Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2C1CCN(C)CC=1.C1(S(Cl)(=O)=O)C=CC=CC=1>CN(C=O)C>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: CN1CC=C(c2c[nH]c3ccc(Br)cc23)CC1
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2[nH]ccc2c1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
NaH (600 mg, 15.00 mmol) was added (in several batches) to a solution of 5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (3 g, 9.79 mmol) in DMF (60 mL) while cooling to a temperature of 0-5° C. The resulting solution was stirred for 1 hour while the temperature was maintained at room temperature. Benzenesulfonyl chloride (2.3 g, 12.89 mmol) was then added dropwise and the reaction was stirred for an additional 4 hours at room temperature. After filtration, the filter cake was washed with ethanol (2×50 mL) and the resulting solid was dried to afford 0.4 g (10%) of 5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-phenylsulfonyl)-1H-indole as a white solid. 1H NMR (DMSO) δ 8.04 (4H), 7.95 (1H), 7.73 (1H), 7.32-7.63 (3H), 6.29 (s, 1H), 3.98 (2H), 3.68 (2H), 2.72-2.89 (5H). m/z 434.1 (M++1)
Reaction SMILES: [CH2:1]([C:3]([C:7]1[S:11][C:10]2[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=2[CH:8]=1)(O)[CH2:4][CH3:5])[CH3:2].[C:19]1([CH3:26])[C:24]([OH:25])=[CH:23][CH:22]=[CH:21][CH:20]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([C:3]([C:7]1[S:11][C:10]2[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=2[CH:8]=1)([C:21]1[CH:22]=[CH:23][C:24]([OH:25])=[C:19]([CH3:26])[CH:20]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(O)(CC)c1cc2ccc(C(=O)O)cc2s1
Reactant: Cc1ccccc1O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(CC)(c1ccc(O)c(C)c1)c1cc2ccc(C(=O)O)cc2s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
A solution of 2-(1-ethyl-1-hydroxy-propyl)-benzo[b]thiophene-6-carboxylic acid (3.80 g, 14.4 mmol) and o-cresol (1.94 g, 18.0 mmol) in CH2Cl2 (100 mL) at −40° C. is added BF3-Et2O (1.02 g, 7.20 mol). After stirring for 10 min, the reaction mixture is allowed to warm up to 0° C. over 30 min. The reaction is quenched with water (15 mL) and the aqueous layer is extracted with EtOAc (50 mL). The organic layer is dried over Na2SO4, concentrated, and purified by silica gel column chromatography (2% HOAc in 50% EtOAc/Hex) to give the product (3.98 g, 78%).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13](=[O:15])[NH:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].N(C(C)(C)C#N)=NC(C)(C)C#N.[Cl:34]N1C(=O)CCC1=O>ClC1C=CC=CC=1>[Cl:34][C:9]1[C:10]2[NH:14][C:13](=[O:15])[N:12]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:11]=2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cn1c(=O)[nH]c2cccc(C(CC)CC)c21
Reactant: O=C1CCC(=O)N1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: CCOC(=O)Cn1c(=O)[nH]c2c(Cl)ccc(C(CC)CC)c21
Temperature: 70 °C
Reaction time: 48 h
Yield: 63.2 %

