Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[C:17]2[O:16][CH2:15][CH2:14][N:13]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:12]=2[CH:11]=[C:10]([CH3:28])[CH:9]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([N:13]2[C:12]3[CH:11]=[C:10]([CH3:28])[CH:9]=[C:8]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[C:17]=3[O:16][CH2:15][CH2:14]2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: C1CNCCN1
Reactant: Cc1cc(Br)c2c(c1)N(S(=O)(=O)c1ccc(Cl)cc1)CCO2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCNCC2)c2c(c1)N(S(=O)(=O)c1ccc(Cl)cc1)CCO2
Temperature: 95 °C
Reaction time: 18 h
Yield: 79.9 %

Procedure:
A three neck flask was charged with tris(dibenzylideneacetone)dipalladium(0) (9.1 mg, 0.001 mmol, 2 mol % Pd), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (15.5 mg, 0.025 mmol, 5 mol %), and sodium-tert-butoxide (67 mg, 0.7 mmol) and flushed with nitrogen. A solution of 8-bromo-4-(4-chloro-benzenesulfonyl)-6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine (201 mg, 0.5 mmol) and piperazine (129 mg, 1.5 mmol) in toluene (5 mL) was added. The mixture was heated to 95° C. and stirred for 18 hours. The mixture was cooled to room temperature, taken up in ethyl acetate and filtered. The organic phase was washed with water (2×20 mL) and extracted into 10% aqueous HCl (2×20 mL). The combined aqueous extracts were basified with solid potassium carbonate and extracted into ethyl acetate (2×20 mL). The combined organic extract was dried (K2CO3), filtered and concentrated to give the title compound as an oil (163 mg, 79.6%). The hydrochloride salt was prepared from ethanol-hydrogen chloride. MS: MH+=408. M.p. 147.9-152.9° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1.N>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: c1ccncc1
Solvent: ClCCl
Product: Clc1ncnc2c1c(I)cn2-c1ccccc1
Temperature: 25 °C
Reaction time: 288 h

Procedure:
A mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (prepared according to: L. B. Townsend et al., J. Med. Chem. 1990, 33 (7), 1984-92) (280 mg, 1.00 mmol), phenylboronic acid (244 mg, 2.00 mmol), pyridine (165 μL, 161 mg, 2.04 mmol), and Cu(OAc)2 (272 mg, 1.50 mmol) in CH2Cl2 (5 mL) was stirred under air at ambient temperature for 12 d. Aqueous ammonia (1 M) and CH2Cl2 were added, the solids were filtered off, the layers of the filtrate were separated, the aqueous layer was extracted with CH2Cl2 (2×30 mL), the combined CH2Cl2 layers were washed with 1 M aqueous ammonia (2×), 2 M NaOH (2×), and brine and dried over MgSO4. The crude material was adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with CH2Cl2], yielding the title compound as off-white solid. 1H NMR (CDCl3, 400 MHz): δ=7.43-7.48 (m, 1H), 7.54-7.60 (m, 2H), 7.61-7.65 (m, 2H), 7.69 (s, 1H), 8.68 (s, 1H). MS (ES+): m/z 355.9/357.9 (100/35) [MH+]. HPLC: tR=3.8 min (OpenLynx, polar—5 min).
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)(=O)C.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[C:26]1(=[O:35])[C:29]2([CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH2:28][O:27]1>CO>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][S:4][CH2:28][C:29]2([C:26]([OH:27])=[O:35])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:10][CH:11]=1
Reactant: O=C1OCC12CCOCC2
Reactant: CC(=O)SCCCOc1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CO
Product: O=C(O)C1(CSCCCOc2ccc(Cl)cc2)CCOCC1
Reaction time: 2 h
Yield: 10.8 %

