Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:5](=[O:37])[CH2:6][N:7]1[C:13](=[O:14])[CH:12]([CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C:11](=[O:26])[N:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]1=2)([CH3:3])[CH3:2].[CH3:46][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>CN(C=O)C.C1COCC1>[CH:1]([N:4]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:5](=[O:37])[CH2:6][N:7]1[C:13](=[O:14])[C:12]([CH3:46])([CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C:11](=[O:26])[N:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]1=2)([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3ccc4ccccc4c3)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(N(C(=O)CN2C(=O)C(C)(Cc3ccc4ccccc4c3)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 200 mg (0.34 mmol) of N-Isopropyl-N-(4-methoxy-phenyl)-2-(3-naphthalen-2-ylmethyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl) acetamide, prepared as in Example 36, in 5 mL of DMF at 0° C. is added 0.60 mL (0.60 mmol, 1.8 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 5 min, and 37 μL (0.60 mmol, 1.8 equiv) of methyl iodide is added. The resulting solution is stirred 3 h at RT, warmed to 50° C. for 16 h, and then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of Et2O and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification of the material by silica gel MPLC on an Si60 column using hexane/EtOAc 5/2 as eluent followed by lyophilization in acetonitrile/H2O afforded 180 mg of the title compound as a white amorphous solid: 1H NMR (DMSO-d6, 300 MHz) δ7.88-7.79 (m, 3H), 7.64-7.19 (m, 14H), 7.05 (m, 2H), 6.92 (dd, 1H, J=1.0, 8.1), 4.87 (m, 1H), 4.30 (s, br, 2H), 3.80 (s, 3H), 2.76 (dd, 2H, J=13.9, 23.9), 1.22 (s, 3H), 1.00 (m, 6H); low resolution MS (FAB)m/e 612 (MH+), 611 (M+), 447.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]3[C:20](=O)[C:19](=[O:22])[C:18]=3[O:23]C)[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH2:34])=[CH:28][CH:27]=1>CO.C(Cl)(Cl)Cl>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]3[C:18](=[O:23])[C:19](=[O:22])[C:20]=3[NH:34][CH2:33][CH2:32][C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: NCCc1ccc(Cl)cc1
Reactant: COc1c(NC2CCCC(c3csc(NC(=N)N)n3)C2)c(=O)c1=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: N=C(N)Nc1nc(C2CCCC(Nc3c(NCCc4ccc(Cl)cc4)c(=O)c3=O)C2)cs1
Reaction time: 5 h

Procedure:
To a solution of 1-[3-(2-guanidinothiazol-4-yl)cyclohexylamino]-2-methoxycyclobutene-3,4-dione (0.19 g.) in 35 ml. of methanol/chloroform (50:50 v/v) was added 2-(p-chlorophenyl)ethylamine (0.18 g.) and the resulting mixture allowed to stand at room temperature for 5 hours. After heating under reflux for 2.5 hours the reaction mixture was cooled and the precipitated buff-coloured solid collected to give 1-[3-(2-guanidinothiazol-4-yl)cyclohexylamino]-2-[2-(p-chlorophenyl)ethylamino]cyclobutene-3,4-dione. The n.m.r. spectrum in d6 dimethylsulphoxide included resonances at 1.2 (m), 1.8 (m), 2.5 (t), 3.7 (m), 6.24 (s), 6.78 (br s).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:13][CH3:14])=[N:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([NH2:10])=[O:9])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:17][N:18]([CH:20]=[N:10][C:8](=[O:9])[C:7]1[CH:11]=[C:3]([CH2:1][CH3:2])[C:4]([O:13][CH3:14])=[N:5][C:6]=1[CH3:12])[CH3:19]
Reactant: CCc1cc(C(N)=O)c(C)nc1OC
Reactant: COC(OC)N(C)C
Product: CCc1cc(C(=O)N=CN(C)C)c(C)nc1OC
Temperature: 100 °C
Reaction time: 1.25 h