Procedure:
To a solution of ethyl [7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate (3.91 g, 13.5 mmol) and 2,2′-azobisisobutyronitrile (222 mg, 1.35 mmol) in chlorobenzene (40 mL) was added portionwise N-chlorosuccinimide (1.80 g, 13.5 mmol) at 65° C., and the mixture was stirred at 70° C. for 2 days. After cooling, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate. The aqueous layer was separated and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 15-50% ethyl acetate/n-hexane gradient mixture, and the fractions containing the title compound were concentrated in vacuo. The mixture was suspended in diisopropyl ether, and the suspension was stirred at 60° C. for 2 hr. After cooling, the resulting solid was collected by filtration and washed with n-hexane to give the title compound (2.77 g, 8.53 mmol, 63%) as a colorless solid.
Reaction SMILES: [NH3:1].[CH2:2]([NH:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1.O>[CH2:2]([NH:9][C:10]1[CH:15]=[C:14]([NH2:1])[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1NCc1ccccc1
Reactant: N
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc([N+](=O)[O-])c(NCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
Ammonia (49 mmol) is purged in THF for 1 h at −70° C., benzyl-(5-fluoro-2-nitro-phenyl)-amine E-1.1″ (6.000 g; 24 mmol) is added to the reaction mixture. The reaction mixture is stirred in a steel bomb vessel at 90° C. for 16 h. The reaction is then cooled to 0° C., diluted with water and extracted with ethyl acetate. The combined organic layers are dried with Na2SO4, filtered and concentrated under reduced pressure. The residue is used in the next step without further purification (yield: 84%; 5.000 g; 20.554 mmol).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=[C:3]1[CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17].B1C2CCCC1CCC2.[OH-:27].[Na+].OO>C1COCC1>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=[C:3]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:27]
Reactant: [OH-]
Reactant: C=CCCCc1nnc(-c2ccccc2)n1C
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(CCCCCO)nnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-3-(4-penten-1-yl)-5-phenyl-4H-1,2,4-triazole (200 mg, 0.88 mmol) in THF (1 mL) was added 9-BBN (0.5M in THF, 1.76 mmol) and the solution was refluxed for 2 h. Two more portions of 9-BBN (0.88 mmol) were added, each after 1 h. The reaction mixture was cooled down at 0 C and was added NaOH (3M, 21Mmol) in one portion followed by dropwise addition of H2O2 (33% in water, 21Mmol). The mixture was stirred for another 2 h at r.t.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:30])[O:13][C:14](=O)[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=3)[N:18]([CH3:28])[CH:17]=2)=[CH:3]1.[NH3:31]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:30])[NH:31][C:14](=[O:13])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=3)[N:18]([CH3:28])[CH:17]=2)=[CH:3]1
Reactant: N
Reactant: Cn1cc(C2=C(c3cn(C)c4ccc([N+](=O)[O-])cc34)C(=O)OC2=O)c2ccccc21
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cn(C)c4ccc([N+](=O)[O-])cc34)C(=O)NC2=O)c2ccccc21
Temperature: 140 °C

Procedure:
0.4 g of 3-(1-methyl-3-indolyl)-4-(1-methyl-5-nitro-3-indolyl)furan-2,5-dione was treated with 3 ml of DMF and 20 ml of 33% aqueous ammonia and heated at 140° C. for 3.5 hours. The cooled mixture was filtered and the residue was washed with water and dried to give 0.29 g of 3-(1-methyl-3-indolyl)-4-(1-methyl-5-nitro-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 282°-284° C.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Cl:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16]C)=[CH:13][CH:14]=2)[N:9]=[N:8][CH:7]=1>C1C=CC=CC=1>[Cl:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[N:9]=[N:8][CH:7]=1
Reactant: COc1ccc2c(Cl)cnnc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Oc1ccc2c(Cl)cnnc2c1
Yield: 53.6 %

Procedure:
Aluminium trichloride (2.6 g, 19 mmol) was added in portions to a suspension of 4-chloro-7-methoxycinnoline (0.9 g, 3.8 mmol), (J. Chem. Soc. 1955, 2100), in benzene (15 ml) and the mixture was heated at reflux for 1 hour. The solvent was removed by evaporation and the residue was partitioned between ice/water and ethyl acetate. Aqueous saturated sodium chloride solution was added and the organic layer was separated. The organic layer was washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether, collected, filtered and dried under vacuum to give 4-chloro-7-hydroxycinnoline (368 mg, 53%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([N:23]([CH2:37][CH2:38][CH3:39])[CH:24]([CH2:27][C:28]1[C:36]2[N:35]=[CH:34][NH:33][C:32]=2[CH:31]=[CH:30][CH:29]=1)[CH2:25]O)[CH2:21][CH3:22].C(Br)(Br)(Br)Br>C(Cl)Cl>[CH2:20]([N:23]([CH2:37][CH2:38][CH3:39])[CH:24]1[CH2:27][C:28]2[C:36]3=[C:32]([N:33]=[CH:34][N:35]3[CH2:25]1)[CH:31]=[CH:30][CH:29]=2)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C(CO)Cc1cccc2[nH]cnc12
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCN(CCC)C1Cc2cccc3ncn(c23)C1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
Triphenylphosphine (625 mg, 2.4 mmol) was added to a stirred solution of β-(dipropylamino)-1H-benzimidazole-4-propanol (600 mg, 2.18 mmol) in methylene chloride (12 mL). After solution was complete, carbon tetrabromide (940 mg, 2.8 mmol) was added and the solution was stirred for 30 minutes. Methylene chloride (20 mL) was added and the solution was extracted with 25 mL 1.0 N hydrochloric acid. The methylene chloride was separated, reextracted with 10 mL 1.0 N HCl, and the combined aqueous extracts were basified (20 mL of 4.0 N NaOH) and extracted with ethyl acetate. After removing the ethyl acetate, the product was chromatographed on silica gel using chloroform as the initial eluant to give 380 mg of product. A sample was crystallized from hexane for analysis; mp 95°-98° C. Anal. Calcd. for C16H23N3 : C, 74.66; H, 9.01; N, 16.33. Found: C, 74.28; H, 9.25; N, 16.36.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.C1(NC2N3N=CC(/C=C4/C(=O)NC(=O)N/4)=C3N=C(S(C)=O)N=2)CC1.[Cl:50][C:51]1[CH:52]=[C:53]([CH:55]=[CH:56][CH:57]=1)[NH2:54].CO>CN1C(=O)CCC1>[Cl:50][C:51]1[CH:52]=[C:53]([NH:54][C:7]2[N:6]=[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=2)[CH:55]=[CH:56][CH:57]=1
Reactant: CS(=O)(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Reactant: Nc1cccc(Cl)c1
Agent: CS(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Solvent: CO
Solvent: CN1CCCC1=O
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)nc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 120 °C

