Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[C:34]([CH:39]1[CH2:44][CH2:43][CH:42]([CH2:45][CH:46]=O)[CH2:41][CH2:40]1)([CH2:37][CH3:38])([CH3:36])[CH3:35]>>[C:34]([CH:39]1[CH2:44][CH2:43][CH:42]([CH2:45][CH:46]=[CH:2][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:41][CH2:40]1)([CH2:37][CH3:38])([CH3:36])[CH3:35]
Reactant: CCC(C)(C)C1CCC(CC=O)CC1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CCC(C)(C)C1CCC(CC=CCc2ccccc2)CC1
Yield: 48.8 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (2.00 g, 4.47 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 2.8 mL, 4.47 mmol, 1.0 equiv.) and 2-(4-tert-pentylcyclohexyl)acetaldehyde (1.32 g, 6.71 mmol, 1.5 equiv.), 0.62 g (48%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane).
Reaction SMILES: Cl[CH2:2][C@@H:3]([CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C:13]([C:14]3[CH2:15][CH2:16][C@@H:17]4[C@:22]([C:24]=3[CH2:25][CH2:26]2)([CH3:23])[CH2:21][CH2:20][C@H:19]([OH:29])[C:18]4([CH3:31])[CH3:30])=[CH:12][CH2:11]1)[CH3:9])[CH3:4].[I-:32].[Na+].O>CC(C)=O>[I:32][CH2:2][C@@H:3]([CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C:13]([C:14]3[CH2:15][CH2:16][C@@H:17]4[C@:22]([C:24]=3[CH2:25][CH2:26]2)([CH3:23])[CH2:21][CH2:20][C@H:19]([OH:29])[C:18]4([CH3:31])[CH3:30])=[CH:12][CH2:11]1)[CH3:9])[CH3:4]
Reactant: C[C@@H](CCl)CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H](CI)CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Temperature: 55 °C
Yield: 68.7 %

Procedure:
A mixture of (25R)-26-chloro-4,4-dimethyl-5α-cholesta-8,14-dien-3β-ol (50 mg, 0.1 mmol) and sodium iodide (0.8 g) in acetone (3 mL) were heated at 55° C. in a sealed reaction vessel for 3 days. Addition of water, extraction with diethyl ether and concentration under reduced pressure gave a residue which was crystallised 3 times from hexane to give the title compound (37 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][OH:11].[O:12]=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1>>[OH:12][C:13]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][CH2:10][OH:11])[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: OCCCc1ccccc1Br
Reactant: CCOC(=O)N1CCC(=O)CC1
Product: CCOC(=O)N1CCC(O)(c2ccccc2CCCO)CC1

Procedure:
The title compound was prepared according to the procedure described in step 2 of example 36 from 3-(2-bromophenyl)propan-1-ol (J. Am. Chem. Soc. 2003, 125, 3509.) and ethyl 4-oxopiperidine-1-carboxylate:
Reaction SMILES: [C:1]1([CH:11]([N:13]2C(=O)C3C(=CC=CC=3)C2=O)[CH3:12])[C:10]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([CH:11]([NH2:13])[CH3:12])[C:10]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:3][CH:2]=1
Reactant: CC(c1ccc2cccccc1-2)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(N)c1ccc2cccccc1-2
Temperature: 30 °C
Reaction time: 72 h
Yield: 97 %

Procedure:
2-[1-(Azulen-1-yl)ethyl]-isoindole-1,3-dione (16.8 g) prepared in Example 72, Step B was dissolved in ethanol (400 mL), added with hydrazine monohydrate (3.1 g, Wako Pure Chemical Industries), and stirred at 30° C. for 72 hours. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was added with saturated aqueous sodium hydrogencarbonate, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel chromatography (NH-DM1020, Fuji Silysia, hexane:ethyl acetate=3:1-1:1) to obtain 9.26 g of the title compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][O:7][C:8]([N:10]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)=[O:9])[CH2:2]1.[H][H]>C(O)C.[Pd]>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][O:7][C:8]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[O:9])[CH2:2]1
Reactant: [H][H]
Reactant: O=C(OCC1CCOC1)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(OCC1CCOC1)N1CCNCC1
Yield: 103.3 %

