Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:22])[N:10]([C:23](=[O:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[H-].[Ca+2].[H-].[CH3:29][N:30]=[C:31]=[O:32]>C1C=CC=CC=1>[C:23]([N:10]1[CH:11]([CH3:22])[CH2:12][C:13]2[CH:18]=[C:17]3[O:19][CH2:20][O:21][C:16]3=[CH:15][C:14]=2[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:31]([NH:30][CH3:29])=[O:32])=[CH:3][CH:4]=2)=[N:9]1)(=[O:25])[CH3:24]
Reactant: CC(=O)N1N=C(c2ccc(N)cc2)c2cc3c(cc2CC1C)OCO3
Reactant: CN=C=O
Agent: [Ca+2]
Agent: [H-]
Solvent: c1ccccc1
Product: CNC(=O)Nc1ccc(C2=NN(C(C)=O)C(C)Cc3cc4c(cc32)OCO4)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
0.70 g (2 mmol) of the product of Example 15 was dissolved in benzene dehydrated over calcium hydride, 0.3 ml (5 mmol) of methyl isocyanate was added and the reaction mixture was stirred at 50° C. for 4 hours. The crystals formed after coling were filtered, washed with 3×3 ml of benzene, then triturated with 20 ml of hot benzene. The hot mixture was filtered, the precipitate was washed with 3×3 ml of benzene and dried to give 0.65 g (79.6%) of the aimed product, m.p.: 168°-170° C. (decomp.).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>C(#N)C>[O:13]1[C:14]2[CH:18]=[CH:17][S:16][C:15]=2[C:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[O:4][CH2:3][CH2:2][NH:32][CH2:31][C:30]2[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:35])[F:36])=[CH:34][CH:33]=2)=[N:12]1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1ccc(CNCCOc2cccc(-c3noc4ccsc34)c2)cc1
Reaction time: 8 h

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 4-(trifluoromethyl)benzylamine and acetonitrile essentially as described above in example 18 except that the reaction is run overnight and the compound is purified by column chromatography using a solvent gradient of 5% ethyl acetate in dichloromethane to 10% methanol in ethyl acetate. Purity by LC/MS (APCI)=98%, [M+H]+=419.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[C:8]([C:14]([OH:16])=[O:15])=[CH:7][CH:6]=1)[CH3:2].C(COC)OC.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH2:1]([O:3][CH2:4][C:5]1[N:10]=[C:9]2[C:11]([O:16][C:14](=[O:15])[C:8]2=[CH:7][CH:6]=1)=[O:13])[CH3:2]
Reactant: CCOCc1ccc(C(=O)O)c(C(=O)O)n1
Solvent: c1ccncc1
Solvent: COCCOC
Solvent: CC(=O)OC(C)=O
Product: CCOCc1ccc2c(n1)C(=O)OC2=O

Procedure:
21 g of 6-ethoxymethylpyridine-2,3-dicarboxylic acid are added to a mixture of 100 ml of dimethoxyethane, 28 ml of acetic anhydride and 15 ml of pyridine while stirring and the whole is further stirred for 6 hours at room temperature before being concentrated by evaporation under a high vacuum. 20 g of anhydride remain in the form of an oily liquid with a refractive index nD22 of 1.5480.
Reaction SMILES: CC(C)(O[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([NH:19][C:20]([CH3:24])([CH3:23])[CH2:21][CH3:22])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6])C.FC(F)(F)C(O)=O.[OH-].[Na+].[N+:35]([C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][C:42](C(O)=O)=[CH:41]2)([O-:37])=[O:36].C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl.O.O1CCCC1>[N+:35]([C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][C:42]([C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]3[C:18]([NH:19][C:20]([CH3:24])([CH3:23])[CH2:21][CH3:22])=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:11][CH2:12]1)=[O:6])=[CH:41]2)([O-:37])=[O:36]
Reactant: CCC(C)(C)Nc1cccnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc([N+](=O)[O-])ccc3[nH]2)CC1
Reaction time: 15 h

