Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3.CC(C)([O-])C.[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O.O>[CH2:26]([N:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: O=C1COc2cccc3nc4c(c(c23)N1)CCCC4
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2cccc3nc4c(c(c23)N1Cc1ccccc1)CCCC4
Reaction time: 0.08 h
Yield: 41 %

Procedure:
To a suspension of 1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.30 g) in dry dimethylformamide (50 ml) was added potassium tert-butoxide (2.1 g). To the solution was added benzyl bromide (2.22 ml), and stirring was continued for five mins. The reaction mixture was diluted with water (150 ml) and extracted with diethyl ether. The organic phase was washed with water, brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. Trituration of the residue with pentane followed by recrystallization from methanol gave 2.42 g (41%) of product, mp 166°-167.5° C.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]([NH2:41])=[O:40])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH:32]5[CH2:33][CH2:34][N:35]([CH2:38][C:39]([NH2:41])=[O:40])[CH2:36][CH2:37]5)=[CH:28][CH:27]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: NC(=O)CN1CCC(c2ccc(N)cc2)CC1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(C5CCN(CC(N)=O)CC5)cc4)nn23)c1

Procedure:
2-(4-{4-[7-(3-tert-Butylsulfamoyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-acetamide was prepared from N-tert-butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide and 2-[4-(4-amino-phenyl)-piperidin-1-yl]-acetamide in an analogous manner to Example 1052a. Product isolated as a red foam (68 mg, 70%). LCMS (m/e) 562 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.85 (s, 1H), 8.73 (s, 1H), 8.24 (d, 1H, J=8.0 Hz), 7.87 (d, 1H, J=7.9 Hz), 7.62-7.54 (m, 3H), 7.29 (d, 2H, J=8.4 Hz), 7.17 (bs, 1H), 7.07 (d, 1H, J=4.8 Hz), 6.98 (s, 1H), 6.85 (d, 1H, J=4.8 Hz), 5.65 (bs, 1H), 4.72 (s, 1H), 3.08-2.95 (m, 4H), 2.59-2.48 (m, 1H), 2.37-2.25 (m, 2H), 1.94-1.73 (m, 4H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:5]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[NH:26]1[CH:30]=[N:29][N:28]=[N:27]1>>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH:6]2[N:5]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:17])=[O:18])[CH:4]([CH2:3][CH2:2][N:26]3[CH:30]=[N:29][N:28]=[N:27]3)[CH2:8][CH2:7]2)=[CH:10][CH:11]=1
Reactant: c1nnn[nH]1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCl)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCn3cnnn3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=416.1 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(2-chloro-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-tetrazole.
Reaction SMILES: [Br-].[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[N:8]1[CH2:17][CH2:16][N+:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1.[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:4]1[CH:5]=[CH:6][CH:7]=[N:2][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:15][CH2:14][CH2:13][CH2:12][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[CH:19]2)[CH2:16][CH2:17]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: c1cnc(N2CC[N+]3(CCCC3)CC2)nc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc(N2CCN(CCCCn3cnc4ccccc43)CC2)nc1

Procedure:
A mixture of 450 g (1.50 moles) of 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4,5]decane bromide, 177 g (1.50 moles) of benzimidazole and 307 g (2.25 moles) of potassium carbonate in 2 l of dimethylformamide is heated to 140°-145° C. for 14 hours. The mixture is evaporated under vacuum, chloroform is added, the solution is washed with water, dried over sodium sulfate and evaporated under vacuum, and 457 g (91%) of 1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-benzimidazole, with a melting point of 85°-88° C., are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:16])[CH:9]([NH2:15])[CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.Cl.[CH2:18]([O:20][C:21]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:22]=1[C:23](=N)OCC)[CH3:19].ClC1C=CC(C2NC(C3C=CC(OC)=CC=3OCC)=NC2CC2CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:16][C:23]([C:22]3[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:21]=3[O:20][CH2:18][CH3:19])=[N:15][CH:9]2[CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[CH:6][CH:7]=1
Reactant: CC(C)CCC(N)C(N)c1ccc(Cl)cc1
Reactant: CCOC(=N)c1ccc(OC)cc1OCC
Agent: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Agent: Cl
Product: CCOc1cc(OC)ccc1C1=NC(CCC(C)C)C(c2ccc(Cl)cc2)N1