Procedure:
4-Benzyl-piperazine-1-carboxylic acid tetrahydro-furan-3-ylmethyl ester (11.0 g) was dissolved in 100 ml ethanol. Palladium on carbon (10% Pd/C, 0.5 g) was added, and a hydrogen atmosphere was applied overnight at room temperature. The solution was filtered through Celite to remove the catalyst, and the Celite cake was rinsed with 50 ml ethanol. The combined filtrates were evaporated to dryness to yield piperazine-1-carboxylic acid tetrahydro-furan-3-ylmethyl ester (8.0 g) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[C:32]([F:33])=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1>>[F:33][C:32]1[C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[N:26][CH:27]=[C:28]([CH:31]=1)[C:29]#[N:30]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: N#Cc1cnc(Cl)c(F)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C#N)cc2F)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 6-chloro-5-fluoronicotinonitrile. ESI-MS (m/z): 434 [M+1]+.
Reaction SMILES: [CH2:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][N:8]=1)[CH2:2][CH3:3].C(OP(/[C:19](=[CH:25]\[CH3:26])/[C:20]([O:22][CH2:23][CH3:24])=[O:21])(OCC)=O)C>>[CH2:1]([C:4]1[S:5][C:6]([CH:9]=[CH:26][CH:25]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:7][N:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1ncc(C=O)s1
Reactant: C/C=C(/C(=O)OCC)P(=O)(OCC)OCC
Product: CCCc1ncc(C=CC=CC(=O)OCC)s1

Procedure:
Using the procedure of Example 4, 2-propyl-5-thiazole-carboxaldehyde [prepared by reaction of manganese dioxide and 2-propyl-5-hydroxymethyl-thiazole in benzene] and ethyl diethylphosphonocrotonate were reacted to obtain ethyl 5-(2-propyl-5-thiazolyl)-2,4-pentadienoate melting at 52°C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C:20](=[O:34])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30]([CH3:33])([OH:32])[CH3:31])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[O:35]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36]1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C:20](=[O:34])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30]([O:32][CH:36]4[CH2:37][CH2:38][CH2:39][CH2:40][O:35]4)([CH3:31])[CH3:33])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: CC(C)(O)Cc1ccccc1CCC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(Cc1ccccc1CCC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1)OC1CCCCO1
Temperature: 25 °C

Procedure:
A solution of the alcohol of Step 2 (390 g, 8.29 mmol), 3,4-dihydro-2H-pyran (7.4 mL, 81 mmol) and pyridinum p-toluenesulfonate (684 mg, 2.7 mmol) in 44 mL of CH2Cl2 was heated at reflux for 23 hours. The reaction mixture was allowed to cool to r.t. and 10% aq. NaHCO3 was added. The title product was extracted with CH2Cl2, dried over Na2SO4 and purified by flash chromatography on silica using EtOAc:toluene 5:95. Yield: 4.22 g, 92%.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH:16]([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:16]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)([CH3:18])[CH3:17]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.05 g, 0.2 mmol), 2-Bromopropane (36 uL, 0.39 mmol, Aldrich, Cat. No. 239909), and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. for 2 h. After cooling it was quenched with water. The product was extracted with ethyl acetate. The extract was washed with water twice, brine once; dried over Na2SO4. After filtration the filtrate was concentrated to yield 53 mg of the product which was directly used in the next step reaction without further purification.
Reaction SMILES: [CH2:1]([S:5]([N-:8][Si](C)(C)C)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[C:13]([O:17][C:18]([NH:20][C@H:21]([C:25](F)=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].CN(C1C=CC=CN=1)C>O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:1]([S:5]([NH:8][C:25](=[O:26])[C@H:21]([CH:22]([CH3:23])[CH3:24])[NH:20][C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)[N-][Si](C)(C)C
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)F
Agent: CN(C)c1ccccn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-butanesulfonyl-N-trimethylsilylamide (prepared according to the procedure described in Example 8) (1.72 g, 8.28 mmol), t-butoxycarbonylvaline fluoride (1.01 g, 4.6 mmol), and dimethylaminopyridine (220 mg, 1.84 mmol) in tetrahydrofuran (25 ml) is stirred at room temperature for 1 hour. The mixture is diluted with 10% citric acid and extracted with ethyl acetate. The organic layer is washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The crude material is chromatographed on silica gel with ethyl acetate/hexane (3:1) to give N-butanesulfonyl-(t-butoxycarbonyl)valineamide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=3)[C:3]=12.CC(C)([O-])C.[Na+].[Cl:30][C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>C1COCC1.CN(C=O)C>[Br:23][C:19]1[CH:18]=[C:17]([C:16]2[C:3]3[C:4](=[N:5][C:6]([CH3:13])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]=3[NH:1][S:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([Cl:30])[CH:32]=3)(=[O:39])=[O:38])[S:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(C)nc2scc(-c3cccc(Br)c3)c2c1N
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2scc(-c3cccc(Br)c3)c2c1NS(=O)(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
To a stirred solution of ethyl 4-amino-3-(3-bromophenyl)-6-methylthieno[2,3-b]pyridine-5-carboxylate (Description 46) (2.87 g, 7.33 mmol) in THF (30 mL) and DMF (15 mL) was added sodium tert-butoxide (1.762 g, 18.34 mmol) and 3-chlorobenzenesulfonyl chloride (2.066 mL, 14.67 mmol). The reaction mixture was then stirred at RT under nitrogen for ca. 30 min and then quenched with saturated ammonium chloride solution (ca. 60 mL). The mixture was extracted with DCM (ca. 30 mL×5) and the combined organics dried and concentrated in vacuo. Purification by chromatography on silica, eluting with a gradient of 0-50% ethyl acetate in DCM afforded the title compound (1.48 g). LCMS (A) m/z: 566/568 [M+1]+, Rt 1.47 min (acidic).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8](N)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[BrH:11].N([O-])=O.[Na+]>C(O)(=O)C.O>[Br:11][C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][N:7]=1
Reactant: CC(C)(C)c1nnc(N)s1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1nnc(Br)s1
Temperature: 65 °C