Procedure:
A solution of Intermediate 3 (0.80 g) in methanol was treated with a solution of sodium hexamethyldisilazide (1 M in THF, 3.3 ml) at 0° C. and the resulting mixture was stirred for 2 h, then a solution of Intermediate 1 (460 mg) in methanol was added. The mixture was stirred for 18 h, then evaporated and the residue dissolved in water and washed with diethyl ether. The aqueous phase was acidified with citric acid and extracted with dichloromethane; the organic layer was then washed with brine, dried over MgSO4 and evaporated to give the title compound (0.12 g) as a colourless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][CH:24]=1)[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19](O)=[O:20].Cl>C1COCC1.O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][CH:24]=1)[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][OH:20]
Reactant: COc1cccc(CC2CCCCC2C(=O)O)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(CC2CCCCC2CO)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
Under N2 gas atmosphere, to a stirred mixture of lithium aluminum hydride (0.703 g) in THF (9 mL) was added 2-(3-methoxybenzyl)cyclohexanecarboxylic acid (2.3 g) in THF (9 mL) dropwise at 0° C. The reaction mixture was stirred at 0° C. for an hour, at ambient temperature for an hour, at 60° C. for 4 hours. The reaction mixture was cooled to 0° C. and was added mixed solution (1M HCl aqueous solution:THF=10:90) dropwise. The resulting mixture was diluted with water and was extracted with diethylether two times. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The mixture was purified by thin-layer chromatography (n-hexane:EtOAc=5:1) to give [2-(3-methoxybenzyl)cyclohexyl]methanol (1.74 g) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH2:11])[C:5]2=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[N:3]=1.[S:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1.C(=O)([O-])[O-].[K+].[K+].COCCOC.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[O:18]([C:15]1[CH:16]=[CH:17][C:12]([C:4]2[N:3]=[C:2]([C:27]3[CH:28]=[CH:29][S:25][CH:26]=3)[N:6]3[CH:7]=[CH:8][N:9]=[C:10]([NH2:11])[C:5]=23)=[CH:13][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1nccn2c(Br)nc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nccn2c(-c3ccsc3)nc(-c3ccc(Oc4ccccc4)cc3)c12

Procedure:
A mixture of 3-bromo-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine (20.0 mg, 0.0525 mmol), 3-thiophenylboronic acid (7.38 mg, 0.0577 mmol), Pd(PPh3)4 (10 mg, 0.01 mmol), potassium carbonate (21.8 mg, 0.157 mmol) and DME/Water (5:1) was microwaved at 300 watt, 100° C. for 30 min. The solution was transferred to a 20 mL vial, and 1 mL of DMF was added. The solution was concentrated in vacuo until only DMF remained. The mixture was passed through a syringe filter pad, and prepared for Gilson HPLC separation. The fractions containing the pure product were collected and concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=6.96 (d, J=5.3 Hz, 1H), 7.07-7.12 (m, 2H), 7.14-7.22 (m, 3H), 7.38-7.43 (m, 2H), 7.55-7.67 (m, 5H), 7.86 (dd, J=3.0, 1.3 Hz, 1H). MS (ES+): m/z 384.94 (100) [MH+]. HPLC: tR=2.58 min (polar—5 min).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2)[CH3:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:51]1[C:52]([C:60]2[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=2)=[CH:53][N:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=12>CN(C=O)C>[N:51]1[C:52]([C:60]2[CH:61]=[C:62]([NH:66][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][CH2:10][CH3:11])=[O:26])[CH:63]=[CH:64][CH:65]=2)=[CH:53][N:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: CCOc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cccc2cc(C(=O)Nc3cccc(-c4cn5ccccc5n4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 41.9 %

Procedure:
DIEA (40.9 μL, 0.23 mmol) was added to 8-ethoxy-3-carboxy-coumarin (50.0 mg, 0.21 mmol) and HATU (89.29 mg, 0.23 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (44.7 mg, 0.21 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 37.4 mg of product in 42% yield: LCMS (ESI) m/z 426 (MH+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([I:11])[CH:5]=1.[NH2:13][NH2:14]>>[I:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH3:10])[C:3]([NH:13][NH2:14])=[O:2]
Reactant: COC(=O)c1ccc(C)c(I)c1
Reactant: NN
Product: Cc1ccc(C(=O)NN)cc1I

Procedure:
3-Iodo-4-methyl benzoic acid methyl ester was treated with hydrazine to form 3-Iodo-4-methyl benzoic acid hydrazide. 2-(3-Iodo-4-methyl-phenyl)-[1,3,4]oxadiazole was prepared from 3-iodo-4-methyl benzoic acid hydrazide according to a method analogous to that described in J. of Medicinal Chemistry (2001), 44(8):1268-85, the entire teachings of which are incorporated herein by reference. Compounds 46, 68, 69, 70, and 71 were prepared via an amide coupling reaction analogous to that described in step A of the synthesis of Compound 1, followed by a Suzuki coupling reaction analogous to that described in step B of the synthesis of Compound 1. The amide coupling reaction and Suzuki coupling reaction are shown for Compound 69 in Scheme XX below:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:11][CH3:12])=[CH:5][C:6]([CH2:9][OH:10])=[N:7][CH:8]=1)[CH3:2].C(Cl)(Cl)Cl>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3]1[C:4]([O:11][CH3:12])=[CH:5][C:6]([CH:9]=[O:10])=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(CO)cc1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCc1cnc(C=O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.5 %

