH3:36][NH:37][C:38](=[O:50])[C@H:39]([CH2:41][C:42]1[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=1)[NH:40][C:14](=[O:16])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CNC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of BOC-L-Leucine (5.26 g, 0.021M) in CH2Cl2 (40 ml) and DMF (10 ml) stirred at 0° was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (4 g, 0.021M). After 15 min., N-methyl morpholine (0.021M) was added followed by, after a further 10 min. at 0°, a solution of O-methyl-L-tyrosine N-Methylamide (4.3 g, 0.019M) in CH2Cl2. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo, and the residue in CH2Cl2, washed in turn with H2O (200 ml), saturated aq. NaHCO3 (200 ml), dilute HCl (1M; 200 ml), saturated aq. NaHCO3 (200 ml) and water (150 ml), dried (Na2SO4) and evaporated in vacuo to a solid. Recrystallisation from ethyl acetate/hexane gave N-(Tertiarybutoxycarbonyl)-L-leucyl-O-methyl-L-tyrosine N-methylamide as a white crystalline solid, (4.5 g), m.p. 159-161; (Found: C, 62.65; H, 8.33; N, 9.96. C22H35N3O5 requires C, 62.69; H, 8.37; N 9.97%). νmax (CDCl3) 3400, 1700 and 1662 cm-1 ; δ(CDCl3) 0.91 (6H, dd, J=7 and 14 Hz, CH(CH3)2); 1.37 (9H, s, OC(CH3)3); 1.47-1.7 (3H, m, CH2CH(CH3)2); 2.71 (3H, d, J=4.7 Hz, NHCH3), 2.98 and 3.14 (each 1H, each m, CH2C6H4); 3.78 (3H, s, OCH3); 4.0 and 4.61 (each 1H, each m, 2×α-CH); 4.86, (1H, br s, OCONH); 6.40 and 6.55 (each 1H, each br s, CONH×2); 6.82 (2H, d, J=8.4 Hz, Tyr H-3 and H-5); 7.08 (2H, d, J=8.4 Hz, Tyr H-2 and H-6); m/e 422 (70%, [m+1]+), 365 (70%, [m-58]+).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[CH3:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:13]([O:16]CC)(=[O:15])C.Cl>CS(C)=O>[CH3:2][O:4][C:9]1[CH:8]=[CH:7][CH:12]=[CH:11][C:10]=1[C:13]([OH:16])=[O:15]
Reactant: CC(C)(C)[O-]
Reactant: CCCCCC
Reactant: CCOC(C)=O
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccccc1C(=O)O
Temperature: 70 °C
Yield: 80 %

Procedure:
To a stirred solution of V (10 g, 240 mmol) in dimethyl sulfoxide (40 mL) was added potassium tert-butoxide (10 g, 890 mmol) in portions. The solution was heated to 70° C. on a water bath for 2 h, and the progress of the reaction was monitored by TLC using a hexane-ethyl acetate (8:2) solvent system. The reaction mass was cooled to 10° C., poured into ice water, and then acidified with 5% dilute hydrochloric acid. The precipitated solid was filtered and washed thoroughly with distilled water, and the crude mass was recrystallized in hexane (50 mL) to yield an off-white solid of 2-Methoxy-benzoic Acid (7.6 g, 80%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13]([O-:16])(=[O:15])=[O:14])[CH:8]=2)[N+:3]=1[CH2:17][CH2:18][CH2:19][S:20]([O-:23])(=[O:22])=[O:21].[Na+:24].[CH2:25]1COS(=O)(=O)CC1>>[CH3:1][C:2]1[C:10]([CH3:11])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13]([O-:16])(=[O:15])=[O:14])[CH:8]=2)[N+:3]=1[CH2:17][CH2:18][CH:19]([S:20]([O-:23])(=[O:22])=[O:21])[CH3:25].[Na+:24]
Reactant: O=S1(=O)CCCCO1
Reactant: CC1=[N+](CCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)C
Agent: [Na+]
Product: CC1=[N+](CCC(C)S(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)C

Procedure:
Compound 38 is prepared analogously to compound 4 (Example 4), except that 1,4-butanesultone is used as a starting material.
Reaction SMILES: [OH:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]2[CH:16]=[C:17]([OH:22])[CH:18]=[C:19]([OH:21])[CH:20]=2)=[CH:9][CH:8]=1.[H][H]>O1CCOCC1.[Pd]>[OH:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]([OH:22])[CH:16]=2)=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: CC(C)(O)CCCCc1ccc(C=Cc2cc(O)cc(O)c2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(C)(O)CCCCc1ccc(CCc2cc(O)cc(O)c2)cc1

