Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:8][CH2:9][C:10]([CH3:13])([NH2:12])[CH3:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:14](ON1C(=O)CCC1=O)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>C(Cl)Cl>[N:1]1([CH2:8][CH2:9][C:10]([NH:12][C:14](=[O:15])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:13])[CH3:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(N)CCN1CCCCCC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Product: CC(C)(CCN1CCCCCC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.1 %

Procedure:
Crude 4-(Azepan-1-yl)-2-methylbutan-2-amine (4.54 g, 24.6 mmol) was dissolved into DCM (120 mL). To this solution was added CbzOSu (6.13 g, 1 equiv, 24.6 mmol) in one portion. The reaction was left to stir at room temperature for 2 d. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (150 mL) and water (100 mL). The layers were separated and the organic layer washed with saturated sodium bicarbonate (2×100 mL), water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil (8.33 g). The crude oil was purified on an ISCO purification system with gradient elution from 1-5% methanol in DCM. The desired fraction was collected and concentrated to give a colorless oil (3.69 g, yield: 47.1%). LRMS (ESI+) for C19H30N2O2 (318.2); Found: 319 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]2)=[C:4](Cl)[N:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]2)=[C:4]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1
Reactant: C1CCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(N2CCCC2)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1

Procedure:
(+)-(1S, 2R, 4R)-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)cyclopentanol (426 mg 1.5 mmol), pyrrolidine (99%, Aldrich, 1.26 mL), and ethanol (8 mL) were refluxed for 20 minutes. To the cooled solution was added 1N sodium hydroxide (1.5 mL). Volatiles were evaporated and the residue chromatographed on silica gel. Title compound was eluted with 12% methanol-chloroform as a white solid foam which solidified from 95% ethanol to white powder (324 mg, 64% ); mp 114°-117°; mass spectrum (Cl, CH4): 319(M+1); 1H-NMR (DMSO-d6)δ: 7.81 (s, 1, H-8), 5.76 (br s, 2, NH2), 5.0-4.8 (m, 1, CHN), 4.76(d, J=4.1 Hz, 1, OH), 4.66 (t, J=5.2 Hz, 1, CH2OH), 4.15-4.0 (m, overlapping br m at 4.1-3.4 and m at 3.6-3.35, total 7, CHO, 2CH2N and CH2O), 2.4-2.2 (m, 1, 1/2CH2), 2.2-1.8 (m, 7,methylenes), 1.7-1.5(m, 1, 1/2CH2); [α]20589 +10.5°, [α]20578 +11.00°, [α]20546 +12.4°, [α]20436 +19.5°, [α]20365 +25.5°(c=1.43, methanol).
Reaction SMILES: O.[SH-:2].[Na+].Br[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[O:12])[N:6]=1.O>C(O)CO>[C:16]1([CH3:19])[CH:17]=[CH:18][C:13]([C:11]([C:7]2[N:6]=[C:5]([SH:2])[CH:10]=[CH:9][CH:8]=2)=[O:12])=[CH:14][CH:15]=1
Reactant: Cc1ccc(C(=O)c2cccc(Br)n2)cc1
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: Cc1ccc(C(=O)c2cccc(S)n2)cc1
Temperature: 110 °C
Yield: 43.6 %

Procedure:
To a stirred solution of sodium hydrosulphide hydrate (22.0 g) in ethylene glycol (100 ml) at 100° C. was added 2-bromo-6-(4-toluoyl)pyridine (27.6 g) in portions. The mixture was then heated at 110° C. for 3 hours, allowed to cool and then poured into water (600 ml). The yellow precipitate of the by-product 6-(4-methylbenzyl)pyridine-2-thiol was filtered off and the filtrate was acidified by the addition of glacial acetic acid (10 ml). The resultant orange solid was then filtered off and well washed with water and dried. This crude solid (19.4 g) was crystallised from a mixture of benzene (500 ml) and methanol (175 ml) to give 6-(4-toluoyl)pyridine-2-thiol (10.0 g) as orange needles. M.p. 179°-181°.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][C:4](=O)[CH:3]=1.C([O-])(=O)C.[Na+].S(O)(O)(=O)=O.[NH2:21]O.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(O)C.O>[CH3:1][C:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH:4]([NH2:21])[CH:3]=1
Reactant: NO
Reactant: CC1=CC(=O)CCC1(C)C
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Product: CC1=CC(N)CCC1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An ethanol-water solution (1:3, 4 mL) of 3,4,4-trimethylcyclohex-2-enone (500 mg, 3.62 mmol) and sodium acetate (356 mg, 4.35 mmol) was stirred with hydroxylamine sulfate (475 mg, 2.89 mmol) at 70° C. for 40 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate, and the resulting organic layer was evaporated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (5 mL), mixed with lithium aluminum hydride (412 mg, 10.9 mmol) at 0° C. and stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was mixed with saturated aqueous sodium sulfate, dried over anhydrous magnesium sulfate and filtered through celite, and the solvent was removed by vacuum distillation to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([NH:22][CH2:21][CH2:20][N:19]([CH3:23])[CH3:18])=[N:7][C:6]=2[CH:17]=1
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: CN(C)CCN
Product: CN(C)CCNC1=Nc2cc(Cl)ccc2Nc2ccccc21
Yield: 63.5 %

Procedure:
8-Chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one (25 mg, 0.1 mmol) and N,N-dimethylethylenediamine (44 mg, 0.5 mmol) were reacted according to GP4 to give 20 mg of the title compound (160FE16D). MS (ESI) 315 (MH+). Purity for MH+ (UV/MS) 100/100.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[N:7]=[CH:6][C:5]=2[NH:4][N:3]=1.[Cl:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([C:20]2[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([C:20]2[CH:27]=[CH:26][C:23]([CH2:24][N:3]3[C:2]([CH3:1])=[C:10]4[C:5]([CH:6]=[N:7][N:8]([CH3:12])[C:9]4=[O:11])=[N:4]3)=[CH:22][CH:21]=2)=[O:19])=[CH:28][CH:29]=1
Reactant: Cc1n[nH]c2cnn(C)c(=O)c12
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c2c(=O)n(C)ncc2nn1Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In DMF (2 ml) was dissolved 3,5-dimethyl-1H-pyrazolo [3,4-d]pyridazin-4(5H)-one (94 mg) followed by addition of 4-(4-chlorobenzoyl)benzyl bromide (279 mg) and potassium carbonate (124 mg), and the mixture was stirred at room temperature for 15 hours. This reaction mixture was extracted with ethyl acetate and the organic layer was serially washed with water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate=1:4), washed with the following solvent, and dried. As the washing solvent, n-hexanediethyl ether was used for 1-[4-(4-chlorobenzoyl) benzyl]-3,5-dimethyl-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one and diethyl ether for 2-[4-(4-chlorobenzoyl)benzyl]-3,5-dimethyl-2H-pyrazolo [3,4-d]pyridazin-4(5H)-one.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:27][N:28]([CH3:38])[C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH3:27][N:28]([CH3:38])[C:29]1[N:34]=[CH:33][C:32]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])=[O:15])[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)=[CH:31][CH:30]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N(C)C)nc3)cc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (110 mg, 0.264 mmol) and [6-(dimethylamino)-3-pyridinyl]boronic acid (66 mg, 0.395 mmol). The product was collected as a white solid (33 mg, 27%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 8.64 (d, J=2.27 Hz, 1H) 8.60 (t, J=4.80 Hz, 1H) 8.35 (s, 1H) 8.02-8.06 (m, 2H) 7.84 (s, 1H) 6.77 (d, J=8.84 Hz, 1H) 5.89 (s, 1H) 5.13 (dt, J=13.14, 6.57 Hz, 1H) 4.39 (br. s., 1H) 4.38 (br. s., 1H) 3.09 (s, 6H) 2.22 (s, 3H) 2.13 (s, 3H) 1.50 (s, 3H) 1.49 (s, 3H) LC-MS (ES) m/z=459.2 [M+H]+
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][O:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH3:25].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[O:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH3:25]
Reactant: O=C1COC(=O)N1CCCCCc1cccc2nccn12
Reactant: CCCC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1OC(=O)N(CCCCCc2cccc3nccn23)C1=O

Procedure:
To a solution of 3.45 g (12 mmol) of 3-[5-(imidazo[1,2-a]pyridin-5-yl)pentyl]oxazolidine-2,4-dione and 1.08 ml (12 mmol) of n-butyraldehyde in 50 ml of ethanol, 0.12 ml (1.2 mmol) of piperidine was added, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/2→ethyl acetate/ethanol=10/1) to yield 1.36 g (33.2%, light yellow oily substance) of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)O)=[C:14]([CH3:25])[C:13]=2[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:29])=O.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([Cl:29])[CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:14]([CH3:25])[C:13]=2[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C(O)C2CCCCC2)oc2ccc(OCc3ccccc3)cc12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C(Cl)C2CCCCC2)oc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of [5-(benzyloxy)-3-methyl-1-benzofuran-2-yl](cyclohexyl)methanol (25.17 g) synthesized above in tetrahydrofuran (250 mL) was added thionyl chloride (9.44 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hr. To the reaction mixture was added aqueous sodium hydrogen carbonate solution cooled to 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (25.39 g, 96%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([C:13]#[N:14])=[CH:5]2.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:7]1[C:6]([C:13]#[N:14])=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cc2cc(Br)ccc2[nH]c1=O
Product: N#Cc1cc2cc(Br)ccc2nc1Cl

Procedure:
6-Bromo-3-cyano-2-[1H]-quinolone (142 g) was heated under reflux in phosphorus oxychloride (500 cm3) for 1.5 hours. Volatile material was removed in vacuo and the solid residue was taken into chloroform (400 cm3) and the resulting slurry was poured onto ice. The mixture was neutralised with aqueous ammonia solution (S.G. 0.880) and the aqueous phase was extracted further with chloroform (2×150 cm3). The dried (MgSO4) organic extracts were concentrated in vacuo and the residue chromatographed on silica (Merck "MK 60.9385") eluting with toluene to give a solid which was recrystallised from ethyl acetate to afford 2-chloro-6-bromo-3-cyano-quinoline, m.p. 228°-230°, (80 g).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:30])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH2:17][CH2:18]2)[C@@H:13]([Cl:28])[CH2:12]3)[CH2:9][C@H:8]1[CH3:29])(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(O)(O)C.C([O-])(=O)C.[Na+]>O.ClCCl.C(O)C.COCCOC>[C:1]([O:4][CH2:5][C:6](=[O:30])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH2:17][CH2:18]2)[C:13]([Cl:28])=[CH:12]3)[CH2:9][C@H:8]1[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](Cl)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: CC(=O)[O-]
Agent: CC(O)(O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reaction time: 1.33 h

Procedure:
5.0 g. of 21-acetoxy-6α-chloro-11β-hydroxy-16α-methyl-4-pregnene-3,20-dione is combined with 45 ml. of ethylene glycol dimethyl ether, as well as 100 mg. of p-toluenesulfonic acid, and the mixture is stirred for 15 minutes at 10°-15°. Then, 18 ml. of ethanol is added thereto, and the mixture is combined with 3.1 ml. of triethyl ester of orthoacetic acid, and again agitated for 40 minutes at 20°-25°. The mixture is cooled to 10°, and a solution of 392 mg. of sodium acetate in 19 ml. of water is added dropwise thereto. The reaction solution is then brought to room temperature, combined with 7 ml. of dichloromethane as well as 30 ml. of water, and agitated for 20 minutes at 10°. The mixture is extracted several times with dichloromethane. The combined organic phases are washed with dilute sodium acetate solution. The product is concentrated under vacuum to 5 ml. and then 0.1 ml. of pyridine is added. The solution is diluted with 20 ml. of dioxane, combined with 2 ml. of water, as well as with 2.5 g. of dichlorodicyanobenzoquinone, and agitated for 80 minutes under ice cooling. One gram of sodium bisulfite, dissolved in 5 ml. of water, is added thereto and the mixture is concentrated under vacuum to 10 ml. and stirred into ice water. The mixture is agitated for one hour, the thus-obtained precipitate is filtered and washed with water. The moist residue is combined with 50 ml. of dichloromethane and stirred for 40 minutes at room temperature. This process is repeated once again. The dichloromethane solutions are washed with water, dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product, 6.2 g. of foam, is chromatographed on silica gel. With 55-67% ethyl acetate-hexane, 1.34 g. of 21-acetoxy-6-chloro-11β-hydroxy-16α-methyl-4,6-pregnadiene-3,20-dione is obtained after recrystallization from acetonediisopropyl ether; m.p. 171° [α]D25 =+176° (methanol). UV: ε285 =17,800 (methanol).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][C:7]3[CH2:9][CH2:10][C:11](=[O:12])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.C1(C)C=CC=CC=1.[NH4+].[Cl-]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:5]2[C:6]3[C:11](=[O:12])[CH2:10][CH2:9][C:7]=3[N:8]=[C:4]2[CH:1]2[CH2:3][CH2:2]2)=[CH:16][CH:15]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=C1CCc2[nH]c(C3CC3)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1CCc2nc(C3CC3)n(Cc3ccc(Cl)cc3)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.5 %

Procedure:
Tetrabutylammonium bromide (270 mg) was added to a stirred mixture of Intermediate 28 (272 mg), 4-chlorobenzyl bromide (414 mg) in sodium hydroxide 20% aq. (3.09 mL) and toluene (10 mL). The RM was stirred at room temp under nitrogen atm. for 16 hours. Sat. NH4Cl aq. solution (50 mL) was added and the mixture was extracted with EtOAc (2×50 ml). The organics were combined, dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (238 mg). LC/MS MH+ 387, Rt 2.51 min (5 minute run)
Reaction SMILES: [CH:1]1([C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9](=[O:17])[CH:8]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH2:32][CH2:33][CH3:34]>CN(C)C=O>[CH:1]1([C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([CH2:32][CH2:33][CH3:34])[C:9](=[O:17])[CH:8]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCI
Reactant: O=C(NC1N=C(C2CCCC2)c2ccccc2NC1=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCC2)c2ccccc21
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 5-cyclopentyl-1,3-dihydro-3(R,S)-[(benzyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one [Example 5, Step 3] (1.48 g, 3.93 mmol) in anhydrous dimethylformamide (40 ml), cooled in an ice bath, was added sodium hydride (60% dispersion in oil, 173 mg, 4.33 mmol) and the resulting mixture stirred under nitrogen for 1 h. Iodopropane (0.46 ml, 4.72 mmol) was then added and the mixture stirred at room temperature for 3 h. The solvent was evaporated and the residue partitioned between dichloromethane (100 ml) and water (100 ml). The aqueous layer was re-extracted with more dichloromethane (100 ml), the organic extracts were combined, dried (MgSO4) and evaporated. The residue was then triturated with ether to afford the title compound (1.36 g, 83%) as a white solid. mp 138°14 140° C. 1H NMR (360 MHz, CDCl3) δ 0.80 (3H, t, J=7.4 Hz), 1.26-1.79 (8H, m), 1.94 (1H, m), 2.12 (1H, m), 3.30 (1H, m), 3.55 (1H, m), 4.29 (1H, m), 5.10 (2H, m), 5.13 (1H, d), 6.52 (1H, d, J=8.1 Hz), 7.23-7.34 (5H, m), 7.48 (1H, t of d, J=8.0 and 1.4 Hz), 7.56 (1H, dd, J=7.8 and 1.4 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH2:22][CH2:21][NH:29][C:2]2[CH:7]=[C:6]([C:8]3[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=4)[N:11]=[C:10]([CH3:20])[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCc1ccccc1
Reactant: Cc1cccc(-n2nc(C)cc2-c2ccnc(Cl)c2)c1
Product: Cc1cccc(-n2nc(C)cc2-c2ccnc(NCCc3ccccc3)c2)c1
Temperature: 200 °C
Yield: 74 %

Procedure:
A mixture of 2-chloro-4-[1-(3-methylphenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 45; 0.5 g, 0.0018 mol) and phenethylamine (15 mL) was heated at 200° C. for 24 hours. The excess amine was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 1:1) to give 0.48 g (74% yield) of product as a yellow oil, which solidified upon standing: mp: 86-87° C. Anal. Calc'd. for C24H24N4: C, 78.23; H, 6.56; N, 15.20. Found: C, 78.07; H, 6.82; N, 14.71.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][C:6](=[O:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]1[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:24][C@H:23]2[C@@H:19]1[CH2:20][N:21](C(OCC1C=CC=CC=1)=O)[CH2:22]2.[H][H]>CO.[Pd]>[C@@H:23]12[CH2:24][N:18]([CH2:17][CH2:16][CH2:15][CH2:14][N:3]3[C:4]4[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=4[C:6](=[O:9])[CH2:7][CH2:8][C:2]3=[O:1])[C@H:19]1[CH2:20][NH:21][CH2:22]2
Reactant: O=C1CCC(=O)N(CCCCN2C[C@@H]3CN(C(=O)OCc4ccccc4)C[C@@H]32)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1CCC(=O)N(CCCCN2C[C@H]3CNC[C@@H]32)c2ccccc21
Yield: 67.9 %

Procedure:
In the presence of Pd/C (0.01 g, 10%), benzyl (1R,5R)-6-[4-(2,5-dioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)butyl]-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate from Example 65 (0.45 mmol, 0.21 g) in methanol (7 ml) was reacted with hydrogen to obtain 0.10 g of the title compound.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:47][CH:46]4[N:48]([CH3:49])[CH:42]([CH2:43][O:44][CH2:45]4)[CH2:41]3)=[CH:36][N:35]=2)[C:30](=[O:50])[N:29]([CH3:51])[CH:28]=1)(=O)C.O[Li].O>CC(O)C.C1COCC1.O>[F:26][C:9]1[CH:8]=[C:7]([C:27]2[CH:32]=[C:31]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH2:41][CH:42]5[N:48]([CH3:49])[CH:46]([CH2:45][O:44][CH2:43]5)[CH2:47]4)=[CH:36][N:35]=3)[C:30](=[O:50])[N:29]([CH3:51])[CH:28]=2)[C:6]([CH2:5][OH:4])=[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])[CH:10]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CC5COCC(C4)N5C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CN1C2COCC1CN(c1ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)nc1)C2
Temperature: 30 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
A mixture of 112l (340 mg, 0.489 mmol) and LiOH hydrate (445 mg, 24.45 mmol) in iPrOH (4 mL), THF (4 mL) and H2O (4 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo, and the residue was purified on prep-HPLC to give 112 as a low yellow solid (105 mg, 32.85%). MS: [M+H]+ 654. 1H NMR (500 MHz, CDCl3) δ 8.46 (d, J=2.5 Hz, 1H), 7.87 (d, J=3.0 Hz, 1H), 7.69 (s, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.23-7.14 (m, 2H), 6.94 (d, J=2.5 Hz, 1H), 6.84 (m, 2H), 4.52 (d, J=11.5 Hz, 1H), 4.31 (m, 2H), 4.12 (m, 5H), 3.89 (m, 3H), 3.69 (s, 3H), 3.43 (m, 4H), 2.84 (s, 2H), 5.62-2.54 (m, 7H), 1.88 (m, 2H), 1.78 (m, 2H)
Reaction SMILES: C(OCC=CCOC(=O)C)(=O)C.C(O)(=O)C.C([O:20][CH2:21][CH:22]([CH:29]=O)[CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27])(=O)C>C1C=CC=CC=1>[CH:21]([C:22]([CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27])=[CH2:29])=[O:20]
Reactant: CC(=O)OCCC(C=O)COC(C)=O
Agent: CC(=O)OCC=CCOC(C)=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: C=C(C=O)CCOC(C)=O
Yield: 90.3 %

Procedure:
A solution of 1,4-diacetoxy-2-butene (170 g.) and hydridocarbonyltris(triphenylphosphine) rhodium (I) (0.5 g.) in benzene (340 g.) was heated in a bomb at 75° C. under 2000 psig of a synthesis gas (50% by volume H2 and 50% by volume CO gas). After a few hours, the bomb was cooled and vented and the benzene was removed from the reaction product by distillation. The resulting crude 1,4-diacetoxy-2-formylbutane was then heated to 120°-130° C. in a distillation apparatus under a vacuum of 5 mm Hg. and a distillate (190.3 g. b.p. 60°-80° C.) was collected. The distillate on redistillation gave acetic acid, 2-formyl-4-acetoxybutene (127.1 g., 90.3% yield, b.p. 77°-79° C./ 6 mm Hg) and 1,4-diacetoxy-2-formyl butane (12.5 g., 6.2% yield, b.p. 110°-113° C./ 1 mm Hg.