Procedure:
5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-(3-methyl-butyl)-4,5-dihydro-1H-imidazole was prepared from 1-(4-chloro-phenyl)-5-methyl-hexane-1,2-diamine and ethyl 2-ethoxy-4-methoxy-benzimidate hydrochloride in an analogous manner as described for the preparation of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 9). HR-MS (ES, m/z) observed 401.1994, calculated for C23H30N2O2Cl [(M+H)+]401.1991.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[CH2:8]Br.[C:18]([O-:21])(=[O:20])[CH3:19].[K+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][O:21][C:18](=[O:20])[CH3:19]
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(Br)c1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc(-c2ccccc2C#N)cc1Br
Temperature: 50 °C
Yield: 64.1 %

Procedure:
To a solution of 662 mg (1.89 mmol) of 3'-bromo-4'-bromomethyl-1,1'-biphenyl-2-nitrile (Step D) in 10 mL of dry dimethyl formamide was added 925 mg (9.43 mmol) of potassium acetate. The reaction mixture was heated at 50° C. for 2 hours then diluted with 100 mL of water. The mixture was extracted with ethyl acetate (3×100 mL). The organic extracts were combined, washed with water (100 mL), saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL). The solution was dried over magnesium sulfate, filtered and the solvent removed under vacuum to give an oil which was purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (75:25), to afford 400 mg (64%) of the product as a white solid. 1H NMR (200 MHz, CDCl3): δ 2.14 (s, 3H), 5.22 (s, 2H), 7.4-7.8 (m, 7H). EI-MS: calculated for C16H12BrNO2 329; found 329, 331 (M+, 7%); 270, 272 (M-Br, 100%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[CH:12]1([C:15](Cl)=[O:16])[CH2:14][CH2:13]1.O>CN(C)C(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:15]([CH:12]3[CH2:14][CH2:13]3)=[O:16])[N:10]=2)[N:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cn2nc(I)ccc2n1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution (10 mL) of 6-iodoimidazo[1,2-b]pyridazin-2-amine (1.0 g, 3.85 mmol) in N,N-dimethylacetamide was added cyclopropylcarbonyl chloride (0.38 mL, 4.23 mmol), and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/ethyl acetate (4/1) to give the title compound (1.01 g, 80%) as a dark brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[C:23]3=[N:24][S:25](=[O:29])(=[O:28])[CH2:26][CH2:27][N:22]3[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.C(N(CC)CC)C>CN(C=O)C.C(O[Cu]OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:11][C:12]1[CH:13]=[CH:14][C:15]([C@@H:18]2[C:23]3=[N:24][S:25](=[O:29])(=[O:28])[CH2:26][CH2:27][N:22]3[CH2:21][CH2:20][CH2:19]2)=[CH:16][CH:17]=1
Reactant: O=S1(=O)CCN2CCC[C@H](c3ccc(O)cc3)C2=N1
Reactant: OB(O)c1cccc(Cl)c1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)CCN2CCC[C@H](c3ccc(Oc4cccc(Cl)c4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
A mixture of 3-chlorophenylboronic acid (167 mg), (9R)-9-(4-hydroxyphenyl)-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (100 mg), diacetoxycopper (130 mg), triethylamine (0.248 mL), and powdered 4A MS (1.50 g) in DMF (10 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (32.0 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH3:17])[CH:13]([C:18]([OH:20])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:24])=O.CN(C=O)C>C(Cl)Cl>[Cl:24][C:18]([CH:13]1[CH:14]([CH3:17])[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)=[O:20]
Reactant: CC1CCN(C(=O)OCc2ccccc2)CC1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1CCN(C(=O)OCc2ccccc2)CC1C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
To a solution of 1-(benzyloxycarbonyl)-4-methylpiperidine-3-carboxylic acid (1.28 g, 4.62 mmol) in DCM (40 mL) was added oxalyl chloride (0.930 mL, 10.6 mmol) followed by the drop-wise addition of DMF (0.072 mL, 0.92 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to yield crude benzyl 3-(chlorocarbonyl)-4-methylpiperidine-1-carboxylate (1.4 g, 4.7 mmol) which was dissolved in a mixture of Et2O and MeCN (1:1, 16 mL) and added to a solution of trimethylsilyldiazomethane (2 M in Et2O, 9.47 mL, 18.5 mmol) in Et2O and MeCN (1:1, 16 mL) that was cooled to about 0° C. The resulting mixture was stirred at about 0° C. for about 4 h and quenched by a drop-wise addition of 48% aqueous HBr. The organic solvents were removed and the residue was purified by silica gel chromatography eluting with a gradient of 10-40% EtOAc in heptane. The product-containing fractions were concentrated under reduced pressure to give benzyl 3-(2-bromoacetyl)-4-methylpiperidine-1-carboxylate (0.78 g, 47%): LC/MS (Table 2, Method a) Rt=2.50 min; MS m/z: 356 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=1[NH2:17])(=O)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]1[CH:40]=[CH:39][C:28]([CH2:29][O:30][C:31]2[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=2)=[CH:27][CH:26]=1.C(OCC)(=O)C>O>[CH2:13]([O:12][C:10]([C:9]1[CH:15]=[CH:16][C:6]2[N:5]=[C:1]([CH2:2][CH3:3])[N:17]([CH2:35][C:34]3[CH:37]=[CH:38][C:31]([O:30][CH2:29][C:28]4[CH:39]=[CH:40][C:25]([F:24])=[CH:26][CH:27]=4)=[CH:32][CH:33]=3)[C:7]=2[CH:8]=1)=[O:11])[CH3:14]
Reactant: CCOC(=O)c1ccc(NC(=O)CC)c(N)c1
Reactant: Fc1ccc(COc2ccc(CBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2nc(CC)n(Cc3ccc(OCc4ccc(F)cc4)cc3)c2c1
Temperature: 75 °C
Reaction time: 16 h
Yield: 23.3 %