Procedure:
To a solution of 1-[1,1-dimethylethoxycarbonyl]-4-[3-(1,1-dimethylpropylamino)-2-pyridinyl]piperazine (PREPARATION 66, 4.99 g) in methylene chloride (75 ml) under nitrogen at 0° is added trifluoroacetic acid (14.3 ml) over 1 min. The resulting mixture is warmed to 20°-25°, stirred for 15 hrs, and then added to a solution of sodium hydroxide (7.44 g) in water (175 ml) at 0°. The layers are separated, the aqueous phase is extracted with methylene chloride (3×70ml), and the combined organic layer is washed with saline (60 ml), dried over sodium sulfate, and concentrated under reduced pressure to give the unprotected intermediate (Rf =0.14, TLC, methanol/chloroform, 10/90). In a flame-dried flask under nitrogen, 5-nitroindole-2-carboxylic acid (2.13 g) and 1,1'-carbonyldiimidazole (1.75 g) are dissolved in dry tetrahydrofuran and stirred for 3 hrs at 20°-25°. Then a solution of the intermediate (2.57 g) in dry tetrahydrofuran (3ml) is added and the resulting mixture is stirred for 1.8 days. The reaction mixture is filtered to give the title compound, NMR (dimethylsulfoxide-de) 12.41, 8.65, 8.09, 7.58, 7.16, 7.11, 6.91, 4.57, 3.93, 3.00, 1.71, 1.31 and 0.84. The filtrate is concentrated and is triturated with cold methanol to give an additional mount of the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21]3[C:25](/[CH:26]=[CH:27]/[S:28]([CH3:30])=[O:29])=[CH:24][N:23]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:22]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1.ClC1C=CC=C(C(OO)=[O:48])C=1.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21]3[C:25](/[CH:26]=[CH:27]/[S:28]([CH3:30])(=[O:48])=[O:29])=[CH:24][N:23]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:22]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/S(C)=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/S(C)(=O)=O)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a mixture of 2-(2-furyl)-4-({2-methoxy-4-[({4-[(E)-2-(methylsulfinyl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole (0.47 g) and tetrahydrofuran (30 mL) was added m-chloroperbenzoic acid (0.18 g) at room temperature, and the mixture was stirred at the same temperature for 1 hr. Saturated aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was stirred at room temperature for 10 min, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give 2-(2-furyl)-4-({2-methoxy-4-[({4-[(E)-2-(methylsulfonyl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as colorless crystals (0.41 g, yield 85%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 152-153° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:8]=[CH:7][CH:6]=1)[CH3:3].[CH3:16][S:17][C:18](SC)=[CH:19][N+:20]([O-:22])=[O:21]>C(#N)C>[CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH2:14][NH:15][C:18]([S:17][CH3:16])=[CH:19][N+:20]([O-:22])=[O:21])[CH:8]=[CH:7][CH:6]=1)[CH3:3]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CN(C)Cc1cccc(SCCCN)n1
Solvent: CC#N
Product: CSC(=C[N+](=O)[O-])NCCCSc1cccc(CN(C)C)n1
Reaction time: 18 h
Yield: 73 %

Procedure:
A mixture of 3-(6-dimethylaminomethyl-2-pyridylthio)-propylamine (1.13 g, 0.005 mol) and 1,1-bis(methylthio)-2-nitroethene (0.86 g, 0.0052 mol) in acetonitrile (10 ml) is warmed briefly to effect solution and then allowed to stand at ambient temperature for 18 hours. The solvent is evaporated and the residue is chromotographed on silica gel (50 g) eluting with 3-7% methanol/chloroform to give 1.25 g of a glassy product.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:5]=[C:6]([C:11](=[O:17])[CH:12]=[CH:13][C:14]([NH2:16])=[O:15])[CH:7]=[CH:8][C:9]=1[Cl:10]>>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[Cl:10])[C:11]([CH:12]1[O:1][CH:13]1[C:14]([NH2:16])=[O:15])=[O:17]
Reactant: NC(=O)C=CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: OO
Product: NC(=O)C1OC1C(=O)c1ccc(Cl)c(Cl)c1

Procedure:
4 was prepared, as a white solid, m.p.: 165°-167° C, by hydrogen peroxide oxidation of 4A by the procedure described in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1.Br[C:17]1[CH:18]=[C:19]2[C:23]3=[C:24]([CH2:26][S:27][CH2:28][CH2:29][N:22]3[C@H:21]3[CH2:30][CH2:31][N:32](C(OC(C)(C)C)=O)[CH2:33][C@@H:20]23)[CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:17]2[CH:18]=[C:19]3[C:23]4=[C:24]([CH2:26][S:27][CH2:28][CH2:29][N:22]4[C@H:21]4[CH2:30][CH2:31][NH:32][CH2:33][C@@H:20]34)[CH:25]=2)=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCSC3
Reactant: COc1ccc(B(O)O)c(C(F)(F)F)c1
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c(C(F)(F)F)c1