Procedure:
In a round bottom flask under a nitrogen atmosphere, 5-ethyl-6-methoxy-2-methyl-nicotinamide (60 mg, 0.309 mmol) is treated with dimethylformamide dimethylacetal (0.5 mL). The resulting mixture is stirred at 100° C. for 1.25 hr to give a yellow solution. LC/MS shows the complete consumption of the starting material. The reaction mixture is evaporated to give N-dimethylaminomethylene-5-ethyl-6-methoxy-2-methyl-nicotinamide directly as a cream solid that is used without purification. MS: m/e=250 (M+H); 1H NMR (CDCl3, δ, ppm): 8.57 (1H, s), 8.19 (1H, s), 5.77 (2H, s), 3.98 (3H, s), 3.19 (6H, s), 2.58 (3H, s), 2.56 (2H, q), 1.20 (3H, t).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]2[C:10]([C:11](=[O:30])[C:12]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.[OH2:33].[CH2:34]([N:36]([CH2:39]C)CC)C.CN>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.O1CCOCC1>[CH3:32][O:31][C:5]1[CH:4]=[N:3][C:2]([C:34]([NH:36][CH3:39])=[O:33])=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:30])[C:12](=[O:13])[N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15]3)[C:6]=12
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCc4c(cccc4-c4ccccn4)C3)c12
Reactant: CCN(CC)CC
Reactant: O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN
Solvent: C1COCCO1
Product: CNC(=O)c1ncc(OC)c2c(C(=O)C(=O)N3CCc4c(cccc4-c4ccccn4)C3)c[nH]c12
Temperature: 80 °C
Yield: 32.7 %

Procedure:
To a stainless steel pressure vessel containing 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione (0.2 g, 0.407 mmol) was added 1,4-dioxane (5 mL), water (0.037 mL, 2.035 mmol), tetrakis(triphenylphosphine)palladium(0) (0.071 g, 0.061 mmol), triethylamine (0.567 mL, 4.07 mmol), and methylamine (2M in THF) (2.035 mL, 4.07 mmol). The vessel was sealed and purged with N2 3 times. The vessel was filled with carbon monoxide to 50 psi, and purged 2 times, then finally was filled to 80 psi of carbon monoxide. The vessel was heated to 80° C. for 16 h then was cooled to rt. The mixture was transferred to a rb flask and the solvent was removed under reduced pressure. The residue was dissolved in DMF and was passed through a plug of CELITE® to remove the solids. The DMF solution was purified by prep HPLC. The fractions containing the expected product were concentrated under reduced pressure. The residue was dissolved in dichloromethane and was partitioned with aq. sat. NaHCO3. The organic layer was collected, and dried with MgSO4. The drying agent was removed by filtration and the organic solution was concentrated under reduced pressure. The residue was purified by BIOTAGE® flash chromatography using a 0-5% MeOH in dichloromethane gradient using a BIOTAGE® flash chromatography. The expected product, 4-methoxy-N-methyl-3-(2-oxo-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (0.065 g, 0.133 mmol, 32.7% yield), was isolated as an off-white solid. LC/MS: m/z 470.24 (M+H)+, 1.582 min (method 1). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.13 (br. s., 1H) 8.60-8.77 (m, 1H) 8.14-8.26 (m, 1H) 7.70-7.94 (m, 3H) 7.02-7.47 (m, 5H) 4.73-5.01 (m, 2H) 3.88-3.97 (m, 3H) 3.66-3.88 (m, 2H) 2.92-3.11 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=3[N:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=3)[N:9]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=3[N:10]([CH2:18][C:19]3[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
A solution of 3-(4-chloro-phenyl)-1-(3-methoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 105, 0.1 mmol) in CH2Cl2 (5 mL) was cooled to 0° C., and 1 M BBr3 in CH2Cl2 (0.5 mL) was added. The mixture was allowed to warm to 25° C. After 2 h, satd. aq. NaHCO3 (5 mL) was added. The layers were separated, and the aqueous layer was extracted with EtOAc (2×5 mL). The combined organic layers were dried over Na2SO4 and concentrated. Purification by flash chromatography (2 M NH3 in MeOH/CH2Cl2) provided the title compound (10 mg). MS (ESI): exact mass calculated for C20H20ClN3O, 353.13. found, m/z 354.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.40-7.38 (m, 2H), 7.35-7.32 (m, 2H), 7.03 (t, J=7.9 Hz, 1H), 6.57 (dd, J=8.1, 2.0 Hz, 1H), 6.49 (d, J=8.1 Hz, 1H), 6.39-6.37 (br m, 1H), 5.20 (s, 2H), 2.81-2.78 (br m, 4H), 2.74-2.72 (br m, 2H), 2.70-2.68 (br m, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[Br:31][C:32]1[CH:33]=[N:34][CH:35]=[C:36]([CH2:38]O)[CH:37]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:31][C:32]1[CH:37]=[C:36]([CH2:38][N:24]2[C:20](=[O:30])[C:21]3=[CH:29][CH:28]=[CH:27][CH:26]=[C:22]3[C:23]2=[O:25])[CH:35]=[N:34][CH:33]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cncc(Br)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
5-Bromo-3-(phthalimidomethyl)pyridine is produced by adding triphenylphosphine (12.1 g, 46.3 mmol) and phthalimide (6.80 g, 46.3 mmol) in dry THF (70 mL) to a stirred suspension of 3-bromo-5-hydroxymethylpyridine (6.70 g, 35.6 mmol), and then adding a solution of diethyl azodicarboxylate (7.30 mL, 46.3 mmol) in dry THF (30 mL) drop-wise. The reaction mixture was stirred at room temperature overnight. After removal of the solvent by rotary evaporation, the crude material was purified by column chromatography to yield 5-bromo-3-(phthalimidomethyl)pyridine (9.5 g, 85% yield).
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[N:11]=[CH:12][S:13][CH:14]=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[C:33]([O:37][C:38](=[O:63])[NH:39][CH2:40][C:41]1[N:42]([CH2:59][CH:60]([CH3:62])[CH3:61])[C:43](=[O:58])[C:44]2[C:49]([C:50]=1[O:51][CH2:52][CH2:53][CH2:54][CH3:55])=[CH:48][C:47]([CH:56]=O)=[CH:46][CH:45]=2)([CH3:36])([CH3:35])[CH3:34].O>CN(C)C=O>[C:33]([O:37][C:38](=[O:63])[NH:39][CH2:40][C:41]1[N:42]([CH2:59][CH:60]([CH3:61])[CH3:62])[C:43](=[O:58])[C:44]2[C:49]([C:50]=1[O:51][CH2:52][CH2:53][CH2:54][CH3:55])=[CH:48][C:47](/[CH:56]=[CH:9]/[C:10]1[N:11]=[CH:12][S:13][CH:14]=1)=[CH:46][CH:45]=2)([CH3:36])([CH3:34])[CH3:35]
Reactant: c1ccc([P+](Cc2cscn2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C=O)cc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(/C=C/c3cscn3)cc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 81.7 %