Procedure:
A mixture of 0.534 g of ethyl 4-propionylamino-3-aminobenzoate, 0.374 g of potassium carbonate, 0.800 g of 4-(4-fluorobenzyloxy)benzyl bromide, 5 ml of ethyl acetate and 3 ml of water was stirred at 75° C. for 16 hours. The organic layer was concentrated, and ethanol and 0.46 g of 36% hydrochloric acid were added to the residue. The mixture was stirred for 2 hours while being heat-refluxed. The reaction mixture was neutralized with potassium carbonate, and the solvent was then concentrated under reduced pressure. The residue was extracted with ethyl acetate and with water. The organic layer was concentrated under reduced pressure, and was purified through silica-gel column chromatography (eluent: a mixture of hexane and ethyl acetate at a ratio of 1:1) to give 0.228 g of 6-ethoxycarbonyl-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole (325).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[C:11]([Cl:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].ClC1C=C(O)C=CC=1C=O.C(CC(Br)(C)C([O-])=O)C.[F:38][C:39]([F:60])([F:59])[C:40]1[C:45]([C:46](O)=[O:47])=[CH:44][N:43]=[C:42]([C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[N:41]=1.C(OC(C1C(C(F)(F)F)=NC(C2C=CC(C(F)(F)F)=CC=2)=NC=1)=O)C>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:46]([C:45]2[C:40]([C:39]([F:60])([F:38])[F:59])=[N:41][C:42]([C:49]3[CH:50]=[CH:51][C:52]([C:55]([F:57])([F:58])[F:56])=[CH:53][CH:54]=3)=[N:43][CH:44]=2)=[O:47])=[C:11]([Cl:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)c(Cl)c1
Reactant: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C(F)(F)F
Agent: CCCC(C)(Br)C(=O)[O-]
Agent: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C(F)(F)F
Agent: O=Cc1ccc(O)cc1Cl
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C(F)(F)F)c(Cl)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-3-chloro-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 2-chloro-4-hydroxy-benzaldehyde by reaction with ethyl-bromoisobutyrate as described in example 52A] followed by oxim formation and reduction as described in examples 97A] and 97B]) was reacted with 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (prepared by saponification from 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester (example 107B]) in analogy to example 53B]) to give 2-[3-chloro-4-({[4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as amorphous light yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][S:24]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)(=[O:26])=[O:25])[CH2:19][CH2:18]1>>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:27]=1[S:24]([NH:23][CH:20]1[CH2:21][CH2:22][N:17]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:18][CH2:19]1)(=[O:26])=[O:25]
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: O=S(=O)(NC1CCNCC1)c1ccc2ccccc2c1
Agent: Cl
Product: O=C(C1CCN(c2ccncc2)CC1)N1CCC(NS(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 28 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with N-(piperidin-4-yl)naphthalene-2-sulphonamide hydrochloride salt to give 4-(2-naphthalenesulphonamido)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]-piperidine in 28% yield;
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([O:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:4]=1.CC1C2C(=CC=CC=2)C=CC=1OC1CCNCC1.Br[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([C:48]1[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=1)=[O:47].ClCCCC(C1C=CC(F)=CC=1)=O>>[F:21][C:2]([F:1])([F:20])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=3)=[O:47])[CH2:16][CH2:15]2)[CH:4]=1
Reactant: FC(F)(F)c1cc(OC2CCNCC2)cc2ccccc12
Reactant: COc1ccc(C(=O)CCCCCBr)cc1
Agent: Cc1c(OC2CCNCC2)ccc2ccccc12
Agent: O=C(CCCCl)c1ccc(F)cc1
Product: COc1ccc(C(=O)CCCCCN2CCC(Oc3cc(C(F)(F)F)c4ccccc4c3)CC2)cc1