Procedure:
Using 4-methoxy-2-(trifluoromethyl)phenyl boronic acid and following the procedures described in EXAMPLE 9, tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate was converted into the title compound of EXAMPLE 12. 1H NMR(CDCl3, 300 MHz): δ 7.20 (m, 3H), 7.05 (m, 2H), 6.89 (s, 1H), 6.79 (s, 1H), 3.84 (s, 3H), 3.81 (m, 2H), 3.59 (m, 1H), 3.45 (m, 1H), 3.21 (m, 2H), 3.0 (m, 2H), 2.92 (m, 3H), 2.60 (m, 1H), 1.80 (m, 2H). LRMS (ES+): 421 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)\[CH3:7])[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)\[CH2:7][Br:17])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C(\C)Oc1cccc(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1cccc(F)c1
Yield: 20 %

Procedure:
To a stirred mixture of (E)-3-(3-fluoro-phenoxy)-but-2-enoic acid ethyl ester (8.60 g, 0.038 mol) in carbon tetrachloride (35 mL) under a nitrogen atmosphere was added N-bromosuccinimide (10.3 g, 0.058 mol) and benzoyl peroxide (900 mg, 0.004 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(3-fluoro-phenoxy)-but-2-enoic acid ethyl ester (2.30 g, 20%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[CH3:17][C:18]1[CH:29]=[CH:28][C:21]([CH2:22][CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)=[CH:20][CH:19]=1>>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[CH2:27][CH2:26][N:25]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:24]2)=[CH:28][CH:29]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: Cc1ccc(CC2CCNC2)cc1
Agent: Cl
Product: Cc1ccc(CC2CCN(C(=O)c3cnoc3-c3ccc(C)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(4-methylbenzyl)pyrrolidine hydrochloride (12.7 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (5.8 mg). Calcd for C23H24N2O2: 360.1838, found 360.1848.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:12]=[N:13][C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=3)=[CH:9][N:10]=2)[CH:7]=1.[O:21]1[CH2:25][CH2:24][NH:23][C:22]1=[O:26].CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.O1CCOCC1>[CH3:18][O:17][C:15]1[CH:16]=[C:11]([C:8]2[N:6]3[CH:7]=[C:2]([N:23]4[CH2:24][CH2:25][O:21][C:22]4=[O:26])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:12]=[N:13][C:14]=1[O:19][CH3:20]
Reactant: O=C1NCCO1
Reactant: COc1cc(-c2cnc3ccc(Br)cn23)cnc1OC
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(-c2cnc3ccc(N4CCOC4=O)cn23)cnc1OC
Temperature: 100 °C
Yield: 28 %

Procedure:
To a 5 mL microwave tube was added 6-bromo-3-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-a]pyridine (0.070 g, 0.21 mmol), 2-oxazolidinone (0.027 g, 0.31 mmol), copper(I) iodide (4.0 mg, 0.021 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (0.0033 ml, 0.021 mmol), potassium carbonate (0.025 ml, 0.42 mmol), and dioxane (3 mL). The resulting reaction mixture was sealed and heated to 100° C. in closed system for 6 h. The mixture was cooled to rt and the solvent was removed. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, 12 g SiO2, methylene chloride:methanol=94%:6%, Flow=30 mL/min). A peak at 15 min was collected. The solvent was removed in vacuo to afford the desired product as white solid (20 mg). MS (ESI pos. ion) m/z: 341.0. Calcd exact mass for C14H12BrN3O2: 340.12. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.87 (s, 3H) 3.94 (s, 3H) 4.12 (t, J=7.89 Hz, 2H) 4.46 (t, J=7.89 Hz, 2H) 7.57 (s, 1H) 7.63 (d, J=1.61 Hz, 1H) 7.69-7.75 (m, 1H) 7.79 (s, 1H) 7.98 (s, 1H) 8.72 (s, 1H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[C:6]([O:11][C:12]3[C:17]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=4)=[O:20])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH:33]1([CH:39]=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.COC(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CO.C(O)(=O)C.CN1C(=O)CCC1>[CH:33]1([CH2:39][N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][C:6]=3[O:11][C:12]3[C:17]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:24][CH:23]=4)=[O:20])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:1]2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)Nc1cccnc1Oc1cccc2c1CCNC2
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: CO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)Nc1cccnc1Oc1cccc2c1CCN(CC1CCCCC1)C2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 29.4 %

