Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[NH:16]1[CH2:22][C:20](=[O:21])[NH:19][C:17]1=[O:18].C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[N:15]1[CH:14]=[CH:13][N:12]2[C:7]([S:6][CH2:5][CH2:4][CH2:3][CH2:2][N:19]3[C:20](=[O:21])[CH2:22][NH:16][C:17]3=[O:18])=[CH:8][CH:9]=[CH:10][C:11]=12
Reactant: ClCCCCSc1cccc2nccn12
Reactant: O=C1CNC(=O)N1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CNC(=O)N1CCCCSc1cccc2nccn12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 2.41 g (10.0 mmol) of 5-(4-chlorobutylthio)imidazo[1,2-a]pyridine and 1.00 g (10.0 mmol) of hydantoin in 30 ml of N,N-dimethylformamide, 1.50 ml (10.0 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, followed by stirring at 80° C. for 16 hours. After the reaction mixture was cooled, water was added; the mixture was extracted with ethyl acetate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=20/1→10/1) to yield 1.27 g (41.7%, yellow solid) of the desired product.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[C:41]([NH:43][C:44]([CH3:47])([CH3:46])[CH3:45])[N:40]=[C:39]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)[CH:38]=2)[CH:34]=[N:35][CH:36]=1>COCCOC.C(Cl)Cl>[C:44]([NH:43][C:41]1[N:40]=[C:39]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=2)[CH:38]=[C:37]([C:33]2[CH:34]=[N:35][CH:36]=[C:31]([C:12]3[CH:11]=[CH:10][C:9]([C:7]([N:1]4[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]4)=[O:8])=[CH:14][CH:13]=3)[CH:32]=2)[CH:42]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCNCC3)cc2)OC1(C)C
Reactant: CC(C)(C)Nc1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(C)Nc1cc(-c2cncc(-c3ccc(C(=O)N4CCNCC4)cc3)c2)cc(-c2ccccn2)n1

Procedure:
To a solution of piperazin-1-yl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (1.2 eq, 0.25 mmol, 0.079 g) and 2M Na2CO3 (3 eq, 0.624 mmol, 0.3 ml) in dry DME (1.5 ml) are added (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-tert-butyl-amine (Ex. 2.48; step 1) (1 eq, 0.208 mmol, 80 mg) and PdCl2dppf (0.1 eq, 0.0208 mmol, 15 mg). The reaction mixture is heated using microwave radiation at 90° C. for 1 hour. The reaction mixture is dissolved in DCM and washed with water. The organic solvent is reduced in vacuo and the residue is purified by reverse phase column chromatography (Isolute™ C18, 0-40% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 493.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[C:20]([C:24]5[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=5C(=O)C)=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)[C:12]([F:34])=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1.C[C:36](C)(C)[C:37]([OH:39])=O.[CH3:42][NH:43][CH2:44][CH2:45]O.C([BH3-])#N>O1CCOCC1>[NH3:1].[N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[C:20]([C:24]5[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=5[CH:44]([N:43]([CH3:42])[CH2:36][CH2:37][OH:39])[CH3:45])=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)[C:12]([F:34])=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: CNCCO
Reactant: CC(C)(C)C(=O)O
Reactant: CC(=O)c1ccc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Agent: [BH3-]C#N
Solvent: C1COCCO1
Product: CC(c1ccc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12)N(C)CCO
Product: N
Temperature: 160 °C
Yield: 10 %
Yield: 36 %