Procedure:
When in the procedure of Example 18, 4-(4-trifluoromethyl-2-naphthalenyloxy)piperidine is substituted for 4-(1-methyl-2-naphthalenyloxy)piperidine and 6-bromo-1-(4-methoxyphenyl)-1-hexanone substituted for 4-chloro-1-(4-fluorophenyl)-1-butanone, 6-[4-(4-trifluoromethyl-2-naphthalenyloxy)-1-piperidyl]-1-(4-methoxyphenyl)-1-hexanone is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:27]([CH:24]4[CH2:26][CH2:25]4)(=[O:29])=[O:28])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C1CC1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine following General Procedure B-3 (500 mg), cyclopropanesulfonyl chloride (0.24 mL) and triethylamine (0.57 mL) in dichloromethane (5 mL) was stirred at room temperature. After stirring for 24 hours, standard work-up yielded 2-chloro-6-(4-cyclopropanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][NH:10][C:4]=2[CH:3]=1.[I:11]I.[OH-].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([I:11])=[N:9][NH:10][C:4]=2[CH:3]=1
Reactant: Clc1cc2[nH]ncc2cn1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1cc2[nH]nc(I)c2cn1
Temperature: 40 °C

Procedure:
A flask was charged with 6-chloro-1H-pyrazolo[4,3-c]pyridine (3.0 g, 19.54 mmol), iodine (13.11 g, 51.7 mmol), KOH (3.29 g, 58.6 mmol), and DMF (60 mL). The mixture was heated at 40° C. for 16 h and then additional iodine (7.8 g, 30.7 mmol) and KOH (1.6 g, 28.4 mmol) were added. The mixture was heated at 70° C. for 3 h then quenched with 1 N Na2S2O3 and extracted with EtOAc. The organic phase was washed with water, brine, and dried over Na2SO4. After evaporation of volatiles DCM was added. A solid precipitated and was collected by filtration to yield 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine, which was carried onto the next step without further purification. MS ESI calc'd. for C6H4ClIN3 [M+1]+ 280. found 280.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5](B(O)O)=[CH:6][CH:7]=1)[CH3:2].Br[C:12]1[S:16][C:15]([S:17]([N:20]2[CH:24]=[CH:23][CH:22]=[CH:21]2)(=[O:19])=[O:18])=[CH:14][CH:13]=1>>[CH2:1]([C:3]1[S:4][C:5]([C:12]2[S:16][C:15]([S:17]([N:20]3[CH:24]=[CH:23][CH:22]=[CH:21]3)(=[O:18])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1)[CH3:2]
Reactant: CCc1ccc(B(O)O)s1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Product: CCc1ccc(-c2ccc(S(=O)(=O)n3cccc3)s2)s1

