Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11](COCC[Si](C)(C)C)[N:10]=2)=[N:6][C:7]=1F.[NH:32]1[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33]1>>[Br:1][C:2]1[C:7]([N:32]2[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33]2)=[N:6][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: O[C@H]1CCNC1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)c(F)n2)c2cc(-c3cccnc3)ncc21
Product: O[C@H]1CCN(c2nc(-c3n[nH]c4cnc(-c5cccnc5)cc34)ccc2Br)C1
Yield: 3 %

Procedure:
Following the procedures as described in Example 241 and starting with 3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (S)-pyrrolidin-3-ol, 318 was obtained as an off-white solid (1.8 mg, 3.0%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.29-9.18 (m, 2H), 9.00 (s, 1H), 8.60 (d, J=4.6 Hz, 1H), 8.40 (d, J=8.0 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.54 (dd, J=8.0, 4.7 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 5.75 (s, 1H), 5.01 (d, J=3.5 Hz, 1H), 4.45 (s, 1H), 4.11-4.00 (m, 2H), 3.90-3.81 (m, 1H), 3.63 (d, J=10.7 Hz, 1H), 2.06 (dd, J=8.4, 4.2 Hz, 1H), 1.95 (s, 1H); ESI MS m/z=437.1 (M+1)
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CS(O[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3ccc([N+](=O)[O-])cc32)CC1
Yield: 24.6 %

Procedure:
6-Nitro-1H-indazole (12.26 mmol, 2 g), tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (12.26 mmol, 3.42 g) and potassium carbonate (24.52 mmol, 3.39 g) were combined and heated to 100° C. in N,N-dimethylformamide (40 mL) for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate and concentrated at reduced pressure. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from 20% ethyl acetate/heptane to 60% ethyl acetate/heptane) to afford the title compound (1.045 g). MS (ESI) m/z 347.2 [M+H]+
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([CH2:14][NH2:15])[OH:13].C(=O)([O-])[O-].[Ca+2]>O1CCOCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:15][CH2:14][CH2:12][OH:13])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(F)cc1NCCO
Temperature: 80 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
A mixture of 2,4-difluoronitrobenzene (6.36 g., 40 mmole), ethanolamine (3.04 g., 50 mmole) and calcium carbonate (4 g., 40 mmole) in dioxane (40 ml) was stirred at 80° C. for 1 hour and filtered while hot. The filtrate was diluted with ethyl acetate and washed with H2O and brine. The organic phase was dried over sodium sulfate and evaporated to give a reddish orange solid. Recrystallization from ethyl acetate gave the compound (11) as reddish orange crystals (5.3 g, 66%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:9]=2[N+:18]([O-])=O)[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:18][C:9]1[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][O:12][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CCOC(=O)c1noc(-c2cccc(Br)c2)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1noc(-c2cccc(Br)c2)c1N
Yield: 17 %

Procedure:
This material from Example 21B was dissolved in a mixture of EtOH (6 mL) and water (2 mL). Ammonium chloride (160 mg, 3 mmol) and iron powder (1.6 g, 28 mmol) were added at r.t. The reaction mixture was filtered after 1 h. The filtrate was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over MgSO4, concentrated, and purified by flash column chromatography (20% ethyl acetate in hexanes) to provide the titled compound (390 mg, 17% for two steps).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[S:17][C:18]([Cl:22])=[C:19]([Cl:21])[CH:20]=2)(=[O:15])=[O:14])[C:8]1=[O:23])#[N:2].[CH2:27](I)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:13]([C:16]2[S:17][C:18]([Cl:22])=[C:19]([Cl:21])[CH:20]=2)(=[O:14])=[O:15])[C:8]1=[O:23])#[N:2]
Reactant: ICc1ccccc1
Reactant: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3cc(Cl)c(Cl)s3)C2=O)c1
Product: N#Cc1cccc(CN2CC[C@H](N(Cc3ccccc3)S(=O)(=O)c3cc(Cl)c(Cl)s3)C2=O)c1