Procedure:
To a solution of 49 mg of (5-ethyl-4-methoxypyridin-2-yl)methanol in 1 mL of dichloromethane, 0.13 g of manganese dioxide was added. The mixture was stirred at room temperature for 1 hour 30 minutes, 0.13 g of manganese dioxide was then added thereto, and the mixture was stirred for 1 hour 30 minutes. Chloroform was added to the reaction mixture, the insoluble substance was filtered off, and the solvent was distilled off under reduced pressure to obtain 54 mg of 5-ethyl-4-methoxypyridine-2-carbaldehyde as a brown oily substance.
Reaction SMILES: N=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[NH:11])[NH:3]1.[S:12]=[C:13]1[NH:17][C:16](=[S:18])[CH2:15][S:14]1>CO>[NH:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[C:15]2[S:14][C:13](=[S:12])[NH:17][C:16]2=[S:18])[NH:3]1
Reactant: N=C1NC(=N)c2ccccc21
Reactant: S=C1CSC(=S)N1
Solvent: CO
Product: N=C1NC(=C2SC(=S)NC2=S)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 7.2 parts of 1,3-diiminoisoindoline in 100 parts of methanol was added to a solution of 7.2 parts of 2,4-dithioxo-thiazolidine in 75 parts of methanol under an atmosphere of nitrogen. The mixture was stirred at room temperature for 24 hours and the solid which separated was collected by filtration, washed with a small volume of fresh methanol and dried in vacuo at 50° C. to obtain 1-imino-3-(2,4-dithioxo-5-thiazolidinylidene)isoindoline as a red-orange crystalline solid which sintered at 268°-270° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([CH2:12][C:13]([O:15][C@H:16]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]4[CH2:41][CH2:40]4)[CH:28]=3)[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N+:21]([O-:25])=[CH:20][C:19]=3[Cl:26])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl.N1C=CC=CC=1>[Cl:24][C:23]1[CH:22]=[N+:21]([O-:25])[CH:20]=[C:19]([Cl:26])[C:18]=1[CH2:17][C@@H:16]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:35])[F:36])=[C:29]([O:37][CH2:38][CH:39]2[CH2:40][CH2:41]2)[CH:28]=1)[O:15][C:13](=[O:14])[CH2:12][N:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([NH:1][S:43]([CH3:42])(=[O:45])=[O:44])=[CH:3][CH:4]=2)[C:8]1=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
(S)-4-(2-(2-(6-amino-1-oxoisoindolin-2-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (50 mg, 0.08 mmol) was dissolved in CH2Cl2 (2 ml) and pyridine (50 μl), then methanesulfonyl chloride was added (11 mg, 0.1 mmol) at 0° C. The mixture was stirred at RT for 2 hours, then diluted with CH2Cl2 (20 ml) and quenched with HCl 1N aqueous solution (30 ml). The two phases were separated, and the organic phase washed with HCl 1N aqueous solution (2×20 ml), dried over Na2SO4 and evaporated under vacuum. The crude was purified by preparative HPLC (Method 2) to yield 41 mg of the title compound. (Yield 75%). 1H NMR (400 MHz, acetone) δ ppm 8.71-8.92 (m, 1H), 8.22 (s, 2H), 7.73 (m, 1H), 7.59 (m, 2H), 7.15-7.30 (m, 2H), 7.05 (dd, J=8.38, 1.76 Hz, 1H), 6.93 (t, 1H, CHF2), 6.15 (dd, J=9.70, 4.85 Hz, 1H), 4.49 (s, 2H), 4.44 (d, J=3.53 Hz, 2H), 3.98 (d, J=7.06 Hz, 2H), 3.55 (dd, J=14.11, 9.26 Hz, 1H), 3.32 (dd, J=14.11, 4.85 Hz, 1H), 3.05 (s, 3H), 1.29 (m, 1H), 0.55-0.69 (m, 2H), 0.27-0.47 (m, 2H); MS/ESI+ 686.51 [MH]+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH:9]([Si:12]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[N:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1)([CH3:11])[CH3:10].N1C=CC=CC=1.CCCCCC>C1COCC1>[Br:8][C:15]1[CH:16]=[CH:17][N:13]([Si:12]([CH:9]([CH3:11])[CH3:10])([CH:18]([CH3:20])[CH3:19])[CH:21]([CH3:23])[CH3:22])[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(Br)c1
Reaction time: 1.5 h
Yield: 89.7 %