Procedure:
414 mg (1.27 mmol) of 5-{2-[4-(5-hydroxy-5-methylhexyl)phenyl]vinyl}benzene-1,3-diol in 40 ml of dioxane and 42 mg of 10% palladium/carbon are placed in a reactor. A hydrogen pressure of 7 bar is exerted for 4 hours at room temperature. The reaction medium is filtered on celite and the filtrate is evaporated. The product is crystallized from an ethyl acetate/hexane mixture.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O.O1CCOCC1>[ClH:19].[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Oc1ccc(Cl)cc1OC1CNC1
Reaction time: 18 h

Procedure:
To 3-(5-Chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.80 g, 2.7 mmol) in EtOAc (2 mL) was added 4M HCl in dioxane (5 mL). After 18 h, EtOAc was added and the resulting white solid filtered to give 2-(azetidin-3-yloxy)-4-chloro-phenol hydrochloride as a white solid. To a CH2Cl2 (25 mL) solution of this compound was added Et3N (0.30 g, 0.42 mL, 3.0 mmol) and TFAA (0.58 g, 0.38 mL, 2.8 mmol). After 18 h, H2O was added and the reaction extracted with CH2Cl2 (2×). The combined organics were dried and concentrated to give 0.54 g (74% yield 2 steps) of the title compound as a brown oil that was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]([CH2:21][CH2:22][CH:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[OH:24])[C:10]2=[O:32])=[CH:5][CH:4]=1.[C:33](O)(=[O:47])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(N(CC)CC)C>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH:23]([OH:24])[CH2:22][CH2:21][CH:11]2[C:10](=[O:32])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:33]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[O:47])=[CH:4][CH:5]=3)[CH:12]2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CN)cc2)cc1
Reactant: O=C(O)CCCCCCCCCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CNC(=O)CCCCCCCCCCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 70 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)azetidin-2-one (5), and 23 μl of triethylamine in 1 ml of dimethylformamide was added to a solution of 371 mg of dodecanedioic acid, 63 μl of diisopropylcarbodiimide, 55 mg of hydroxybenzotriazole in 2 ml of dimethylformamide, and the mixture was stirred at room temperature for 12 h. The reaction solution was concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20->10/90). This gave the product of molecular weight 646.81 (C38H47F1N2O6); MS (ESI) 647.35 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[F:20].[CH3:21]C1C=CC(S(O)(=O)=O)=CC=1.O>C(OC)(OC)OC>[F:20][C:3]1[C:2]2[N:1]=[CH:21][O:11][C:10]=2[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1c(O)cc(C(=O)O)c(Nc2ccccc2F)c1F
Solvent: COC(OC)OC
Solvent: O
Product: O=C(O)c1cc2ocnc2c(F)c1Nc1ccccc1F
Reaction time: 1 h
Yield: 1842.8 %

Procedure:
To a solution of 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxy benzoic acid (7.58 g, 27.08 mmol) in trimethyl orthoformate (50 mL) was added p-TsOH (233 mg, 1.35 mmol). The reaction mixture was stirred for 1 h and treated with water (300 mL). The precipitate was filtered off and the filter cake was washed with water to afford the desired product (7.22 g, 92% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.28 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 7.14 (m, 1H), 7.11 (m, 1H), 7.04 (m, 1H), 6.85 (m, 1H).
Reaction SMILES: N1CCCC1.[OH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:8]=1[C:18](=O)[CH3:19].[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1>CO>[CH3:14][O:13][C:11]1[CH:12]=[C:7]2[C:8]([CH:18]=[CH:19][C:25]3([O:6]2)[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)=[CH:9][C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: COc1cc(O)c(C(C)=O)cc1[N+](=O)[O-]
Reactant: CN1CCC(=O)CC1
Solvent: CO
Solvent: C1CCNC1
Product: COc1cc2c(cc1[N+](=O)[O-])C=CC1(CCN(C)CC1)O2
Temperature: 50 °C
Yield: 68.3 %