Procedure:
The title compound is prepared as described in EXAMPLE 25, Part A using 4,5-dichlorothiophene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as described in EXAMPLE 80, part A, and benzyl iodide. The crude product is purified by column chromatography eluting with gradient of 20% EtOAc/hexanes to 40% EtOAc/hexanes to afford the title compound as a white foam.
Reaction SMILES: [CH3:1][N:2]1[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:4]2([CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)[C:3]1=[O:24].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:4]2([CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[C:3]1=[O:24]
Reactant: CN1C(=O)C2(CCCN(C(=O)OC(C)(C)C)C2)C1c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C2(CCCNC2)C1c1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution comprising tert-butyl 2-methyl-1-oxo-3-phenyl-2,6-diazaspiro[3.5]nonane-6-carboxylate (1.2 g, 3.63 mmol) and TFA (1.399 ml, 18.16 mmol) in DCM (20 ml) was stirred at RT for 4 days. The reaction mixture was concentrated in vacuo and the resulting crude product was dissolved with methanol (5 ml) and passed through a 10 g SCX-2 cartridge. The product was eluted with 2M NH3 in methanol (70 ml) and the relevant fractions were combined and concentrated in vacuo to afford the title compound as a yellow oil;
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[Cl:18][C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([S:25]([NH:15][CH:12]2[CH2:13][CH2:14][N:9]([C:4]3[C:3]([C:2]([F:16])([F:1])[F:17])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:10][CH2:11]2)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: NC1CCN(c2ncccc2C(F)(F)F)CC1
Product: O=S(=O)(NC1CCN(c2ncccc2C(F)(F)F)CC1)c1cccc(Cl)c1
Yield: 40.3 %

Procedure:
Using the procedure from Example 17A, Step 17C, 1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-amine (100 mg, 0.42 mmol) was reacted with 3-chlorobenzenesulfonyl chloride (106 mg, 0.50 mmol) to afford the title compound (71 mg), a white solid, in 40% yield.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]([CH3:27])[N:20]1[C:24](=[O:25])[CH2:23][S:22][C:21]1=[S:26]>>[CH3:4][C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:23]2[S:22][C:21](=[S:26])[N:20]([N:19]([CH3:27])[CH3:18])[C:24]2=[O:25])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CN(C)N1C(=O)CSC1=S
Product: CN(C)N1C(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)SC1=S
Yield: 65 %

Procedure:
The title compound was prepared in 65% yield from 3,5-di-tert-butyl-4-hydroxybenzaldehyde and N-dimethylaminorhodanine following the procedure of Example 1.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[Cl:20][C:21]1[CH:22]=[C:23]([CH2:27]O)[CH:24]=[CH:25][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[CH2:27][O:18][C:15]1[CH:16]=[CH:17][N:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[C:10]([CH3:11])[N:2]([CH3:1])[N:3]=3)[CH:8]=2)[C:13](=[O:19])[CH:14]=1
Reactant: OCc1cccc(Cl)c1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c2cc(-n3ccc(OCc4cccc(Cl)c4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 48.4 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (3-chlorophenyl)methanol (56 mg) and triphenylphosphine (154 mg) in tetrahydrofuran (5 ml) was added bis(2-methoxyethyl)azodicarboxylate (138 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (36 mg).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]([NH:36]C(OC(C)(C)C)=O)[C:6]([NH:8][CH:9]([C:32]([O:34][CH3:35])=[O:33])[CH2:10][C:11]1[CH:31]=[CH:30][C:14]([O:15][C:16]2[CH:29]=[CH:28][C:19]([CH:20]=[C:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1)=[O:7].[ClH:44]>ClCCl>[ClH:44].[CH3:1][S:2][CH2:3][CH2:4][CH:5]([NH2:36])[C:6]([NH:8][CH:9]([C:32]([O:34][CH3:35])=[O:33])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH:20]=[C:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:28][CH:29]=2)=[CH:30][CH:31]=1)=[O:7]
Reactant: COC(=O)C(Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1)NC(=O)C(CCSC)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1)NC(=O)C(N)CCSC
Yield: 80.6 %