Procedure:
A mixture of triphenyl(1,3-thiazol-4-ylmethyl)phosphonium chloride (0.44 g, 1.1 mmol), potassium carbonate (15 g, 1.1 mmol) and tert-butyl(4-butoxy-6-formyl-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.47 g, 1.1 mol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from ethyl acetate-diisopropyl ether to give tert-butyl{4-butoxy-2-isobutyl-1-oxo-6-[(E)-2-(1,3-thiazol-4-yl)ethenyl]-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.46 g, 80.7%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([O:23][CH3:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:3]=1[NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].O.C>CS(C)=O.C(OCC)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.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([C:17]3([O:23][CH3:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:3]=1[NH:25][C:26](=[O:31])[C:27]([CH3:29])([CH3:28])[CH3:30]
Reactant: COC1(c2ccc(C=Cc3cc(F)cc(F)c3NC(=O)C(C)(C)C)cc2)CCOCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: COC1(c2ccc(/C=C/c3cc(F)cc(F)c3NC(=O)C(C)(C)C)cc2)CCOCC1

Procedure:
The product from Example 6 (3.0 g) was dissolved in dimethylsulphoxide and Pd(dba)2 (200 mg) was added. The mixture was treated with H2 at atmospheric pressure until gas uptake ceased. On completion, the reaction was added to water (500 ml) and extracted with ethyl acetate (2×400 ml). The combined organic extracts were washed with water (2×300 ml) and then dried on MgSO4, and filtered. Removal of the solvent in vacuo gave a yellow oil which was dissolved in diethyl ether, treated with charcoal, then filtered through, Hyflo. Removal of the solvent from the filtrate gave the crude title product. Precipitation from ethyl acetate/40°-60° petroleum ether afforded the title product as a white solid; mp 150°-151° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CO.[CH:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)=O.[BH3-]C#N.[Na+]>CCOC(C)=O.C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:22][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.8 %