Procedure:
Combine 1-(2-(2-(2-(2-(1H-1,2,3-triazol-1-yl)ethylamino)-5-fluoropyrimidin-4-yl)benzo[b]thiophen-7-yl)-4-fluorophenyl)ethanone (0.1 g, 0.21 mmol), 10% trimethylacetic acid in dioxane (2 mL), 2-(methylamino)ethanol (18.2 mg, 0.252 mmol) and silica-supported cyanoborohydride (0.276 g, 0.262 mmol). Heat the reaction mixture at 160° C. for 2 h in a microwave reactor. Add 2-(methylamino)ethanol (0.157 g, 2.1 mmol) and silica-supported cyanoborohydride (0.138 g, 0.131 mmol). Heat the reaction mixture at 160° C. for 4 h in a microwave reactor. Pour the crude reaction mixture onto a strong cation exchange (SCX) (10 g) column. Elute with 2 N methanolic ammonia (40 mL) and concentrate. Purify the residue by normal phase chromatography (0-100% B at 25 mL/minute for 25 minutes on a 12 g silica column, Solvent A: DCM, Solvent B: 10% 2 N methanolic ammonia in DCM) to give the title compound (41 mg, 36%). MS (ES) m/z 536 [M+1]+.
Reaction SMILES: [CH:1]1[C:6]2[S:7][CH2:8][CH2:9][CH2:10][O:11][C:5]=2[C:4]([C:12]([OH:14])=O)=[CH:3][CH:2]=1.C1C=CC2N(O)N=[N:21]C=2C=1.CCN=C=NCCCN(C)C.Cl.N>CN(C=O)C.C(OCC)(=O)C>[CH:1]1[C:6]2[S:7][CH2:8][CH2:9][CH2:10][O:11][C:5]=2[C:4]([C:12]([NH2:21])=[O:14])=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2c1OCCCS2
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1OCCCS2
Reaction time: 48 h
Yield: 64 %

Procedure:
To 7,8-dihydro-6H-5-oxa-9-thia-benzocycloheptene-4-carboxylic acid (16.5g, 78.4 mmol) in 100 mL DMF was added in succession solid HOBT (21.3g, 157.3 mmol), solid EDC hydrochloride (30.1 g, 157.0 mmol), and 25% aqueous ammonia (18 mL, 128.4 mmol). After stirring for 48 h, the reaction mixture was diluted with 200 mL ethyl acetate and washed with water, 1N HCl, saturated NaHCO3, saturated NH4Cl, and brine. Drying over Na2SO4 and concentration yielded the amide as a tan solid (10.5 g, 64%).
Reaction SMILES: [Na].[CH3:2][NH:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[NH:6][CH:7]=[N:8]2.[C:13]1([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27]Cl)[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(C)C>[CH3:2][NH:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH2:27][CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][N:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][CH2:21]1
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Reactant: CNc1ncnc2nc[nH]c12
Agent: [Na]
Solvent: CC(C)O
Product: CNc1ncnc2c1ncn2CCCN1CCN(c2ccccc2)CC1
Yield: 45.1 %

Procedure:
1.38 g (0.06 mole) of sodium are dissolved in 120 ml of isopropanol. 8.9 g (0.06 mole) of N6 -methyl-adenine are added to this solution, which is then heated under reflux for 10 minutes, cooled and 15.8 g (0.066 mole) of 3-(4-phenyl-piperazino)-propyl chloride in 30 ml of isopropanol are added thereto. This reaction mixture is heated under reflux for 6 hours. Thereafter, it is cooled, suction filtered and sodium chloride washed out from the residue with water. After washing with water and drying, the product is recrystallized from isopropanol. There are obtained 9.5 g (45% of theory) of N6 -methyl-9-[3-(4-phenyl-piperazino)-propyl]-adenine, which has a melting point of 162°-163° C.
Reaction SMILES: CC[N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C.[Br:10][C:11]1[C:12](Cl)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]>CC#N.CCOCC>[Br:10][C:11]1[C:12]([N:3]2[CH2:4][CH2:6][C:13]([C:14]#[N:15])([CH3:12])[CH2:9][CH2:7]2)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Solvent: CC#N
Solvent: CCOCC
Product: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(C)(C#N)CC2)c1Br
Temperature: 80 °C
Reaction time: 72 h
Yield: 76.1 %