Procedure:
A solution of 5-[4-(4-(2-(4-methylthio-2-t-butoxycarbonylaminobutyramido)-2-methoxy carbonylethyl)phenoxy)benzylidene]thiazolidin-2,4-dione (1.38 g, 2.2 mmol) in dichloromethane (30 ml) was bubbled with HCl gas at −10° C. for 80 minutes. The excess HCl gas was removed by N2 bubbling and the solvent was removed by distillation to furnish the title compound (1 g, yield 80.6%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])[CH:2]=[CH2:3].[F-].[K+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N+](C1C=C(S(O[CH2:45][C@H:46]2[O:48][CH2:47]2)(=O)=O)C=CC=1)([O-])=O>C1COCC1.O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:45][C@@H:46]1[O:48][CH2:47]1)[CH:2]=[CH2:3]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: C=CCOc1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOc1ccccc1OC[C@H]1CO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
o-Allyloxyphenol (1.0 g) was dissolved in THF (10 ml) under nitrogen atmosphere and the solution was cooled to 0° C. Potassium fluoride (1.55 g) and tetrabutyl ammonium fluoride (0.2 g) were added thereto and the mixture was stirred for 1 hour. Then (S)-glycidyl M-nitrobenzenesulfonate (1.73 g, 99.3% e.e.) was added thereto and the mixture was stirred for 40 hours at the same temperature. After the reaction water was added to the mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, condensed and the residue was subjected to silica gel chromatography (hexane/ethyl acetate; 3:2) to give 0.96 g of (R)-3-(o-allyloxyphenoxy)-1,2-epoxypropane (yield 70%, optical purity 95.9% e.e.) as a colorless oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]2[CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[O:13][C:9]=2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=1Br)(=[O:3])[CH3:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[C:12]([C:14]([CH3:16])([CH3:17])[CH3:15])[O:13][C:9]2[C:10]=1[C:11]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:7][C:8]=2[C:18]([O:20][CH3:21])=[O:19])(=[O:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(Br)c(NC(C)=O)c2cc(C(C)(C)C)oc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ccccc2)c2c(NC(C)=O)cc(C(C)(C)C)oc1-2
Temperature: 100 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
Under nitrogen atmosphere, methyl 4-acetylamino-5-bromo-2-tert-butyl-1-benzofuran-7-carboxylate (I-252) (147 mg, 0.4 mmol), phenylboronic acid (61 mg, 0.5 mmol), aqueous 2 M cesium carbonate solution (0.5 ml, 1.0 mmol) and tetrakistriphenylphosphine palladium(0) (23 mg, 0.02 mmol) were added, followed by stirring at 100° C. for 6 hours. After cooling to room temperature, ethyl acetate was added to the reaction liquid, followed by washing with saturated sodium bicarbonate water and saturated brine and drying over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with n-hexane/ethyl acetate (2:1) gave the entitled compound (117 mg, 80%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][C:8](=O)[C:7]=2[CH:12]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:20][C:21](=[O:23])[CH3:22])C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:20][C:21]([CH3:22])=[O:23])[C:7]=2[CH:12]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2c(c1)C(=O)CO2
Solvent: Cc1ccccc1
Product: COc1ccc2occ(CC(C)=O)c2c1

Procedure:
A mixture of 5-methoxy-benzofuran-3 (2H)-one (1.64 g, 10 mmol) and 1-triphenylphosphoranylidene-2-propanone (4.77 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixture was concentrated and loaded over silica-gel column. The column was eluted with hexane (500 ml) and later with 25% ethyl acetate. The product, 1-(5-methoxy-1-benzofuran-3-yl)acetone, was obtained as a red oil. Yield: 1.1 g (53%); (M+H): 205.
Reaction SMILES: [O:1]1[C:5]2([CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][N:8]2[CH2:9][CH2:10][CH2:11][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:16][CH:17]=1
Reactant: C1CNCCC2(C1)OCCO2
Reactant: COc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(CCN2CCCC3(CC2)OCCO3)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A mixture of intermediate (5) (0.114 mol), 1-(2-bromoethyl)-4-methoxy-benzene (0.172 mol) and K2CO3 (0.219 mol) in ACN (200 ml) was stirred at 80° C. for 2 hours. Water was added and the mixture was extracted with DCM. The organic layer was separated, dried , filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.2). The pure fractions were collected and the solvent was evaporated, yielding 28.5 g of 8-[2-(4-methoxyphenyl)ethyl]-1,4-dioxa-8-azaspiro[4.6]undecane (intermediate 6).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([CH3:3])[CH3:2].[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)[CH2:12][CH3:13].CC1C=CC(S(O)(=O)=O)=CC=1>>[CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[N:6]=[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][CH3:13])([CH3:3])[CH3:2]
Reactant: CCC(=O)c1ccccc1
Reactant: CC(C)c1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCC(=Nc1ccccc1C(C)C)c1ccccc1
Temperature: 200 °C