Procedure:
To a solution of crude 5-tert-butyl-1,3,4-thiadiazol-2-amine (120.8 g) in glacial acetic acid (800 ml) was added aqueous hydrobromic acid (≧40%, 218 ml) at room temperature. The resulting solution was heated to 65° C., and a solution of sodium nitrite (167 g, 2.42 mol) in water (300 ml) was added dropwise such that the internal temperature was maintained at 65˜75° C. After addition was complete, the resulting yellow solution was cooled to room temperature, poured into ice and then extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium carbonate solution until the pH was neutral, dried over magnesium sulfate, filtered and concentrated. The resulting oil was purified via flash column chromatography (ethyl acetate/petroleum ether) to obtain 2-bromo-5-tert-butyl-1,3,4-thiadiazole.
Reaction SMILES: [CH3:1][N:2]1[C:6](Cl)=[C:5]([N+:8]([O-:10])=[O:9])[C:4]([CH3:11])=[N:3]1.[C-]#N.[K+].[I-].[K+].[CH3:17][N:18](C=O)C>C(#N)C>[CH3:1][N:2]1[C:6]([C:17]#[N:18])=[C:5]([N+:8]([O-:10])=[O:9])[C:4]([CH3:11])=[N:3]1
Reactant: CN(C)C=O
Reactant: Cc1nn(C)c(Cl)c1[N+](=O)[O-]
Agent: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nn(C)c(C#N)c1[N+](=O)[O-]

Procedure:
Fifty-five g of 1,3-dimethyl-4-nitro-5-chloropyrazole was dissolved in 400 ml acetonitrile and 17.45 g potassium cyanide added, followed by 0.5 g potassium iodide and 5 ml DMF. The mixture was refluxed for 22 hours, then cooled, and filtered. The filtrate was concentrated under reduced pressure, then added to stirred water. The resulting percipitate was collected, dried, and recyrstallized in isopropanol. mp, 85°-87° C. A second recrystallization again in ethanol gave the product having increased purity, mp 96°-98° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:12]1([CH3:19])[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:1]([O:18][C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1ccccc1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccccc1C
Temperature: 65 °C