Procedure:
To a solution of 4-methylpiperidine-4-carbonitrile, HCl (1.0 g, 6.22 mmol) and DIEA (4.4 mL, 24.9 mmol) in anhydrous CH3CN (30 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (2.1 g, 6.22 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 72 h; cooled, diluted with ether, washed with water, brine, and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient eluted (5-35% EtOAc/hexanes) using an Isolera chromatography station to give isopropyl 2-(5-bromo-4-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate 1.0 g (38%). 1H NMR (500 MHz, DMSO-d6) δ 5.08-5.03 (m, 1H), 3.54-3.40 (m, 4H), 2.61 (s, 3H), 2.30 (s, 3H), 1.92 (d, J=12.4 Hz, 2H), (2H missing), 1.35 (s, 3H), 1.28 (d, J=5.9 Hz, 6H). UPLC (M+H)=424.3.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:9]=1)=[O:4].[OH-].[Na+].CO>C1COCC1.O>[Cl:25][C:23]1[CH:24]=[C:19]([C:13]2([C:15]([F:18])([F:16])[F:17])[O:12][N:11]=[C:10]([N:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[N:7]3)[CH2:14]2)[CH:20]=[C:21]([Cl:26])[CH:22]=1
Reactant: COC(=O)c1cnn(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnn(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
To a solution of methyl ester of example 19.1 (513 mg) in 12.5 ml THF:water (4:1) was added sodium hydroxide (75 mg). The reaction mixture was stirred at room temperature for 3 hours before adding 2 ml of methanol. The reaction was stirred overnight before evaporation of the solvent in vacuo. The aqueous layer was extracted with ethyl acetate before being acidified. It was then extracted several times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford the title acid (452 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz): 8.55 (s, 1H), 8.05 (s, 1H), 7.50 (m, 2H), 7.45 (m, 1H), 4.35 (d, 1H), 4.00 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12]1([CH2:18][CH2:19][CH2:20][Mg]Br)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[Cl-].[NH4+]>C(OCC)C>[CH:12]1([CH2:18][CH2:19][CH2:20][CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Br[Mg]CCCC1CCCCC1
Reactant: O=CCOCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC(CCCC1CCCCC1)COCc1ccccc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A solution of 1.01 g (6.73 mmol) of 2-benzyloxyacetaldehyde in 6 ml of diethyl ether was added dropwise over a period of 3 minutes to 14 ml (8.6 mmol) of a 0.6M diethyl ether solution of 3-cyclohexylpropylmagnesium bromide, whilst ice-cooling, and the resulting mixture was stirred for 30 minutes at the same temperature and then for 10 minutes at room temperature. In order to stop the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction mixture. The reaction mixture was then diluted with diethyl ether, and the diluted mixture was washed with water and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 150 g of silica gel, using a 1:3 by volume mixture of ethyl acetate and hexane as the eluent, to give 1.27 g (yield 68%) of the title alcohol derivative as an oil.
Reaction SMILES: [CH2:1]([C@@H:8]([NH:25][CH3:26])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:34]1([N:40]=[C:41]=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[CH2:1]([C@@H:8]([N:25]([CH3:26])[C:41]([NH:40][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:42])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NC1CCCCC1
Reactant: CN[C@H](Cc1ccccc1)CN1CCC(c2cc(F)ccc2OC)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)cc1C1CCN(C[C@@H](Cc2ccccc2)N(C)C(=O)NC2CCCCC2)CC1
Reaction time: 8 h
Yield: 100.7 %