Procedure:
A (1:1) mixture of (Z)-5-((4-(cyclopropylamino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione and (Z)-5-((4-(cyclopropylamino)-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione (15 mg) was mixed with 3-chloroaniline (0.1 ml) in NMP (0.2 ml) and the mixture heated in a microwave oven at 120° C. for 15 min. Methanol was added and the resulting solid filtered and dried to provide (Z)-5-((2-(3-chlorophenylamino)-4-(cyclopropylamino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione as a solid (7 mg). LCMS (ES): >95% pure, m/z 411 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[N:7]([CH3:14])[CH:6]=[C:5]2[CH:15]([CH3:17])[CH3:16].[NH2:18][CH2:19][C:20]1[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=1[CH3:26].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH:18][CH2:19][C:20]3[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[O:13])[CH:10]=1)[N:7]([CH3:14])[CH:6]=[C:5]2[CH:15]([CH3:17])[CH3:16]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)c1cn(C)c2c(C(=O)O)cc(Br)cc12
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c(C(C)C)cn(C)c23)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.1 %

Procedure:
To a stirred suspension of 5-bromo-1-methyl-3-(1-methylethyl)-1H-indole-7-carboxylic acid (300 mg, 1.013 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (280 mg, 1.484 mmol) and HOAt (200 mg, 1.469 mmol) in DMF (15 mL) was added N-methylmorpholine (170 μL, 1.546 mmol) and EDC free base (310 mg, 1.997 mmol). The reaction was stirred for 18 h at RT. LCMS showed that the reaction was complete. The reaction was evaporated to near dryness under vacuum. Water (˜15 mL) was added and the solids which precipitated out were triturated, filtered and dried under vacuum. LCMS indicated that the solids were only 87% pure. The solid was partially dissolved in CH2Cl2. Noticed that the product began to crystallize out. Slowly added an equal volume of hexanes, triturated, filtered and dried under vacuum to give the product 5-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-methyl-3-(1-methylethyl)-1H-indole-7-carboxamide (188 mg, 0.437 mmol, 43.1% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=11.50 (br. s., 1H), 8.54 (t, J=4.8 Hz, 1H), 7.75 (d, J=1.8 Hz, 1H), 7.14 (s, 1H), 7.09 (d, J=2.0 Hz, 1H), 5.87 (s, 1H), 4.31 (d, J=5.1 Hz, 2H), 3.65 (s, 3H), 3.11 (dt, J=6.9, 13.5 Hz, 1H), 2.22 (s, 3H), 2.12 (s, 3H), 1.26 (d, J=6.8 Hz, 6H). MS (ES)+ m/e 429.9 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].[Br:12]N1C(C)(C)C(=O)N(Br)C1=O>CCCCCCC.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:12][CH:1]([C:3]1[S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CCc1cc2ccccc2s1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCCC
Product: CC(Br)c1cc2ccccc2s1
Temperature: 20 °C
Reaction time: 1 h
Yield: 113.7 %

Procedure:
A solution of 9.78 g (60 mmol) of 2-ethylbenzo[b]thiophene in 10 ml of heptane is added, over 10 minutes, to a mixture of 9.43 g (33 mmol) of 1,3-dibromo-5,5-dimethylhydantoin and 0.49 g (3 mmol) of azobisisobutyronitrile in 117.5 ml of heptane preheated to 60° C. The mixture is maintained for 1 additional hour at this temperature. After cooling to 20° C., stirring is continued for 1 hour and then the 5,5-dimethylhydantoin which has precipitated is filtered off and washed with 10 ml of heptane. The filtrate is washed with an aqueous sodium thiosulphate solution (3 g/100 ml) and then with 3 times 100 ml of water. After drying over sodium sulphate, the heptane phase is concentrated to approximately 40 ml and then cooled to -10° C. for one hour and a half. The precipitate formed is filtered off and dried under partial vacuum at 20° C. to provide 9.05 g of the desired compound in the form of a beige powder, which represents a yield of 57% (M.p.: 53° C., purity by liquid phase chromatography: 92%). A second, less pure sample is obtained by concentrating the mother liquors (16%).
Reaction SMILES: C([NH:4][C:5]1([CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=O)C.[ClH:32]>>[ClH:32].[NH2:4][C:5]1([CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2
Reactant: CC(=O)NC1(CCCCc2ccccc2)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: Cl
Product: NC1(CCCCc2ccccc2)c2ccccc2-c2[nH]c(=O)c3nccn3c21