Procedure:
Pyrrolidine (1.15 mL, 13.8 mmol) was added to 1-(2-Hydroxy-4-methoxy-5-nitro-phenyl)-ethanone (2.57 g, 12.2 mmol) (Banks, C. K.; Hamilton, C. S. J. Am. Chem. Soc. 1938, 60, 1370) and 1-Methyl-piperidin-4-one (1.60 mL, 13.0 mmol) in Methanol (50.0 mL) and the reaction was stirred under an atmosphere of nitrogen. After overnight stirring, ˜50% conversion was achieved. The mixture was heated at 50° C. for 30 h. Following basic workup, the crude material was purified on ISCO (0-12% MeOH:DCM) to afford 7-methoxy-1′-methyl-6-nitrospiro[chromene-2,4′-piperidin]-4-((3H)-one (2.42 g; Yield=64.9%).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([SH:16])[CH:11]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:10]1([CH3:9])[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[CH:11]=1
Reactant: Cc1cccc(S)c1
Reactant: Nc1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Cc1cccc(Sc2ccc(N)cc2)c1
Yield: 90.1 %

Procedure:
The general procedure in example 39 was followed. 4-Iodoaniline (219 mg, 1.0 mmol), m-thiocresol (119 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 4-(3-tolyl)sulfanylaniline (194 mg, 90% yield) as pale yellow liquid. Column chromatographic solvent (hexane/ethyl acetate=4/1). Rf=0.4 (hexane/ethyl acetate=4/1). 1H NMR (CDCl3, 300 MHz) δ 7.28 (dt, 2 H, J=7.5 Hz, 0.9 Hz), 7.08 (t, 1 H, J=7.8 Hz), 6.91 (t, 3 H, J=7.5 Hz), 3.71 (brs, 2 H), 2.26 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 138.8, 138.1, 136.2, 128.9, 128.1, 126.4, 124.6, 117.5, 116.1, 100.0, 21.8. IR (neat, cm−1) 3460 (broad), 3377 (broad), 3211, 3051, 3027, 2919. MS (EI) m/z (relative intensity) 219 (100), 92 (80). HRMS (EI), Cald. for C13H13NS 215.0769; Found 215.0766.
Reaction SMILES: [O:1]1[C:8]2[CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1.[OH-].[K+].[I:15]I.Cl>CN(C=O)C.O>[I:15][C:7]1[C:8]2[O:1][CH:2]=[CH:3][C:4]=2[NH:5][C:6]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc2occc2[nH]1
Reactant: II
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1[nH]c2ccoc2c1I
Temperature: -10 °C
Reaction time: 12 h
Yield: 45.9 %

Procedure:
A mixture of methyl 4H-furo[3,2-b]pyrrole-5-carboxylate (5.00 g, 30.3 mmol) and KOH (3.40 g, 60.6 mmol) in DMF (100 mL) was cooled to −10° C. Iodine (7.31 g, 28.8 mmol) in DMF (40 mL) was charged via an addition funnel over 30 min. The resulting mixture was warmed to rt and stirred for additional 12 h. The reaction mixture was poured into water, adjusted with HCl (2 N) to pH 6-7, and extracted with EtOAc. The crude product was purified by flash chromatography (silica gel, 0 to 30% ethyl acetate in hexanes) to give a light tan solid methyl 6-iodo-4H-furo[3,2-b]pyrrole-5-carboxylate (3.85 g, 44% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.98 (br, s, 1H); 7.55 (d, J=2 Hz, 1H); 6.52 (d, J=2 Hz, 1H); 3.91 (s, 3H). MS (m/z 291).
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4][CH3:5])[CH3:2].Cl[C:9]([O:11][CH3:12])=[O:10]>ClCCl.N1CC=CC1>[CH3:12][O:11][C:9]([N:3]1[CH2:4][CH:5]=[CH:2][CH2:1]1)=[O:10]
Reactant: CCN(CC)CC
Reactant: COC(=O)Cl
Agent: C1=CCNC1
Solvent: ClCCl
Product: COC(=O)N1CC=CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
In dichloromethane (20 ml), 3-pyrroline (1.1 ml) was dissolved, followed by the addition of triethylamine (2.6 ml) and methyl chloroformate (1.2 ml) under ice cooling. The resulting mixture was stirred at room temperature for 17 hours. The residue obtained by distilling the reaction mixture under reduced pressure was purified by chromatography on a silica gel column (hexane:ethyl acetate=4:1), whereby the title compound (0.95 g, 52%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.Br[CH2:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[C:24]#[N:25].O>CN(C)C=O>[CH3:12][C:11]1[C:2]([CH3:1])=[CH:3][C:4]2[N:8]=[C:7]([S:9][CH2:21][C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[NH:6][C:5]=2[CH:10]=1
Reactant: N#Cc1ccccc1CBr
Reactant: Cc1cc2nc(S)[nH]c2cc1C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc2nc(SCc3ccccc3C#N)[nH]c2cc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To 5,6-dimethylbenzimidazole-2-thiol (713 mg, 4 mmol) in dimethylformamide (10 ml), triethylamine (836 μl, 6 mmol) and 2-bromomethylbenzonitrile (1176 mg, 6 mmol) were added. After stirring at 80° C. overnight, water was added to the mixture, followed by extraction with ethyl acetate. After the ethyl acetate phase was dried with anhydrous sodium sulfate, it was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to obtain 2-((5,6-dimethylbenzimidazole-2-ylthio)methyl)benzenecarbonitrile (1159 mg, yield 99%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([NH2:8])[CH:7]=1.[NH2:9][NH2:10]>>[ClH:1].[ClH:1].[NH2:8][C:6]1[CH:7]=[C:2]([NH:9][NH2:10])[N:3]=[N:4][CH:5]=1
Reactant: Nc1cnnc(Cl)c1
Reactant: NN
Product: Cl
Product: NNc1cc(N)cnn1
Temperature: 25 °C