Procedure:
2-Isopropylaniline (11.6 mL, 82 mmol, Aldrich) was mixed with propiophenone (10 mL, 74.5 mmol, Aldrich) and p-TsOH (1.4 g, 7.3 mmol, Aldrich). The resulting mixture was heated for 2 h at 200° C. under a slow stream of Ar to remove H2O that formed. After cooling to RT the reaction mixture was poured into hexanes (100 mL), filtered, the precipitate washed with additional hexanes (2×100 mL) followed by the evaporation of the filtrate. The residue was filtered through a 9×4.1 cm plug of silica gel in hexanes/ether 10/1 (300 mL collected). After evaporation of the solvent the residue was distilled in vacuo. The initial fraction contained unreacted starting materials (45–50 C/0.4 mm), in the next fraction the product was collected as an orange oil, bp 125–135 C/0.4 mm, 8.0 g, (42.7%). 1H NMR (CDCl3) 8.03–7.95 (m, 2H); 7.53–7.46 (m, 3H); 7.34 (dd, 1H; J=1.4; 7.6 Hz); 7.21 (dt, 1H; J=1.4; 7.6 Hz); 7.1 (dt, 1H; J=1.4; 7.6 Hz); 6.65 (dd, 1H; J=1.4; 7.6 Hz); 3.00 (septet, 1 H; J=6.9 Hz); 2.67 (q, 2H; J=7.6 Hz); 1.22 (d, 6H; J=6.8 Hz); 1.11 (t, 3 H; J=7.6 Hz).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=1>CN(C)C=O.C(OCC)(=O)C>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:19]2[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: N#Cc1cnc(Cl)s1
Reactant: CC(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(Oc2ncc(C#N)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 1A (1.18 g, 7.75 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (1.1 g, 7.96 mmol), 2-chlorothiazole-5-carbonitrile (CAS 51640-36-9, 1.12 g, 7.75 mmol) and then the reaction was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (3×50 mL) and brine (50 mL). The organics were dried over magnesium sulfate, filtered, and evaporated. The product was purified via silica-gel column chromatography using dichloromethane as the eluent. The title compound was obtained as white solid (2.0 g), 1H NMR (300 MHz, CDCl3) δ ppm 7.76 (s, 1H) 7.12-7.23 (m, 2H) 6.87-7.00 (m, 2H) 4.44-4.65 (heptet, J=6.25 Hz, 1H) 1.36 (d, J=6.25 Hz, 6H), MS (DCI): m/z 261 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[H-].[Na+].[CH2:27](Br)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:14])=[O:15])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCBr
Reactant: COC(=O)c1cccc(C=O)c1NS(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCCN(c1c(C=O)cccc1C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To a solution of 1.0 g (2.865 mmol) of the product of Example 321 in 7.5 mL of DMF was added 0.143 g (3.582 mmol) of 60% sodium hydride followed by 0.74 mL (4.30 mmol) of n-octyl bromide. The reaction was stirred overnight at room temperature then diluted with ether, washed with water, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel eluting with EtOAc/hexanes (1:3) to provide 0.592 g (49%) of the product as a white solid. Electrospray Mass Spec: 462.1 (M+H)+.
Reaction SMILES: [N:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]3=[O:22])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1>>[N:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([N:4]2[CH2:3][CH2:2][N:1]([C@H:7]3[CH2:12][CH2:11][C@H:10]([N:13]4[C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=5[NH:15][C:14]4=[O:22])[CH2:9][CH2:8]3)[CH2:6][CH2:5]2)=[O:31])[CH:26]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=c1[nH]c2ccccc2n1[C@H]1CC[C@H](N2CCNCC2)CC1
Agent: Cl
Product: O=C(c1cccnc1)N1CCN([C@H]2CC[C@H](n3c(=O)[nH]c4ccccc43)CC2)CC1