Procedure:
A suspension of 200 mg of (10 RS)-10-acetamido-10-(4-phenylbutyl)-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one in 15 ml of 6N hydrochloric acid is refluxed for 2 hours. The reaction medium is cooled and filtered on a sinter funnel. The solid obtained is crystallized from 5 ml of ethanol. 85 mg of (10RS)-10-amino-10-(4-phenylbutyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride are thus obtained [1H NMR spectrum: (300 MHz, (CD3)2SO-d6 ; δ in ppm): 0.65 (mt, 2H: CH2); 1.38 (mt, 2H: CH2); 2.35 (mt, 2H: hetero-CH2); from 2.50 to 2.80 (mt, 2H: ArCH2); 6.95 (d, J=7.5 Hz, 2H: aromatic ortho H of the phenyl); from 7.00 to 7.20 (mt, 3H: aromatic meta and para H of the phenyl); 7.52 and 7.58 (2 t, J=8 Hz, 1H each: H 7 and H 8); 7.72 and 8.68 (2 broad s, 1H each: H of the imidazole); 7.92 and 8.02.(2 broad d, J=8 Hz), 1H each: H 6 and H 9); 9.48 (mult., 3H: NH2+Cl-); 12.72 (broad s, 1H: NH 5)].
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([CH:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([C:20]([NH2:22])=O)[CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].O>C1COCC1>[NH2:22][CH2:20][CH:16]1[CH2:17][CH2:18][CH2:19][N:14]([CH:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:15]1
Reactant: NC(=O)C1CCCN(C(c2ccccc2)c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC1CCCN(C(c2ccccc2)c2ccccc2)C1

Procedure:
Step 2): To a suspension of LiAlH4 (10 g, 263 mmol) in THF (100 ml) was added dropwise a solution of 1-diphenylmethylpiperidin-3-carboxamide (32 g, 109 mmol) in THF (130 ml) for 40 mins under stirring and cooling in an ice-bath. After the addition was complete, the mixture was refluxed for 2 hours and then cooled. To the resulting mixture, 15% NaOH aqueous solution and H2O were added dropwise in order, and the insoluble materials were filtered off. The filtrate was dried over MgSO4 and evaporated. The residue was purified by column chromatography on silica gel to give 3-aminomethyl-1-diphenylmethylpiperidine as a colorless oil, 23 g (75.5%).
Reaction SMILES: Br/[C:2](=[CH:8]\[CH3:9])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:6]([O:5][C:3](=[O:4])/[CH:2]=[CH:8]/[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:7]
Reactant: C1CCNCC1
Reactant: C/C=C(\Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)/C=C/CN1CCCCC1
Yield: 79.6 %

Procedure:
A mixture of ethyl bromocrotonate (193 mg), piperidine (94 mg) and potassium carbonate (276 mg) in acetonitrile (10 ml) was stirred and heated at reflux for 3 hours. The reaction mixture was cooled and the solvent was removed in vacuo. The residue was partitioned between water (2×15 ml) and ethyl acetate (20 ml). The organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as an orange oil (157 mg). Tlc Silica. (100:8:1)Mixture of dichloromethane, ethanol and ammonia (S.G=0.88) Rf=0.55 Mass spec MH+ (found)=198 MH+ (calculated)=198.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[NH2-].[Na+].Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].N>O1CCCC1>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:4]1[CH2:3][CH:2]([CH3:1])[CH2:7][CH2:6][C:5]1=[O:8]
Reactant: CC1CCC(=O)CC1
Reactant: COc1ccccc1Cl
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1C1CC(C)CCC1=O