Procedure:
7 g. of 3-chloro-5-aminopyridazine is added to 125 ml. of hydrazine and the mixture is stirred under nitrogen for 17.5 hours at a temperature below reflux. The reaction mixture is cooled to room temperature, and the residual hydrazine removed by evaporation. The residue is treated with 250 ml. of methanol to extract the product. After separating the extractant and washing the residue with small amounts of methanol, the combined extractant-filtrate is treated with hydrogen chloride gas. The solution is then treated with ether to give a crystalline product which is recrystallized from methanol to give 5-amino-3-hydrazinopyridazine dihydrochloride; m.p. 220°-222°C.
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH3:14])=[CH:11][CH:12]=2)[C:7]([N:15]2[CH:19]=[N:18][N:17]=[C:16]2[S:20][CH2:21][C:22]([O:24]CC)=[O:23])=[CH:6][CH:5]=1>C1COCC1.C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH3:14])=[CH:11][CH:12]=2)[C:7]([N:15]2[CH:19]=[N:18][N:17]=[C:16]2[S:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CSc1nncn1-c1ccc(C)c2ccc(C)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(C)ccc(-n3cnnc3SCC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
Lithium hydroxide solution (1M aqueous, 0.88 mL, 0.488 mmol) was added to a solution of 4 ethyl 2-(4-(4,7-dimethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate (0.15 g, 0.44 mmol) in THF/ethanol/water (1:1:1, 7 mL) and the mixture stirred for 2 h at room temperature. The crude reaction mixture was then concentrated, acidified with HCl (1M, 3 mL) and extracted with ethyl acetate (3×5 mL). The combined organics extracts were concentrated to afford 2-(4-(4,7-dimethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid as an off-white solid (0.129 g, 94%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[F:34]C(F)(F)S([O-])(=O)=O.ClC1C=CC=C(Cl)[N+]=1F>ClCCl.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=4)=[CH:23][C:22]=3[F:34])[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(O)c1cnc(-c2cc(F)c(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-[2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3-thiazol-5-yl]ethanol (420 mg) in dichloromethane (5 mL) was added 2,6-dichloro-1-fluoropyridinium trifluoromethanesulfonate (410 mg), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give a mixture of the title compound and a positional isomer thereof (35.0 mg). The mixture of the obtained positional isomers was dissolved in hexane-ethanol (850:150, volume ratio, 114 mL), and the solution was subjected to HPLC using TSK GEL SHILICA-60 (20 mmID×250 mL, manufactured by Tosoh Corporation-silica). Using hexane-ethanol (850:150, volume ratio) as a mobile phase, the solution was eluted at flow rate 20 mL/min and at room temperature, and the fraction was separated at retention time 34.5 min, and concentrated. The obtained solid was dissolved in ethyl acetate and the insoluble material was filtered off. The filtration was concentrated to give the title compound (18.1 mg, yield 3%) as a colorless amorphous solid. MS: 505 (MH+).