Procedure:
From 1,3-dihydro-1-{trans-4-[1-piperazinyl]-1-cyclohexyl}-2H-benzimidazol-2-one and nicotinoylchloride hydrochloride using the procedure described for Example 11, Step 3 there was obtained 1,3-dihydro-1-{trans-4-[4-(3-pyridinecarbonyl)piperazin-1-yl]-1-cyclohexyl}-2H-benzimidazol-2-one as a white solid: 1H NMR (400 MHz, CDCl3) 9.51 (s, 1H), 8.68 (s, 2H), 7.77 (m, 1H), 7.38 (m, 1H), 7.12-7.04 (m, 4H), 4.26 (m, 1H), 3.83 (s, 2H), 3.47 (s, 2H), 2.71 (s, 2H), 2.58 (s, 2H), 2.53 (m, 2H), 2.30 (q, 2H), 2.0 (q, 4H), 1.53 (m, 2H), 1.26 (m, 2H). The hydrochloride salt was precipitated from chloroform/toluene: Analysis calculated for C23H27N5O2.HCl.0.20 CHCl3.0.45 CH3C6H5C: 57.99, H: 6.43, N: 12.83 found C: 58.04, H: 6.36, N: 12.75.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[Br:12][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:8]=1
Reactant: Oc1ccccc1C(F)(F)F
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Br)cc1C(F)(F)F
Yield: 153.8 %

Procedure:
First, 41.33 g of 2-trifluoromethylphenol and 1800 ml of chloroform were charged into a reaction vessel, and 129.16 g of tetra-n-butylammonium tribromide was slowly added at room temperature over about one hour with stirring. After stirring at room temperature for 72 hours, the reaction solution was concentrated. Then, 500 ml of 10% hydrochloric acid was added to the resultant residue, and the mixture was extracted four times with 200 ml of diethyl ether. The ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give 49.5 g of 4-bromo-2-trifluoromethylphenol as a crude product (yield, 81%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:18]=3[N:19]=2)[CH:11]=[C:10]([Cl:25])[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>>[Cl:25][C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[C:12]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:18]=3[N:19]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)cc(Oc2nc3cc(Cl)ccc3s2)c1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(Cl)cc(Oc2nc3cc(Cl)ccc3s2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.5 %

Procedure:
To [3-chloro-5-(5-chloro-benzothiazol-2-yloxy)-phenyl]-carbamic acid tert-butyl ester (263, 1.17 g, 2.85 mmol) was added trifluoroacetic acid. The mixture was stirred at ambient temperature for 5 h, at which time TLC showed there was no starting material remained. The mixture was concentrated to dryness under reduced pressure, dissolved in EtOAc. The organic solution was washed with 1N NaOH, washed twice with a brine solution, dried over Na2SO4 and concentrated. The residue was purified by chromatography with CH2Cl2 to give 785 mg of product. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J=8.6 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.40 (dd, J=8.6, 2.0 Hz, 1H), 6.62 (t, J=1.9 Hz, 1H), 6.58 (t, J=1.8 Hz, 1H), 6.50 (t, J=1.9 Hz, 1H), 5.81 (s, 2H). MS (EI): m/z 311 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(N1C=CN=C1)([N:15]1C=CN=C1)=O.[NH4+].[OH-]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:15])=[O:12]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cc2ccccc2[nH]1

Procedure:
Add to the 2-indole carboxylic acid (31.0 mmol) dissolved in anhydrous THF (50 ml), carbonyldiimidazole (1.10 equiv, 5.5 g, 34.0 mmol) and stir 1 h. Then add concentrated NH4OH (50 mL) in one portion and stir the reaction at rt. After 16 hours collect the solid that separates by filtration, wash with H2O and dry under vacuum at 40° C. to afford the desired 2-indole carboxamide.