Procedure:
N-[5-(5-ethyl-2-thienyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 32C from 2-ethylthiophene-5-boronic acid (411 mg, 2.64 mmol) and N-(5-bromothiophene-2-sulfonyl)pyrrole (700 mg, 2.39 mmol). Purification by column chromatography using 2% ethyl acetate/hexanes gave 6.30 mg of the pure product as a dark brown solid (90% yield).
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][N:13]1[CH2:20][CH2:19][C:16]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:17]#[N:18])[CH2:15][CH2:14]1.S(=O)(=O)(O)[OH:29].[OH-].[NH4+]>>[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][C:16]([NH:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:17]([NH2:18])=[O:29])[CH2:19][CH2:20]1
Reactant: N#CC1(Nc2ccccc2)CCN(CC2CCc3ccccc3C2O)CC1
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)C1(Nc2ccccc2)CCN(CC2=Cc3ccccc3CC2)CC1
Temperature: 70 °C

Procedure:
A mixture of 1-[(1,2,3,4-tetrahydro-1-hydroxy-2-naphthalenyl)-methyl]-4-anilino isonipecotonitrile (5.0 g) and 90% sulfuric acid (60.0 g) is heated for 10 minutes at 70° C. The mixture is then stirred at room temperature for an additional hour. The reaction mixture is poured into ice-water, basified with ammonium hydroxide, and extracted with chloroform. Concentration of the dried chloroform solution followed by trituration with benzene yields the title compound.
Reaction SMILES: [H-].[Na+].C([N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])(=O)C.[CH:12](=O)[C:13]1[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[CH:17][CH:18]=1.Cl>O1CCCC1.O>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]=[C:8]1[CH2:9][CH2:10][NH:6][C:7]1=[O:11]
Reactant: CC(=O)N1CCCC1=O
Reactant: COc1ccccc1C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1C=C1CCNC1=O
Yield: 11.8 %

Procedure:
Sodium hydride (16 g) was suspended in tetrahydrofuran (100 ml) and a solution of N-acetylpyrrolidone (25 g) and o-anisaldehyde (26.8 g) in tetrahydrofuran (100 ml) was added dropwise under ice-cooling. After completion of the reaction, the reaction mixture was poured into water. The mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give oily 3-(2′-methoxybenzylidene)-2-pyrrolidone (4.7 g). The oil was dissolved in methylene chloride (60 ml). By demethylation using boron tribromide under ice-cooling, 3-(2′-hydroxybenzylidene)-2-pyrrolidone (4.0 g) was obtained as yellow crystals. To the crystals (1.5 g) were added dimethylformamide (50 ml) and potassium carbonate (2.2 g). (S)-Glycidyl nosylate (2.3 g) was added and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure and water was added. The mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate to give an oily compound (1.8 g). By the reaction of the oil (0.5 g) and 4-(5,6,7,8-tetrahydronaphthalen-2-yl)piperidine (0.5 g) in methanol in the same manner as in Example 307, the title compound (0.4 g) was obtained, melting point 157–159° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[CH2:11][C:10]3=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:18]([O-])([OH:20])=[O:19]>>[N+:18]([CH:11]1[C:10](=[O:17])[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)[C:12]1=[O:16])([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: O=C1CC(=O)c2cc(-c3ccccc3)ccc21
Product: O=C1c2ccc(-c3ccccc3)cc2C(=O)C1[N+](=O)[O-]

Procedure:
Nitration of 5-phenyl indane-1,3-dione with fuming nitric acid as described in Example 16 (c) gave 2-nitro-5-phenyl indane-1, 3-dione, m.p. (water, hydrochloric acid) 119° C. (Found: C, 65.54; H, 3.39; N, 4.93; C15H9NO4. 1/2 H2O requires: C, 65.21; H, 3.65; N, 5.07%).