Procedure:
The operation is carried out as in Stage 2 of Example 7 starting from 280 mg of the product obtained in Stage 1 of Example 7, 4 ml of methanol, 230 mg of methyl 4-formylbenzoate in place of the benzaldehyde and 0.2 ml of acetic acid then the reaction medium is agitated at ambient temperature for 5 hours. Then 100 mg of NaBH3CN is added and the reaction medium is agitated at ambient temperature for approximately 1 hour. 10 ml AcOEt is added, followed by washing with 2×5 ml H2O, then 5 ml of a saturated aqueous solution of NaCl, drying and evaporating the solvent. After purification by chromatography on silica eluting with methylene chloride/methanol/ammonium hydroxide in a proportion of 95/05/0.5, 260 mg of expected product is obtained.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH3:16])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH2:16][CH:28]([OH:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: CNC(=O)c1c(-c2ccccc2)noc1C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccccc2)noc1CC(O)c1ccccc1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A suspension of 75 g. (0.348 mole) of 3-phenyl-5,N-dimethyl-isoxazole-4-carboxamide and 1 liter of tetrahydrofuran is cooled to -65° C. and 478 ml. of 1.6M n-butyllithium in hexane (0.765 mole) is added dropwise maintaining the temperature between -60° and -70° C. After the addition is complete, the orange suspension is stirred for 11/2 hours at -60° to -70° C., and then 37.2 g. (0.350 mole) of benzaldehyde in 375 ml. tetrahydrofuran is added dropwise maintaining the temperature between -60° and -70° C. After addition is complete the mixture is stirred 11/2 hours at -60° to -70° C. and then warmed to -30° C. and quenched by the addition of saturated ammonium chloride solution. The mixture is further diluted with tetrahydrofuran and the layers are separated. The tetrahydrofuran layer is washed twice with 50% brine, and once with brine, dried over anhydrous magnesium sulfate, filtered with a 50:50 mixture of ether:petroleum ether, filtered and washed with cold ether to give 3-phenyl-5-(β-hydroxyphenethyl)-N-methyl-isoxazole-4-carboxamide; m.p. 183°-184° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:9]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:38]=[N+:39]=[N-:40].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]4[NH:40][N:39]=[N:38][N:24]=4)=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:9]1[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCc1c(-c2ccccc2)n(Cc2ccccc2)c2ccc(-c3ccc(OCC#N)cc3)cc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCc1c(-c2ccccc2)n(Cc2ccccc2)c2ccc(-c3ccc(OCc4nnn[nH]4)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(1-benzyl-3-pentyl-2-phenyl-1H-indol-5-yl)-phenoxy]-acetonitrile (0.252 g, 0.520 mmol) was reacted with NaN3 (0.169 g, 2.6 mmol) and NH4Cl (0.139 g, 2.6 mmol) in DMF (5 ml) to give the product (0.137 g, 0.260 mmol, 50%) as a white solid, mp 165-168° C. 1H NMR (DMSO-d6) δ 0.76 (t, J=7.0 Hz, 3H), 1.15-1.22 (m, 4H), 1.53-1.59 (m, 2H), 2.68 (t, J=7.5 Hz, 2H), 5.27 (s, 2H), 5.52 (s, 2H), 6.83 (d, J=7.2 Hz, 2H), 7.13-7.16 (m, 3H), 7.20 (t, J=6.9 Hz, 2H), 7.34-7.38 (m, 4H), 7.43 (t, J=7.0 Hz, 1H), 7.48 (t, J=6.9 Hz, 2H), 7.63 (d, J=8.6 Hz, 2H), 7.77 (S; 1H), 16.79 (broad s, 1H); IR (solid) 3030, 2920, 2850, 1605, 1520, 1480, 1260 and 1240 cm−1; [ESI(−)], m/z 527 (M−H)−; Anal. Calcd. for C34H33N5O: C, 77.39; H, 6.30; N, 13.27; Found: C, 77.34; H, 6.33; N, 13.30.
Reaction SMILES: [O:1]1[NH:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:11](N(CC)CC)[CH3:12].Cl[C:19]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:30][C:31](Cl)=[O:32])=[O:20]>C1C=CC=CC=1>[O:20]=[C:19]1[CH2:21][O:22][C:23]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:29][CH2:30][C:31](=[O:32])[N:10]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5][N:4]1[CH2:3][CH2:2][O:1][CH2:11][CH2:12]2
Reactant: C1COCCNOCCN1
Reactant: O=C(Cl)COc1ccccc1OCC(=O)Cl
Reactant: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C1COc2ccccc2OCC(=O)N2CCOCCN1CCOCC2

Procedure:
In a manner similar to that described in Example 5, treat the cyclic diamine obtained in Example 45 and triethylamine in anhydrous benzene with 1,2-di-(chlorocarbonylmethoxy)-benzene (compound of Example 61) utilizing high dilution technique. Isolate and purify the resultant product in a manner similar to that described in Example 5 to obtain 2,13-dioxo-4,11,17,22-tetraoxa-1,14-diaza-tricyclo[12,5,5,05,10 ]tetracosa-5,7,9-triene.
Reaction SMILES: [F:1][C:2]([F:16])([CH:13]([F:15])[F:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[C@H:17]12[CH2:23][C@H:20]([NH:21][CH2:22]1)[CH2:19][N:18]2[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]([F:16])([CH:13]([F:15])[F:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:21]2[CH2:22][C@@H:17]3[CH2:23][C@H:20]2[CH2:19][N:18]3[CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(CN2C[C@@H]3C[C@H]2CN3)cc1
Reactant: O=Cc1ccc(OCC(F)(F)C(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(CN2C[C@@H]3C[C@H]2CN3Cc2ccc(OCC(F)(F)C(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.8 %