Procedure:
Under a N2 atmosphere, a solution of {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-ethyl}-methyl-amine (0.12 g, 0.33 mmole, described as intermediate 7 above) and triethylamine (0.10 mL, 0.74 mmole) in dichloromethane (10 mL) was cooled to 0° C. Cyclohexyl isocyanate (0.050 rmL, 0.35 mmole) was added dropwise and the resulting mixture was stirred at 0° C. to room temperature (ice melt) overnight. The solvent was evaporated and the residue dissolved in EtOAc (25 mL) and water (25 mL). The layers were separated and the organic layer washed with water (25 mL) and brine. The combined organic washings were extracted three times with EtOAc (25 mL), then dried over Na2SO4, filtered and concentrated. Flash chromatography (elution with 7:3 EtOAc-hexane) to give 0.16 g (100% yield) of 1-{(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-ethyl}-3-cyclohexyl-1-methyl-urea. An ethanolic solution of the product was heated to gentle reflux and 1 equivalent of fumaric acid in hot ethyl alcohol solution was added to afford the fumarate salt of the titled compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH2:28][CH3:29])[C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH2:28][CH3:29])[C:25]([NH:9][CH2:8][C:7]3[CH:10]=[CH:11][C:4]([S:3][C:2]([F:12])([F:1])[F:13])=[CH:5][CH:6]=3)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CCC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1ccc(SC(F)(F)F)cc1
Agent: O=C(O)Cc1cccc2cnccc12
Product: CCC(C(=O)NCc1ccc(SC(F)(F)F)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-[(trifluoromethyl)thio]benzylamine and 2-(5-isoquinolinyl)butanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 405 (M+H)+; MS (ESI−) m/z 403 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 0.91 (t, J 7.5, 3H), 1.81 (m, 1H), 2.21 (m, 1H), 3.39 (m, 1H), 4.34 (m, 2H), 7.31 (m, 2H), 7.58 (m, 2H), 7.62 (d, J 7.8, 1H), 8.00 (m, 2H), 8.22 (d, J 7.1, 1H), 8.45 (m, 1H), 8.77 (m, 1H), 8.82 (m, 1H), 9.06 (t, J 6.8, 1H), 9.87 (s, 1H), 10.30 (br s, 1H); Anal. Calcd for C21H19F3N2OS+0.65 HCl: C, 58.91; H, 4.63; N, 6.54. Found: C, 59.24; H, 4.30; N, 6.60.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7]([OH:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>>[Cl:11][S:12]([C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[C:2]([CH:3]=1)[C:7]([OH:9])=[O:8])(=[O:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccccc1C(=O)O
Product: Cc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Temperature: 100 °C
Yield: 78 %

Procedure:
A mixture of o-toluic acid (15 g, 0.11 mol) and chlorosulfonic acid (30 ml) was heated at 100° C. under nitrogen for 2.5 h. The reaction mixture was then poured onto ice (500 ml) and the resulting precipitate was filtered, yielding the title compound as an off-white solid (20 g, 78% yield). MP 151–155° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=O.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][N:6]=2)[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc2ncccc2[nH]1
Product: Clc1ccc2ncccc2n1
Temperature: 100 °C

Procedure:
A 250 mL round bottomed flask charged with 1,5-naphthyridin-2(1H)-one (2.98 g, 20.37 mmol) and phosphorus oxychloride (40 ml, 437 mmol) was heated at 100° C. for 3 h. The reaction was cooled to room temperature and excess POCl3 was removed in vacuo. The residue was poured onto ice and neutralized with NaHCO3. The mixture was extracted with DCM (4×) and the combined organic layers were evaporated onto silica gel and purified by flash chromatography (ISCO (80 gram)) eluting with EtOAc:DCM (0:1→1:4) to give 1.08 g (32%, 2 steps) of a light-yellow amorphous solid. ESI-MS 164.9, 166.9 [M+1].
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:14]2[C:6](=[CH:7][C:8]3[CH:9]=[CH:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([CH3:16])([CH3:15])[CH2:4][CH2:3]1.[C:18]([C:22]1[CH:23]=[C:24](Br)[CH:25]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:27]=1)([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.CN(C)C=O>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:18]([C:22]1[CH:23]=[C:24]([C:10]2[CH2:11][C:12]3[CH:13]=[C:14]4[C:2]([CH3:17])([CH3:1])[CH2:3][CH2:4][C:5]([CH3:16])([CH3:15])[C:6]4=[CH:7][C:8]=3[CH:9]=2)[CH:25]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:27]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)C=CC3
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)c1cc(C2=Cc3cc4c(cc3C2)C(C)(C)CCC4(C)C)cc(C(C)(C)C)c1
Temperature: 60 °C