Procedure:
A mixture of 1-(2-(1,2,3,4-tetrahydroisoquinolin-5-yloxy)pyridin-3-yl)-3-(4-(trifluoromethoxy)phenyl)urea (238f, 15 mg, 0.034 mmol), cyclohexanecarboxaldehyde (38 mg, 034 mmol), acetic acid (50 μL) were added to NMP (0.75 mL) and trimethylorthoformate (0.5 mL) and stirred at rt for 2.5 h. Triacetoxyborohydride (36 mg) was added and stirring was continued for 18 h. A solution of acetic acid in methanol (50% v/v, 0.5 mL) was added and reation mixture was directly purified on preparative HPLC to yield the desired material (5.4 mg). (M+H)+=541. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.6-1.9 (m, 10H), 2.32 (m, 1H), 3.04-3.06 (m, 2 H), 3.66-3.75 (m, 2 H), 4.31-4.43 (m, 2 H), 4.60-4.70 (m, 2 H), 7.11 (dd, J=7.83, 4.80 Hz, 1 H), 7.18 (t, J=7.83 Hz, 2 H), 7.33 (d, J=8.08 Hz, 2 H), 7.39 (t, J=7.83 Hz, 1 H), 7.56 (d, J=9.09 Hz, 2 H), 7.65 (dd, J=4.80, 1.76 Hz, 1H), 8.53 (d, J=7.84 Hz, 1 H), 8.78 (s, 1 H), 9.54 (s, 1 H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:7][CH3:8])=[N:5][N:6]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([C:2]3[S:3][C:4]([S:7][CH3:8])=[N:5][N:6]=3)=[CH:25][CH:24]=2)[CH:20]=[CH:21]1
Reactant: CSc1nnc(Br)s1
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CSc1nnc(-c2ccc3[nH]ccc3c2)s1
Temperature: 110 °C
Yield: 47 %

Procedure:
To a solution of 2-bromo-5-(methylthio)-1,3,4-thiadiazole (18.5 g, 87 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (21 g, 86 mmol) in p-dioxane (5 mL)/H2O (5 mL) was added Pd(PPh3)4 (15.1 g, 13 mmol) followed by K2CO3 (48.2 g, 349 mmol). The reaction was heated under argon atmosphere at 110° C. for 4 h, then cooled to RT. The mixture was diluted with EtOAc and H2O, and the two layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The crude material was recrystallized in EtOH to give 2-(1H-indol-5-yl)-5-(methylthio)-1,3,4-thiadiazole (10 g, 50%) as an off-white solid. MS (ESI, pos. ion) m/z: 247.8 (M+1). 1H-NMR (DMSO-d6, 300 MHz): 2.8 (s, 3H), 6.6 (d, 1H), 7.5 (t, 1H), 7.55 (dd, 1H), 8.1 (s, 1H), 11.5 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6][CH2:5]2.C1CCCCC1.[CH3:19][O:20][CH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[NH2:27].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[N:27][N:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[CH2:21][O:20][CH3:19])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCCc2cc(I)ccc21
Reactant: COC[C@@H]1CCCN1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: COC[C@@H]1CCCN1N=C1CCCc2cc(I)ccc21
Yield: 98.7 %

Procedure:
To a stirred mixture of 6-iodo-3,4-dihydronaphthalen-1(2H)-one (I-8A, 20.90 g, 77 mmol), p-toluenesulfonic acid monohydrate (0.584 g, 3.07 mmol), and cyclohexane (40 mL) was added (S)-2-(methoxymethyl)pyrrolidin-1-amine (10 g, 77 mmol) dropwise at room temperature under nitrogen. The mixture was heated with azeotropic removal of water for 5 h. The reaction mixture was diluted with ethyl acetate (20 mL) and mixed with saturated aqueous sodium bicarbonate solution (15 mL). The aqueous layer was separated and extracted with ethyl acetate (2×30 mL). The combined organic solutions were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Flash chromatography purification (330 g silica gel column, gradient elution from 0% to 20% EtOAc in hexanes) afforded (S)—N-(6-iodo-3,4-dihydronaphthalen-1(2H)-ylidene)-2-(methoxymethyl)pyrrolidin-1-amine (29.1 g, 76 mmol) as a yellow liquid. LC/MS M+1=385.
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=O)[CH2:4][CH2:3]1.[CH3:8][CH:9]([SH:11])[CH3:10]>CCOCC>[CH:9]([S:11][CH:5]1[NH:6][C:2](=[O:1])[CH2:3][CH2:4]1)([CH3:10])[CH3:8]
Reactant: CC(C)S
Reactant: O=C1CCC(O)N1
Solvent: CCOCC
Product: CC(C)SC1CCC(=O)N1
Temperature: 25 °C