Procedure:
4-(2,2,3,3-Tetrafluoropropoxy)benzaldehyde (250 mg, 1.06 mmol) and methyl 4-[[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate (260.7 mg, 1.06 mmol) were dissolved in dichloromethane (5.9 mL). After 15 min, sodium triacetoxyborohydride (448.7 mg, 2.12 mmol) was added. The reaction mixture was stirred overnight at room temperature. Then, saturated sodium bicarbonate solution was added. The mixture was stirred for 30 min and then extracted with dichloromethane. The combined organic layers were washed with water, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 177 mg of methyl 4-[[(1S,4S)-5-[[4-(2,2,3,3-tetrafluoropropoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate; 1H NMR (300 MHz, CDCl3) δ 7.98 (d, 2H), 7.43 (d, 2H), 7.31 (d, 2H), 6.87 (d, 2H), 6.07 (tt, 1H), 4.33 (tt, 2H), 3.91 (s, 3H), 3.81 (d, 1H), 3.76 (d, 1H), 3.71 (d, 1H), 3.64 (d, 1H), 3.28 (br s, 2H), 2.84 (d, 2H), 2.65 (dd, 2H), 1.74 (s, 2H) ppm.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]2[CH:11]=[CH:12][NH:13][C:8]2=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[K+].[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C(OC(=O)C)(=O)C>CO>[C:1]([NH:4][C:5]1[N:10]=[C:9]2[C:11]([C:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH:19]=3)=[CH:12][NH:13][C:8]2=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CN1CCC(=O)CC1
Reactant: CC(=O)Nc1ccc2[nH]ccc2n1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)Nc1ccc2[nH]cc(C3=CCN(C)CC3)c2n1
Yield: 58.9 %

Procedure:
A solution of 0.477 gm (2.7 mMol) of the 5-(N-acetylamino)pyrrolo[3,2-b]pyridine, 0.54 mg (9.5 mMol) potassium hydroxide, and 0.43 mL (3.5 mMol) 1-methyl-4-piperidone in 15 mL methanol was heated at reflux for 18 hours. The reaction mixture was then concentrated under reduced pressure and the residue dissolved in pyridine. To this solution was added 0.20 mL (2.2 mMol) acetic anhydride and the resultant mixture stirred for 1 hour. This reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of ethyl acetate (2-40% methanol). Fractions containing product were combined and concentrated under reduced pressure to provide 0.43 gm (59%) 5-(N-acetylamino)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine as an ivory foam. A portion was recrystallized from methanol/ethyl acetate to provide an analytical sample.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1.[CH:13]1([C:18](O)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([C:18]([CH2:1][NH:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CNc1ccc(C(=O)OC)cc1
Reactant: O=C(O)C1CCCC1
Product: O=C(O)c1ccc(NCC(=O)C2CCCC2)cc1

Procedure:
Methyl 4-methylaminobenzoate was reacted with cyclopentanecarboxylic acid by method E and then hydrolyzed by method P-a. This resulted in the product with the molecular weight of 247.30 (C14H17NO3); MS (ESI): 248 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:11]=[CH:10][C:9]([CH3:12])=[N:8][C:6]=2[N:7]=1.[OH-:14].[Na+]>>[ClH:1].[Cl:1][C:2]1[NH:3][C:4](=[O:14])[C:5]2[CH:11]=[CH:10][C:9]([CH3:12])=[N:8][C:6]=2[N:7]=1
Reactant: [OH-]
Reactant: Cc1ccc2c(Cl)nc(Cl)nc2n1
Agent: [Na+]
Product: Cc1ccc2c(=O)[nH]c(Cl)nc2n1
Product: Cl

Procedure:
In analogy to the procedure described in example 97.2, 2,4-dichloro-7-methyl-pyrido[2,3-d]pyrimidine (R. K. Robins, G. H. Hitchings, J. Am. Chem. Soc. 1958, 80, 3449-57) was treated with 1N NaOH solution to give 2-chloro-7-methyl-3H-pyrido[2,3-d]pyrimidin-4-one hydrochloride as orange solid. MS: m/e=196.1 [M+H+].