Procedure:
A 100 mL round bottom flask fit with a magnetic stirrer was charged with 5,5,8,8-tetramethyl-5,6,7,8-tetrahydrobenz(f)indene (4.0 g, 0.018 mol), 3,5-di-t-butyl-bromobenzene (7.0 g, 0.026 mol), tri-o-toylphosphine (2.46 g, 0.0081 mol), triethylamine (4.3 mL, 0.31 mol), and dimethylformamide (60 mL, anhydrous, Aldrich). The solution was degassed, charged with palladium(II) acetate (00876 g, 0.0039 mol) and heated to 60° C. for 93 hours. At that point, after degassing ng again, additional palladium(II) acetate (0.876 g, 0.0039 mol) was added and heated to 60° C. for a total of 161 hours. The reaction mixture was dissolved in 200 mL diethyl ether, washed with 5% HCl (3×100 mL), sodium bicarbonate solution (3×100 mL), water (3×100 mL), and dried over anhydrous magnesium sulfate. The resulting crude oil weighed 11.0 g after rotary evaporation. This material was purified by column chromatography with silica/hexane followed by recrystallization from pentane to yield a fraction (0.8 g) enriched in the desired product. The mother liquid was resubmitted to the coupling conditions. A 50 mL round bottom flask was charged with the mother liquor (7.7 g), tri-o-toylphosphine (2.46 g, 0.0081 mol), triethylamine (4.3 mL, 0.31 mol), and dimethylformamide (35 mL, anhydrous, Aldrich). The solution was degassed, charged with palladium(II) acetate (0.876 g, 0.0039 mol) and heated to 60° C. During heating, periodically more reagents were added such that the totals charged were: tri-o-toylphosphine (3.46 g, 0.011 mol), 1,2-bis(diphenylphosphino)ethane (2.05 g, 0.0051 mol) triethylamine (5.3 mL, 0.38 mol), and dimethylformamide (35 mL, anhydrous, Aldrich), and palladium(II) acetate (3.27 g, 0.0145 mol). The reaction was cooled to room temperature, and worked up as above to yield 11.0 g of crude product. The paste was purified by column chromatography on silica/hexane three times, and the combined most enriched fractions gave 2.3 g which was then purified by preparative HPLC to yield 1.7 g of a semisolid paste. The paste was repeatedly recrystallized from methanol/acetone to yield the pure 2-(3,5-di-t-butylphenyl)-5,5,8,8 tetramethyl-5,6,7,8-tetrahydrobenz(f)indene (0.92 g). 1HNMR (CD2Cl2, 500 MHz) δ7.54 (d, J=1.5 Hz, 2H); 7.48 (s, 1H); 7.42 (s, 1H); 7.39 (s, 1H); 7.24 (s, 1H); 3.82 (s, 2H); 1.77 (s, 4H); 1.43 (s, 18H); 1.38 (s, 12H).
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].C[N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23]([O:25][CH3:26])=[O:24].Cl.[CH2:28](Cl)Cl>>[C:1]([C:21]1[NH:17][C:18]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:19]([CH3:28])[CH:20]=1)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: COC(=O)Cc1cccn1C
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)Cc1[nH]c(C(=O)c2ccc(OC)cc2)cc1C
Reaction time: 0.42 h