Procedure:
4-Methylcyclohexanone (224 g, 2 moles) was added dropwise rapidly to a cooled, stirred suspension of 170 g (4 moles) of sodium amide in 2 l of tetrahydrofuran under nitrogen. After the addition was complete, the ice bath was removed and the mixture was heated at reflux until the evolution of ammonia ceased (~3 hours). While still at reflux, 142.5 g (1 mole) of o-chloroanisole was added rapidly dropwise and the mixture was heated for an additional hour, until evolution of ammonia ceased.
Reaction SMILES: O=[C:2]1C[CH2:5][CH:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.CO[CH:16]([O:19][CH3:20])[O:17][CH3:18]>CC1C=CC(S(O)(=O)=O)=CC=1.O.C(Cl)Cl.CO>[CH3:20][O:19][C:16]1([O:17][CH3:18])[CH2:2][CH2:3][CH:4]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:5]1
Reactant: COC(OC)OC
Reactant: CC(C)(C)OC(=O)C1CCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COC1(OC)CCC(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of tert-butyl 3-oxocyclopentanecarboxylate (19.8 g, 107 mmol) in 1:1 DCM/methanol (150 mL) was added trimethylorthoformate (46.8 mL, 428 mmol), followed by TsOH.H2O (˜0.5 g). The reaction mixture was stirred at room temperature for 2 h. Then more TsOH.H2O (˜0.25 g) was added and the reaction mixture was stirred overnight. The reaction mixture was concentrated at room temperature and the resulting residue was dissolved in ether and washed with saturated NaHCO3 solution, then with brine. The ethereal layer was dried over anhydrous MgSO4, filtered, and concentrated. Purification by flash chromatography (silica, 15% ethyl acetate/hexane) gave 22.2 g (90%) of tert-butyl 3,3-dimethoxycyclopentanecarboxylate. 1H NMR (500 MHz, CDCl3): 3.21 (s, 3H), 3.20 (s, 3H), 2.80 (m, 1H), 2.10 to 1.80 (bm, 6H), 1.46 (s, 9H). 13C NMR (125 MHz, CDCl3): 174.9, 111.2, 80.3, 67.8, 49.2, 42.5, 37.4, 33.8, 28.3, 22.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11]C)[CH:6]=[O:7].CNC>>[OH:11][C:10]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C=O)cc1OC
Agent: CNC
Product: COc1cc(C=O)ccc1O
Temperature: 140 °C
Reaction time: 10 h
Yield: 66.7 %

Procedure:
A metal autoclave is charged with 14.0 g (84.0 mmol) of 3,4-dimethoxybenzaldehyde and 120 g (1.0 mol) of dimethylamine (40% solution in water). The autoclave is closed and the biphasic reaction mixture is stirred at 140° C. (autogenous pressure 14 bar) for 10 h. Excess dimethylamine and water are removed under reduced pressure, methyl tert-butyl ether is added and the mixture is acidified with 30% hydrochloric acid in water. After phase separation and removal of all volatile constituents of the organic phase, 8.5 g (56.0 mmol, 67% yield) of 4-hydroxy-3-methoxybenzaldehyde are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[C:9]=2[N:10]=1.[Cl:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:9]=[C:11]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:32]4[CH:31]=[CH:30][CH:29]=[C:28]([Cl:27])[C:33]=4[Cl:34])=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:13][C:14]=2[N:10]=1
Reactant: CN(C)CCN(C)c1nc2c(NC(=O)c3ccc(I)cc3)cccc2s1
Reactant: OB(O)c1cccc(Cl)c1Cl
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(-c4cccc(Cl)c4Cl)cc3)cc2s1

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-yl}-4-iodo-benzamide (0.15 g, 0.31 mmol) and 2,3-dichloro-phenyl boronic acid (0.072 g, 0.38 mmol) to afford 0.13 g (83%). LC/MS, Retention time=5.08 min; (m/z): calcd for C25H24Cl2N4OS: 499.5; found: 499.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15]O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:46].[Cl-].[NH4+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15][Br:46])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@H](CCCO)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: BrC(Br)(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C[C@H](CCCBr)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 12 h
Yield: 87.8 %

Procedure:
To a solution of 4-chloro-N-[5-fluoro-2-flurophenyl]-N-[(R)-1-methyl-4-hydroxybutyl]-benzenesulfonamide (317 mg, 0.813 mmol) in acetonitrile (4 mL) was added triphenylphosphine (425 mg, 1.62 mmol) and carbon tetrabromide (537 mg, 1.62 mmol) at 0° C. The resulting mixture was allowed to stir at 22° C. for 12 h followed by the addition of 25 mL of sat. ammonium chloride. The product was extracted with ether (2×25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:4 ethyl acetate:hexanes) of the concentrate afforded 323 mg of 4-chloro-N-[5-fluoro-2-flurophenyl]-N-[(R)-1-methyl-4-bromobutyl]benzenesulfonamide as a yellow oil in 86% yield.