Procedure:
NBS (N-bromosuccinimide; 0.8 g, 4.5 mmol) was added to a stirred solution of N-(triisopropylsilyl)pyrrole (1.0 g, 4.5 mmol) in anhydrous THF (10 mL) at −78° C. The reaction mixture was kept at −78° C. for 1-2 h and then left to reach room temperature (ca. 1 h). Pyridine (0.1 mL) and hexane (10 mL) were added, the resulting suspension was filtered through a plug of neutral alumina, and the filtrate was evaporated in vacuum. Purification by column chromatography on silica gel (hexane/ethyl acetate=10:1) gave oil (1.22 g, 90.1% yield). 1H NMR (CDCl3) δ 6 1.08 (d, 18 H, Hz, Me), 1.42 (sept, 3 H, CH), 6.26 (dd, 1H, H-4), 6.66 (t, 1 H, H-5), 6.72 (dd, 1H, H-2). MS (M+H) m/z 302.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].N1C=CC=CC=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:32])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccccc2)CC1
Yield: 83.5 %

Procedure:
To a stirred solution of 1-(2-tert-butylphenyl)piperazine dihydrochloride (0.150 g, 0.52 mmol) and pyridine (0.166 g, 2.13 mmol) in dichloromethane (5 mL) was added benzoyl chloride (0.079 g, 0.56 mmol) at room temperature. After 16 h the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 90:10 to 70:30 heptanes/ethyl acetate, gradient elution) to provide [4-(2-tert-butylphenyl)piperazin-1-yl](phenyl)methanone (0.140 g, 83%) as a white powder, mp 104-106° C.
Reaction SMILES: C1(C(=[N:14][C:15]2[N:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][C@@H:22]3[CH3:34])=[N:19][CH:20]=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.NO>CO>[NH2:14][C:15]1[N:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][C@@H:22]2[CH3:34])=[N:19][CH:20]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1cnc(N=C(c2ccccc2)c2ccccc2)cn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1cnc(N)cn1
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a solution of 230b (3.3 g, 7.2 mmol) in methanol (25 mL) were added sodium acetate (708 mg, 8.6 mmol) and hydroxylamine hydrochloride (907 mg, 8.6 mmol). The reaction mixture was stirred for 0.5 h. It was then concentrated in vacuo. The residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 30:1) to afford 230c as yellow oil (1.35 g, 64%). MS: [M+H]+ 294.3.
Reaction SMILES: C(OC)(=O)CCCCC.C[O-].[Na+].[C]=O.[CH3:15][O:16][C:17](=[O:25])[CH:18]([CH:23]=[O:24])[CH2:19][CH2:20][CH2:21][CH3:22].[Cl:26][CH2:27][CH2:28][CH2:29][CH2:30]Br>CC(N(C)C)=O.CO>[CH3:15][O:16][C:17](=[O:25])[C:18]([CH2:19][CH2:20][CH2:21][CH3:22])=[CH:23][O:24][CH2:30][CH2:29][CH2:28][CH2:27][Cl:26]
Reactant: ClCCCCBr
Reactant: CCCCC(C=O)C(=O)OC
Agent: C[O-]
Agent: [C]=O
Agent: [Na+]
Solvent: CCCCCC(=O)OC
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CCCCC(=COCCCCCl)C(=O)OC
Reaction time: 5 h
Yield: 60 %