Procedure:
A solution of 17.0 g. (0.1 mole) of ρ-anisoyl chloride and 13.3 g. (0.1 mole) of aluminum chloride in 200 ml. of methylene chloride is added over 5 minutes to a solution of methyl 1-methylpyrrole-2-acetate in 100 ml. of methylene chloride at ice bath temperature. The mixture is stirred for 25 minutes and poured into ice acidified with dilute hydrochloric acid. The organic layer is separated, and the aqueous layer is washed with methylene chloride. The combined organic solutions are washed successively with dimethylaminopropylamine solution, dilute hydrochloric acid and brine, and then dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo to give a dark oily residue which is crystallized from 40 ml. of cold methanol, and recrystallized from methanol to give white crystalline methyl 5-(ρ-anisoyl)-methylpyrrole-2-acetate, M.P. 104°-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:22]=1.CN1CC[O:27][CH2:26][CH2:25]1.[CH:30]1[CH:31]=[CH:32][C:33]2N(O)N=[N:36][C:34]=2C=1.C(Cl)Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([N:16]3[CH2:17][CH2:18][N:19]([C:26](=[O:27])[CH2:25][C:32]4[CH:31]=[CH:30][N:36]=[CH:34][CH:33]=4)[CH2:20][CH2:21]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:22]=1
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2N1CCNCC1
Reactant: CN1CCOCC1
Reactant: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1ccncc1)N1CCN(C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a mixture of 8.5 g (27.2 m mole) of 8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1 ,2-b]pyridine (Preparative Example 7) in 256 mL of anhydrous DMF at room temperature and under an argon atmosphere was added 2.98 g (27.2 m mole of 4-methylmorpholine, 7.81 g (27.2 m mole) of DEC, 3.68 g (27.2 m mole) of HOBT, and 3.72 g (27.2 m mole) of 4-pynidylacetic acid. The mixture was stirred at room temperature for 22 hours. The mixture was poured into 3300 mL of CH2Cl2 and washed with 500 mL of water. The aqueous layer was extracted with 500 mL of CH2Cl2. The combined organic portions were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a solution of 1.5% (10% NH4OH in MeOH) in CH2Cl2. The product was obtained as a white amorphous solid, M.S. (Mass Spec) M+=433.
Reaction SMILES: [CH2:1]([C:5]([CH2:12][CH3:13])([CH2:8][CH2:9][C:10]#[N:11])[CH:6]=O)[CH2:2][CH2:3][CH3:4].[NH3:14]>[H][H]>[CH2:1]([C:5]([CH2:12][CH3:13])([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:6][NH2:14])[CH2:2][CH2:3][CH3:4]
Reactant: N
Reactant: CCCCC(C=O)(CC)CCC#N
Reactant: [H][H]
Product: CCCCC(CC)(CN)CCCN
Yield: 87.3 %

Procedure:
80.0 g per hour of 2-butyl-2-ethyl-4-cyanobutanal (purity 99.3%, 0.44 mol) and 200 g (330 ml, 11.76 mol) per hour of liquid ammonia were pumped from bottom to top at 250 bar and 80° C. through a tubular reactor (diameter 16 mm, fill level 20 cm, oil-heated twin jacket) upstream of the hydrogenation reactor and filled with 25.4 g (40 ml) of TiO2 (anatase) in the form of 1.5 mm pellets. 100 l(S.T.P.)/h of hydrogen were then fed in, and the product stream from the upstream imination reactor was passed through the hydrogenation reactor from bottom to top at 250 bar and 110° C. The product stream was decompressed to atmospheric pressure and the ammonia was removed by distillation. According to gas-chromatographic analysis, the hydrogenation product stream contained 89.2% of 2-butyl-2-ethylpentane-1,5-diamine and 4.3% of 3-butyl-3-ethylpiperidine. The product from 80.5 hours was separated by fractional distillation on a 30 cm packed column (3 mm glass rings), giving 5738 g of 2-butyl-2-ethylpentane-1,5-diamine, corresponding to a yield of 87.3% of theory.