Procedure:
First 235.5 g (3.3 moles) acetyl chloride then 282.8 g (2.8 moles) triethylamine are added dropwise to a mixture of 324 g (3 moles) o-cresol and 36.6 g (0.3 mole) 4-dimethylaminopyridine in 1 liter of toluene. The mixture is then heated for 3 h at 65° C. The resulting solid hydrochloride is separated by filtration and the organic phase is washed twice with 1 N hydrochloric acid then with water. The solution is dried and then the solvent is recovered under vacuum. The remaining oil is distilled under vacuum. It has a boiling point of 87° C. at 12 Torr. The yield is 428.8 g.
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.S(O[CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=O)(=O)C>C(O)C>[ClH:1].[ClH:1].[O:39]([CH2:38][CH2:37][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CS(=O)(=O)OCCOc1ccccc1
Reactant: O=C(NCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCC1CCN(CCOc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
Synthesis of N-[1-(2-phenoxyethan-1-yl)piperidin-4-ylmethyl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide Under nitrogen gas, 0.37 ml (4.78 mM) of methanesulfonyl chloride was added to a solution of 0.44 g (3.18 mM) of phenoxyethanol and 0.89 ml (6.39 mM) of triethylamine in methylene chloride (6 ml) at 0° C. and the mixture was stirred at the prevailing temperature for 35 minutes. The reaction was stopped by adding saturated aqueous solution of sodium hydrogen carbonate and the reaction mixture was extracted with diethyl ether. The organic layer was washed serially with water and saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide 0.6989 g (<3.18 mM) of phenoxyethyl mesylate. To a solution of 0.58 g (1.5 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.2 mM) of triethylamine in ethanol (6.0 ml) was added 0.6989 g (<3.18 mM) of the above phenoxyethyl mesylate at room temperature and the mixture was refluxed under nitrogen for 17 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (methanol/ethyl acetate 30-40%) to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](OCC)=[O:7])=[CH:4][C:3]=1[I:13].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[NH2:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[I:13]
Reactant: CCOC(=O)c1ccc(N)c(I)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Nc1ccc(CO)cc1I
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 4-amino-3-iodobenzoate (8.0 g) in CH2Cl2 (56 mL) cooled to 0° C. is added diisobutylaluminum hydride in CH2Cl2 (110 mL of a 1M solution). The reaction is stirred at 0° C. for 2 h then quenched by the addition of MeOH (50 mL). To this is added 1N HCl (100 mL). The mixture is concentrated to remove the organics. The aqueous solution is extracted with CH2Cl2 (3×). The combined organic layers are dried over Na2SO4, filtered and condensed. The resulting residue is adsorbed onto silica and chromatographed (Biotage flash 40M, gradient from CH2Cl2 to 2% MeOH/CH2Cl2). Fractions homogeneous by TLC are combined and condensed to afford (4-amino-3-iodophenyl)methanol.
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]=1[SH:12].Cl[CH2:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1>CN(C)C=O>[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12][CH2:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: ClCc1nc2ccccc2s1
Reactant: Sc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2[nH]c(SCc3nc4ccccc4s3)nc2c1
Reaction time: 2 h
Yield: 58.1 %

Procedure:
1.5 g (50 mmol-80%) of sodium hydride were added under nitrogen to a stirred solution of 7.6 g (50 mmol) of 2-benzimidazolethiol in 76 ml of dimethylformamide and after one hour, 7.2 g (40 mmol) of 2-chloromethyl-benzothiazole were added with ice cooling. The mixture stood at room temperature for 2 hours and the solution was concentrated under reduced pressure in a nitrogen stream. The residue was dissolved in ethyl acetate and the solution was washed with ice cold 2N sodium hydroxide solution and aqueous saturated sodium chloride solution, was dried over magnesium sulfate and evaporated to dryness under reduced pressure to obtain 6.91 g (58% yield) of 2-(1H-benzimidazol-2-yl-thiomethyl)-benzothiazole in the form of pale yellow crystals after crystallization from dichloromethane melting at 159°-162° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[S:15])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.Br[CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=O>C(O)C>[CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[S:15][C:26]4[CH2:27][CH2:28][CH2:29][CH:24]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:18][CH:19]=5)[C:25]=4[N:16]=3)=[CH:11][CH:12]=2)=[CH:5][N:6]=1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Reactant: Cc1ncc(-c2ccc(NC(N)=S)cc2)o1
Solvent: CCO
Product: Cc1ncc(-c2ccc(Nc3nc4c(s3)CCCC4c3ccccc3)cc2)o1
Yield: 43.8 %