Procedure:
162.5 g Methyl caproate (1.25 mole), 28 g 96% sodium methylate (0.5 mole), and 10 ml methanol were reacted with carbon monoxide in the manner described in Example 4, and approximately 100 g crude sodium enolate of 2-formylcaproic acid methyl ester was obtained as an evaporation residue. It was suspended in 180 ml dimethylacetamide and mixed with 103 g 4-chlorobutyl bromide. The mixture was stirred about 4-6 hours at 65°-70° C., and worked up in a manner analogous to the procedure of Example 5. 74.5 g 3-(4-chlorobutoxy)-2-butyl-acrylic acid methyl ester boiling at 155° C./2 torr was obtained for a 60% yield based on the sodium methylate employed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]([NH2:14])=O)[CH:6]=[C:7]([CH:11]=1)[C:8]([NH2:10])=O.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]#[N:14])[CH:6]=[C:7]([CH:11]=1)[C:8]#[N:10]
Reactant: COc1cc(C(N)=O)cc(C(N)=O)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C#N)cc(C#N)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 37.1 %

Procedure:
A suspension of the 5-methoxyisophthalamide (3.1 g, 16 mmol) in a dichloromethane (27 mL) at 0° C. was treated with pyridine (5.2 mL, 65 mol) and then trifluoroacetic anhydride drop-wise (5.4 mL, 39 mmol). The reaction was stirred at 0° C. for 20 minutes and then stirred overnight at ambient temperature. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane afforded 940 mg (46%) of the 5-methoxyisophthalonitrile as a white solid.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].BrC[C:16]1[N:17]=[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2.O>O1CCCC1>[C:26]1([C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:25]=[C:16]([CH2:3][CH2:2][C:1]([OH:9])=[O:8])[N:17]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: BrCc1cc2ccccc2c(-c2ccccc2)n1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1cc2ccccc2c(-c2ccccc2)n1
Reaction time: 1 h
Yield: 37.6 %

Procedure:
A solution of diethyl malonate (17.9 g) in anhydrous tetrahydrofuran (100 cc) is added dropwise under nitrogen to sodium hydride (3.36 g, 80% strength in oil) and anhydrous tetrahydrofuran (80 cc). After 1 hour's stirring, a solution of 3-bromomethyl-1-phenylisoquinoline (8.3 g) in tetrahydrofuran (100 cc) is added dropwise, and the mixture is left with stirring at room temperature (approximately 20° C.) for 1 hour. Water (200 cc) is added and the aqueous phase extracted with ethyl acetate (3×200 cc). The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure. The residue is chromatographed on silica gel with a cyclohexane/ethyl acetate (4:1 by volume) mixture as eluant. An oil (9.6 g) is recovered, taken up in concentrated hydrochloric acid (95 cc) and brought to boiling for 20 hours. After the mixture is cooled, water (200 cc) is added, the aqueous phase is washed with ethyl acetate (2×50 cc), potassium hydroxide solution is added until the pH is 5 and the mixture is extracted with chloroform (3×50 cc). The organic phase is dried over magnesium sulphate and evaporated to dryness under reduced pressure. 1-Phenyl-3-isoquinolinepropanoic acid (2.9 g), m.p. 146° C., is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[CH2:11]([O:13][CH2:14][CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][C:34]2([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:38][CH2:37][NH:36][CH2:35]2)[CH2:27][CH2:26]1)[CH3:12].C([BH3-])#N.[Na+].Cl>CO.BrCOC1C(O)=CC=C(C)C=1.C(OCC)(=O)C>[CH3:2][CH:1]([N:36]1[CH2:37][CH2:38][C:34]([CH2:33][CH2:32][N:28]2[CH2:29][CH2:30][CH2:31][N:25]([C:17]3[N:16]([CH2:15][CH2:14][O:13][CH2:11][CH3:12])[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=3)[CH2:26][CH2:27]2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:35]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: CC(=O)c1ccccc1
Agent: Cc1ccc(O)c(OCBr)c1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(C)c4ccccc4)C3)CC2)nc2ccccc21

Procedure:
According to the method of J. Am. Chem. Soc., 93, 2897 (1971), combine acetophenone (10 mmol) and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (10 mmol) in methanol (100 mL). Add bromocreosol green (0.5% by weight in methanol, 1 drop). Add dropwise, a solution of sodium cyanoborohydride (10 mL, 1M in tetrahydrofuran, 10 mmol) and at the same time maintain the pH of the reaction mixture, as indicated by a yellow color for the indicator, by the addition of a 5 M solution of hydrochloric acid in methanol. When the reaction is complete, concentrate the reaction mixture in vacuo to obtain a residue. Dilute the residue with ethyl acetate and extract with water. Separate the layers, dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound.