Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]=[C:22]([C:24]4[O:28][N:27]=[C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:25]=4[C:35]([OH:37])=O)[O:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:38][C:39]([F:43])([F:42])[CH2:40][NH2:41].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCN(CC)CC>CN(C=O)C>[C:29]1([C:26]2[C:25]([C:35](=[O:37])[NH:41][CH2:40][C:39]([F:43])([F:42])[F:38])=[C:24]([C:22]3[O:21][N:20]=[C:19]([C:16]4[CH:17]=[CH:18][C:13]([CH2:12][N:10]5[CH2:11][CH:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]5)=[CH:14][CH:15]=4)[N:23]=3)[O:28][N:27]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(=O)O)n3)cc2)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(=O)NCC(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
A mixture of 5-(3-(4-((3-(tert-butoxycarbonyl)azetidin-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-phenylisoxazole-4-carboxylic acid (30 mg, 0.060 mmol), 2,2,2-trifluoroethylamine (7.15 μL, 0.090 mmol), BOP-Cl (18.24 mg, 0.072 mmol) and Et3N (0.025 mL, 0.179 mmol) in DMF (0.5 mL) was stirred at rt over the weekend. The reaction mixture was partitioned between EtOAc (30 mL) and saturated sodium bicarbonate solution (30 mL). The organic layer was washed with water (2×30 mL) and brine (30 mL). After drying (MgSO4) and filtration, the organic layer was concentrated to a colorless solid that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-70% EtOAc/Hex gradient. The essentially pure fractions containing product were concentrated to afford tert-butyl 1-(4-(5-(3-phenyl-4-(2,2,2-trifluoroethylcarbamoyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (18 mg, 0.031 mmol, 51.7% yield) as a white solid. This material was deemed suitable to use in the next step without further purification. HPLC retention time=1.71 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient. MS: (M+H)=584.10.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].C(O)C(N)(CO)CO.[N-]=C=O>C(Cl)Cl>[C:33]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1)(=[O:35])[CH3:34]
Reactant: O=C(Nc1ccc2c(c1)NCCC2)c1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: NC(CO)(CO)CO
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-(1,2,3,4-tetrahydroquinolin-7-yl)-1,1′-biphenyl-4-carboxamide (Example 24) (66 mg, 0.2 mmol) in DCM (1 ml) was added triethylamine (42 ul, 0.3 mmol) followed by acetyl chloride (20.5 ul, 0.3 mmol). The reaction was stirred at ambient temperature for 15 mins then treated with polymer supported trisamine resin (31 mg, 0.1 mmol) and polymer supported isocyanate resin (20 mg, 0.04 mmol). After 5 mins the resins were removed by filtration and the filtrate was washed with 2M hydrochloric acid, dried over MgSO4 and concentrated in vacuo to give the title compound as an off-white solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 7.94 (d, 2H), 7.84 (d, 1H), 7.78 (br, 1H), 7.72 (d, 2H), 7.64 (d, 2H), 7.45 (m, 4H), 7.15 (d, 1H), 3.80 (t, 2H), 2.74 (t, 2H), 2.33 (s, 3H), 1.98 (qn, 2H).
Reaction SMILES: [Na].[CH2:2]([CH:4]1[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][C:9]=2[CH2:8][CH2:7][CH2:6][C:5]1=O)[N:15]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[N:14]=[CH:13]3)[CH3:3].[CH:26]([C:28]([CH3:30])=[O:29])=[CH2:27]>CCO>[CH2:2]([C:4]12[CH2:27][CH2:26][C:28](=[O:29])[CH:30]=[C:5]1[CH2:6][CH2:7][CH2:8][C:9]1[CH:17]=[C:16]3[C:12](=[CH:11][C:10]=12)[CH:13]=[N:14][N:15]3[C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)[CH3:3]
Reactant: CCC1C(=O)CCCc2cc3c(cnn3-c3ccc(F)cc3)cc21
Reactant: C=CC(C)=O
Agent: [Na]
Solvent: CCO
Product: CCC12CCC(=O)C=C1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
A three necked round bottom flask with septum, nitrogen line, thermometer and stir bar was charged with EtOH (50 mL) and sodium (0.348 g, 15.1 mmol). The mixture was stirred until the reaction was complete, then 5-ethyl-1-(4-fluorophenyl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (7, R1=4-Fluorophenyl, R2=Ethyl) (3.25 g, 10.1 mmol) suspended in EtOH (50 mL) was added. The mixture was heated to about 35° C. for about 10 min then methyl vinyl ketone (0.777 g, 11.09 mmol) was added. The mixture was stirred for about 45 min at about 35° C. then heated to about 60° C. for about 1 h. Methyl vinyl ketone (0.27 g, 3.85 mmol) was added and stirring was continued for about 30 min. Methyl vinyl ketone (0.22 g, 3.14 mmol) was added then heating was continued for about 45 min. The mixture was cooled to rt then concentrated under reduced pressure. Water (100 mL) and EtOAc (100 mL) were added then the mixture was acidified to about pH 1 with 6 N aq. HCl. The layers were separated then the aqueous layer was extracted with EtOAc (20 mL). The combined organic solutions were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (120 g) using a gradient of 10-50% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure to yield 12b-Ethyl-9-(4-fluorophenyl)-1,2,6,7,9,12b-hexahydro-5H-9,10-diaza-benzo[3,4]cyclohepta[1,2-f]inden-3-one (8, R1=4-Fluorophenyl, R2=Ethyl) (3.03 g, 80%); LC/MS, method 3, Rt=2.73 min, MS m/z 375 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.32 (s, 1H), 7.89 (s, 1H), 7.85-7.78 (m, 2H), 7.63 (s, 1H), 7.47-7.38 (m, 2H), 5.89 (s, 1H), 3.03-2.95 (m, 1H), 2.88-2.63 (m, 2H), 2.58-2.27 (m, 4H), 2.21-2.00 (m, 2H), 1.93-1.73 (m, 3H), 0.92-0.84 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6](=[NH:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:15][C:16](=O)[CH2:17][C:18](=O)[CH3:19]>C1C=CC=CC=1>[CH3:14][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]1[N:13]=[C:18]([CH3:19])[CH:17]=[C:16]([CH3:15])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(=O)CC(C)=O
Reactant: CCOC(=O)CC(=N)NCCN(C)C
Solvent: c1ccccc1
Product: CCOC(=O)c1c(C)cc(C)nc1NCCN(C)C

Procedure:
A solution of crude ethyl 3-(2-dimethylamino-ethylamino)-3-iminopropionate (15.3 g, 50 mmol) and pentane-2,4-dione (7.7 ml, 75 mmol) in dry benzene (80 ml) is refluxed for 18 hours. This solution is dried over anhydrous sodium sulfate and evaporated to give 18.4 g of crude title B product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]([C:11]#[N:12])=[CH:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2].[N+]([CH3:17])([O-])=O.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:1]([O:3][C:4]([C:5]1([C:11]#[N:12])[CH2:17][CH:6]1[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:13])[CH3:2]
Reactant: CCOC(=O)C(C#N)=CCC(C)C
Reactant: C[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)C1(C#N)CC1CC(C)C
Temperature: 60 °C
Yield: 70.3 %

Procedure:
To a solution of 2-cyano-5-methyl-hex-2-enoic acid ethyl ester (0.74 g, 4.08 mmol) in 16 mL acetonitrile was added nitromethane (1.11 mL, 20.4 mmol), followed by DBU (0.61 mL, 4.08 mmol) resulting in an orange solution. The reaction was heated to 60° C. for 16 hours, then cooled and partitioned between Et2O and 1N HCl (aq). The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated. Flash chromatography of the residue (5→10% EtOAc/hexanes) afforded 0.56 g (70%) of 1-cyano-2-isobutyl-cyclopropanecarboxylic acid ethyl ester as a pale yellow oil. 1H NMR (CDCl3) δ 4.22 (m, 2H), 1.75–1.90 (m, 3H), 1.63 (m, 1H), 1.36 (m, 2H), 1.30 (t, J=7.3 Hz, 3H), 0.95 (m, 6H). 13C NMR δ 168.25, 117.72, 62.94, 39.12, 30.25, 28.12, 25.66, 22.63, 22.40, 19.56, 14.30. LRMS: m/z 196.0 (M+1). Anal. Calcd for C11H17NO2: C, 67.66; H, 8.78; N, 7.17. Found: C, 67.32; H, 8.74; N, 7.32.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]([CH2:12][O:13][CH3:14])[CH3:11].[H][H]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.ClCCl.O1CCCC1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][CH:10]([CH2:12][O:13][CH3:14])[CH3:11]
Reactant: COCC(C)=Nc1c(C)cccc1C
Reactant: [H][H]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCC(C)Nc1c(C)cccc1C
Reaction time: 91 h

Procedure:
The general procedure described in Example B1 is repeated, with the following modifications to the reaction conditions: A catalyst solution is prepared consisting of 5.3 mg of [Ir((1,5-cyclooctadien)Cl]2 (0.0079 mmol), 10.2 mg of A (0.017 mmol) and 11.9 mg of tetrabutylammonium iodide (0.032 mmol) in 5 ml of tetrahydrofuran/dichloromethane (1:1). A substrate solution consisting of 1.5 g of N-(2', 6'-dimethylphenyl)-1-methoxymethyl-ethylideneamine (7.8 mmol) in 5 ml of tetrahydrofuran is also used. Hydrogenation is carded out with hydrogen under a pressure of 40 bar. The reaction temperature is 30° C. After 91 hours the conversion is 90%, the ee is 59% CR).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20].Cl.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C1COCC1>[O:28]=[C:22]1[CH:21]([N:14]2[CH2:13][C:12]3[C:16](=[CH:17][CH:18]=[CH:19][C:11]=3[CH2:10][NH:9][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[C:15]2=[O:20])[CH2:26][CH2:25][C:24](=[O:27])[NH:23]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3c(CNC(=O)c4ccncc4)cccc3C2=O)C(=O)N1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 62.9 %

Procedure:
Triethylamine (0.7 g, 7.4 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and isonicotinoyl chloride hydrochloride (0.5 g, 2.5 mmol) in THF (30 mL) at 5-10° C. After stirring for 10 minutes at 5° C., the mixture was stirred at room temperature overnight. The mixture was filtered, and the solid was slurried with hot methanol (30 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-isonicotinamide (0.5 g, 63%): mp 282-284° C.; 1H NMR (DMSO-d6) δ 2.01-2.06 (m, 1H), 2.38-2.66 (m, 2H), 2.86-2.98 (m, 1H), 4.41-4.64 (m, 4H, 2CH2), 5.12-5.19 (dd, J=4.6 and 13.0 Hz, 1H, CH), 7.48-7.67 (m, 3H, Ar), 7.78-7.80 (d, J=4.8 Hz, 2H, Ar), 8.73-8.75 (m, d, J=4.8 Hz, 2H, Ar), 9.39 (s, 1H, NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.59, 31.18, 39.67, 46.27, 51.61, 121.25, 121.83, 128.38, 130.76, 131.68, 134.11, 140.24, 140.98, 150.27, 164.87, 168.03, 171.00, 172.84; Anal. calcd. for C20H18N4O4: C, 63.49; H, 4.79; N, 14.81. Found: C, 63.22; H, 4.73; N, 14.62.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24]O)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[NH:39]1[CH:43]=[N:42][CH:41]=[N:40]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][N:39]4[CH:43]=[N:42][CH:41]=[N:40]4)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: c1nc[nH]n1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: O
Solvent: C1CCOC1
Product: C(=C/c1nc(COc2ccc(CCCn3cncn3)cc2)co1)\c1ccccc1
Yield: 61.7 %

Procedure:
To a solution of 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol (760 mg), tributyl phosphine (1.01 g) and 1,2,4-triazole (280 mg) in tetrahydrofuran (15 ml) was added dropwise, at 0° C., diethyl azodicarboxylate (700 mg). The mixture was heated for one hour under reflux, poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to a silica gel column chromatography. The crystals obtained from the fraction eluted with ethyl acetate-hexane (2:1, v/v) were recrystallized from ethyl acetate-hexane to give 1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-1,2,4-triazole (540 mg, 70%) as colorless prisms, mp 108-109° C.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH2:14])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:16]([CH2:19][CH3:20])=[C:17]=[O:18]>O1CCCC1>[CH2:19]([NH:16][C:17]([NH:14][CH2:13][C@@H:11]1[CH2:12][C@H:10]1[C:6]1[C:5]2[N:4]([N:3]=[C:2]([CH3:1])[CH:15]=2)[CH:9]=[CH:8][CH:7]=1)=[O:18])[CH3:20]
Reactant: Cc1cc2c([C@@H]3C[C@H]3CN)cccn2n1
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCNC(=O)NC[C@@H]1C[C@H]1c1cccn2nc(C)cc12
Yield: 38.4 %

Procedure:
To a solution of trans-1-[2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methanamine (100 mg, 0.497 mmol) in tetrahydrofuran (5 mL) was added isocyanatoethane (43.3 μL, 0.547 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 10 min. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=3/97→15/85) and recrystallization (ethyl acetate/hexane) to give the title compound (52.0 mg, yield 38%).
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:9]=[C:8]([O:18][CH3:19])[C:5]=1[C:6]#[N:7])([CH3:3])[CH3:2].N.S(=O)(=O)(O)[OH:22]>>[CH:1]([C:4]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:9]=[C:8]([O:18][CH3:19])[C:5]=1[C:6]([NH2:7])=[O:22])([CH3:3])[CH3:2]
Reactant: COc1cc(N2CCOCC2)cc(C(C)C)c1C#N
Reactant: O=S(=O)(O)O
Agent: N
Product: COc1cc(N2CCOCC2)cc(C(C)C)c1C(N)=O
Yield: 86 %

Procedure:
A solution of 2-isopropyl-6-methoxy-4-morpholin-4-yl-benzonitrile (0.37 g, 1.42 mmol) in sulfuric acid (20 ml) is heated at 100° C. for 3 h. After completion of the reaction (monitored by TLC), the mixture is poured onto ice water. The aqueous layer is basified with aqueous ammonia to pH 10 and extracted with ethyl acetate (3×20 ml). The combined organic layers are washed with water (10 ml), dried over sodium sulfate and concentrated in vacuo yielding 2-isopropyl-6-methoxy-4-morpholin-4-yl-benzamide (0.34 g, 1.22 mmol, 86%).
Reaction SMILES: [CH:1]1([C:4]2[C:12](I)=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH2:14][CH3:15])[CH:5]=2)[CH2:3][CH2:2]1.C([Li])CCC.Cl[C:22]([O:24][CH3:25])=[O:23]>C1COCC1.CCOCC>[CH:1]1([C:4]2[C:12]([C:22]([O:24][CH3:25])=[O:23])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH2:14][CH3:15])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)Cl
Reactant: CCc1cc(C2CC2)c(I)cc1C(=O)O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1cc(C2CC2)c(C(=O)OC)cc1C(=O)O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 102 %

Procedure:
To a solution of 4-cyclopropyl-2-ethyl-5-iodobenzoic acid (compound 226.5, 500 mg, 1.58 mmol, 1.00 equiv) in THF/Et2O (10/10 mL) under nitrogen at −78° C. was added dropwise n-butyllithium (2.5 M, 1.88 mL, 3.00 equiv) over 3 min. After stirring for 10 min at −78° C., methyl chloroformate (230 mg, 2.43 mmol, 1.50 equiv) was added dropwise at −78° C. The resulting solution was stirred for 40 min at −78° C., then warmed slowly to −35° C. The reaction was carefully quenched with 2 mL of water. The pH was adjusted to ˜4-5 with hydrogen chloride (aq., 1 M). The resulting mixture was extracted with 3×20 mL of ethyl acetate and the combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to yield 400 mg the title compound as a yellow solid.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][CH2:12][CH2:13][Cl:14])=[O:10]>O.C(O)=O>[CH2:7]([NH:8][C:9]([N:11]([N:1]=[O:3])[CH2:12][CH2:13][Cl:14])=[O:10])[CH2:6][Cl:5]
Reactant: O=N[O-]
Reactant: O=C(NCCCl)NCCCl
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: O=NN(CCCl)C(=O)NCCCl
Reaction time: 2 h

Procedure:
A cold solution of 0.2346 g (3.4 mmole) sodium nitrite in 2 ml water was slowly added to a stirred solution of 0.2727 g (1.47 mmole) 1,3-bis(2-chloroethyl)urea in 2 ml 88% formic acid at 0°. After 2 hours at 0°, 0.1449 g (46.0%) of an oil solid phase was removed. The ir spectrum of this fraction failed to agree with that of BCNU. After 2 days a small amount of crystalline BCNU slowly formed in this oil phase. A methylene dichloride extract of the aqueous phase yielded 0.0943 g (30.0%) of an amber oil whose ir spectrum agreed with that of a known sample of BCNU. Treatment of this oil with 5 ml hexane and cooling to 0° gave crystalline BCNU which formed an oil on warming to ambient temperature.
Reaction SMILES: C(O[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[C:6](=[O:8])[CH3:7])C.[CH3:12][NH:13][N:14]=[C:15]([CH3:17])[CH3:16]>CCOCC>[CH3:12][N:13]([CH:4]=[C:5]([C:6](=[O:8])[CH3:7])[C:9](=[O:11])[CH3:10])[N:14]=[C:15]([CH3:17])[CH3:16]
Reactant: CCOC=C(C(C)=O)C(C)=O
Reactant: CNN=C(C)C
Solvent: CCOCC
Product: CC(=O)C(=CN(C)N=C(C)C)C(C)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-(ethoxymethylene)pentane-2,4-dione (Preparation 2, 8.6 g) was dissolved in Ether (30 mL) and cooled to 0° C. The reaction solution was then slowly treated with 1-methyl-2-(propan-2-ylidene)hydrazine (Preparation 1, 4.8 g) dropwise over 5 minutes, and then warmed and stirred at room temperature overnight. The reaction solution was purified directly by flash column chromatography (Biotage Quad 25; Eluent: 20% EtOH in EtOAc) to afford the title compound as a light red solid. (9.1 g, 84.0%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[NH:5][C:4](=[O:13])[C:3]=1[C:14]#[N:15].[N:16]1([C:22]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[N:7][CH:8]=1)[NH:5][C:4](=[O:13])[C:3]([C:14]#[N:15])=[C:2]2[N:19]1[CH2:20][CH2:21][N:16]([C:22]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:17][CH2:18]1
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: N#Cc1c(Cl)c2cc(Cl)cnc2[nH]c1=O
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2[nH]c1=O
Yield: 74 %

Procedure:
This compound was prepared from 4,6-dichloro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (97) and piperazin-1-yl-thiophene-2-yl-methanone according to general procedure E to yield 6.8 g (74%) of 6-chloro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (100) as yellow solids. MP 158° C.; 1H-NMR (DMSO-d6): δ 3.64 (m, 4H), 3.90 (m, 4H), 7.16 (dd, J=3.6, 4.8 Hz, 1H), 7.49 (dd, J=1.2, 3.6 Hz, 1H), 7.81 (dd, J=1.2, 5.2 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.66 (d, J=2.4 Hz, 1H); EIMS: 400 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[C:13]([OH:32])[CH:12]=1.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[F:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]2[N:18]([CH:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:23][CH2:24]3)[C:34](=[O:36])[O:32][C:13]=2[CH:12]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(O)cc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cc1F)oc(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 276.3 %

Procedure:
Hünig's base (0.5 mL, 2.86 mmol) was added to a solution of 1,1-dimethylethyl 4-[(4-fluoro-2-hydroxy-5-methylphenyl)amino]-1-piperidinecarboxylate (D1, 593 mg, 1.34 mmol) in dichloromethane (10 mL) at rt under argon. The reaction was cooled to 0° C. and the triphosgene (167 mg, 0.564 mmol) was added. The reaction was then stirred for 1.5 h at 0° C. and quenched with saturated aqueous NaHCO3 (10 mL) before being partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×) and the combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give an orange oil. The residue was purified via chromatography (silica, dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) to give 1,1-dimethylethyl 4-(6-fluoro-5-methyl-2-oxo-1,3-benzoxazol-3(2H)-yl)-1-piperidine carboxylate (D2, 546 mg, 73% purity, 85% yield) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[H-].[Na+].[CH3:23][N:24]([CH2:26][CH2:27]Cl)[CH3:25].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33]>CN(C)C=O.O>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].[CH3:23][N:24]([CH3:25])[CH2:26][CH2:27][S:20][C:11]1[CH2:10][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: CN(C)CCCl
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Agent: O=C(O)/C=C\C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCSC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6.4 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in 50 ml of anhydrous dimethylformamide is added under ice cooling with stirring 1.2 g of sodium hydride (50% oily suspension), and the resulting mixture is stirred at room temperature for 20 minutes. To the mixture is added dropwise 6.6 g of N,N-dimethyl-2-chloroethylamine over a period of 10 minutes, followed by stirring at room temperature for 1 hour. The reaction mixture is poured into iced water and then extracted with chloroform. The extract is water washed and dried over magnesium sulfate, and the solvent is distilled off. An oily product obtained as the residue is subjected to column chromatography on alumina and eluted from the column with benzene. The eluate is concentrated to obtain a crude 2-(2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The crude product thus obtained is treated, according to usual procedure, with maleic acid and then recrystallized from an anhydrous isopropyl alcohol-acetone mixture to obtain 4.8 g of 2-(2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine maleate, m.p. 140°-142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.I.[NH2:12][NH:13][C:14]([NH:16][CH2:17][C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1)=[NH:15].C(O)C.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[N:12][NH:13][C:14]([NH:16][CH2:17][C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1)=[NH:15]
Reactant: N=C(NN)NCc1cnccn1
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: N=C(NCc1cnccn1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 2.83 g. of 2,6-dichlorobenzaldehyde and 1-amino-3-(pyrazinylmethyl)guanidine hydriodide from Example 10 in 50 ml. of absolute ethanol and 5.0 ml. of glacial acetic acid is heated at reflux for 4 hours. The cooled solution is made basic by addition of 10N sodium hydroxide and extracted with ether. The ether extract is evaporated to give a residual orange gum which is crystallized from absolute ethanol to give the desired product as colorless crystals, m.p. 168°-169° C.