Procedure:
A solution of [4-(2-methyl-oxazol-5-yl)-phenyl]-thiourea (100 mg, 0.43 mmol) and 2-bromo-6-phenyl-cyclohexanone (114 mg, 0.45 mmol) in ethanol (5 mL) was heated to reflux over night. The solvent was removed under reduced pressure and the residue purified on silica gel using methylene chloride and methylene chloride/methanol (19:1 v/v) as eluent to yield the title compound (73 mg, 44%) as a yellow gum. MS ISP (m/e): 388.2 (100%) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.18 (s, 1H), 7.49 (m, 4H), 7.11-7.29 (m, 6H), 4.04 (m, 1H), 2.70 (m, 2H), 2.43 (s, 3H), 2.14 (m, 1H), 1.70-1.93 (m, 3H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(Cl)Cl.[CH3:11][O:12][C:13]1[CH:42]=[CH:41][C:16]([C:17]([NH:19][C:20](=[S:40])[NH:21][C:22]2[S:32][C:25]3[CH2:26][O:27][C:28]([CH3:31])([CH3:30])[CH2:29][C:24]=3[C:23]=2[C:33]([O:35]C(C)(C)C)=[O:34])=[O:18])=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:42]=[CH:41][C:16]([C:17]([NH:19][C:20](=[S:40])[NH:21][C:22]2[S:32][C:25]3[CH2:26][O:27][C:28]([CH3:31])([CH3:30])[CH2:29][C:24]=3[C:23]=2[C:33]([OH:35])=[O:34])=[O:18])=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)NC(=S)Nc2sc3c(c2C(=O)OC(C)(C)C)CC(C)(C)OC3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(=O)NC(=S)Nc2sc3c(c2C(=O)O)CC(C)(C)OC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
A solution of 40% v/v TFA/DCM (2.5 mL total) was added to tert-butyl 2-(3-(4-methoxybenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (34 mg, 0.071 mmol) and the mixture was stirred at room temperature for 1 h. The volatiles were removed at 30° C. and the material was purified by mass-directed reverse-phase chromatography. 2-(3-(4-Methoxybenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylic acid (14 mg, 0.033 mmol, 46% yield) as a white solid. 1H NMR (500 MHz, DMSO) δ 14.86 (s, 1H), 13.38 (s, 1H), 11.59 (s, 1H), 8.04-7.97 (m, 2H), 7.11-7.03 (m, 2H), 4.65 (s, 2H), 3.86 (s, 3H), 2.73 (s, 2H), 1.22 (s, 6H). 13C NMR (126 MHz, DMSO) δ 174.55, 165.94, 165.28, 163.16, 146.98, 131.01, 129.02, 123.95, 123.75, 116.39, 113.76, 70.12, 58.80, 55.58, 37.25, 26.16. LCMS retention time: 3.264 min; LCMS purity at 214 nm=99%. HRMS m/z calculated for C19H21N2O5S2 [M++1]: 421.0886. found 421.0893. Melting point 213.2° C., decomposition.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].C([Li])CCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>C1COCC1.CCCCCC>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:16]([OH:21])[OH:17])=[C:3]([CH3:10])[CH:4]=1
Reactant: COc1ccc(Br)c(C)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(B(O)O)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
A solution of 4-bromo-3-methylanisole (7, 92 g, 0.457 mol) in anhydrous THF (400 ml) was treated dropwise with a solution of n-butyl lithium (2.5 M solution in hexane, 201 mL, 0.503 mol, 1.1 equiv) in hexane at −60–−65° C. under N2. The resulting reaction mixture was stired at −60–65° C. for an additional 30 min before being treated dropwise with B(OiPr)3 (94.56 g, 116 mL, 0.503 mol, 1.1 equiv) at −60–−65° C. The reaction mixture was stirred at −60–−65° C. for an additional 1 h. The reaction was then quenched with saturated NH4Cl aqueous solution (400 mL) at −60–−65° C., and the resulting mixture was gradually warmed to 0° C. for 1 h and subsequently to room temperature. The two layers were separated, and the aqueous layer was extracted with EtOAc/THF (1:1, 200 mL). The combined organic extracts were then washed with H2O (200 mL), and saturated NaCl aqueous solution (200 mL), dried over MgSO4, and concentrated in vacuo. The residual white solids were then suspended in heptane (400 mL), and the resulting suspension was stirred at room temperature for 30 min. The solids were collected by filtration and washed with heptane (2×100 mL), dried in vacuo at 40–45° C. for overnight. The crude product (8, 57.9 g, 75.86 g theoretical, 76.3%) was obtained as a white powder.