Procedure:
A mixture of 9 g of 5-hydroxy-pyrrolidin-2-one in 40 cm3 of 2-propanethiol and 5 g of Amberlite resin IR 120 H is maintained for 80 hours at ambient temperature. After diluting with ether, filtering, and concentrating under reduced pressure, 8.5 g of the expected product is obtained. m.p. 77°-79° C., crystallized from isopropyl ether. m.p. 85°-87° C. after re-crystallization.
Reaction SMILES: [CH3:1][C:2]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][N:17]1C(=O)C3C(=CC=CC=3)C1=O)=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH3:5])[CH:3]=[CH2:4]>CO.C(Cl)Cl>[CH3:5][C:2]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][NH2:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH3:1])[CH:3]=[CH2:4]
Reactant: C=CC(C)(C)c1[nH]c2ccccc2c1CCN1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: CO
Product: C=CC(C)(C)c1[nH]c2ccccc2c1CCN
Reaction time: 8 h

Procedure:
To a solution of 2-[2-[2-(1,1-dimethyl-2-propenyl)-1H-indol-3-yl]ethyl]-1H-isoindole-1,3(2H)-dione (1.10 g, 3.07 mmol) in 3:1 MeOH/CH2Cl2 (20 mL) at rt under argon was added N2H4.H2O (0.52 mL). The reaction mixture was stirred overnight, concentrated in vacuo, diluted with CHCl3, then extracted with H2O. The CHCl3 layer was separated. The H2O layer was extracted further with CHCl3. The combined CHCl3 extracts were washed, dried, filtered, and concentrated to give the title compound: MS (ESI+) m/z 229.2.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:6]1[CH:18]=[CH:17][C:9]([O:10][CH2:11][C:12]([O:14]CC)=[O:13])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[OH-].[Na+]>CO>[F:1][C:2]([F:19])([F:20])[C:3]([C:6]1[CH:18]=[CH:17][C:9]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]
Reactant: CCOC(=O)COc1ccc(C(C)(C)C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(c1ccc(OCC(=O)O)cc1)C(F)(F)F
Yield: 66 %

Procedure:
To a mixture of 4-(2,2,2-trifluoro-1,1-dimethylethyl)phenol (408 mg, 2.0 mmol, WO 9708144A1) and potassium carbonate (552 mg, 4.0 mmol) in N,N-dimethylformamide (DMF) (30 ml) was added ethyl bromoacetate (334 mg, 2.0 mmol) and the mixture was stirred for 3 hours at ambient temperature. The reaction was partitioned with water and a 1:10 by volume mixture of ethylacetate/hexane, and the organic layer was separated and dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was passed through a silica gel chromatography column and eluted with a 1:1 by volume mixture of ethyl acetate/hexane to furnish ethyl [4-(2,2,2-trifluoro-1,1-dimethylethyl)phenoxy]acetate. Then, ethyl [4-(2,2,2-trifluoro-1,1-dimethylethyl)phenoxy]acetate was treated with 2M aqueous sodium hydroxide (3.0 ml) and methanol (3.0 ml) for 2 hours at room temperature and was quenched with 2M aqueous hydrogen chloride to acidify the mixture adjusting to pH 1. Crude product was extracted with ethyl acetate, and then the organic layer was dried over magnesium sulfate. After filtration, solvent was evaporated under reduced pressure to give 345 mg (66% yield) of the title compound as a white solid.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[C:13]([O:17][C:18]([N:20]1[C:24]2[CH:25]=[C:26]([OH:29])[CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH:30]([CH3:32])[CH3:31])=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43](O)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:13]([O:17][C:18]([N:20]1[C:24]2[CH:25]=[C:26]([O:29][CH:43]3[CH2:44][CH2:45][N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[CH2:41][CH2:42]3)[CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH:30]([CH3:32])[CH3:31])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)c1nc2ccc(O)cc2n1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1nc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2n1C(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
DEAD (0.60 mL, 3.80 mmol) was added to a solution of 1-tert-butoxycarbonyl-6-hydroxy-2-isopropylbenzimidazole (690 mg, 2.30 mmol), 1-tert-butoxycarbonyl-4-hydroxypiperidine (925 mg, 4.60 mmol), triphenylphosphine (904 mg, 3.45 mmol) and THF (5 mL) at 25° C. After stirring for 12 hours, the solvent was removed in vacuo. Chromatography (SiO2, 100 g) of the resulting oil with hexane/ethyl acetate (1:1) afforded 1-tert-butoxycarbonyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-2-isopropylbenzimidazole.