Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28]C)[CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]#[N:15])[CH2:9]1)C1C=CC=CC=1.[OH-:30].[K+].B(Br)(Br)Br.C(Cl)Cl.N>C(O)(C)(C)C.CCOCC.O>[OH:28][C:24]1[CH:23]=[C:22]([C@@:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[C:14]([NH2:15])=[O:30])[CH:27]=[CH:26][CH:25]=1
Reactant: [OH-]
Reactant: COc1cccc(C(C#N)(c2ccccc2)[C@@H]2CCN(Cc3ccccc3)C2)c1
Agent: BrB(Br)Br
Agent: N
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: NC(=O)[C@@](c1ccccc1)(c1cccc(O)c1)C1CCNC1
Temperature: 110 °C
Reaction time: 336 h

Procedure:
To a stirred solution of ((S)-1-benzylpyrrolidin-3-yl)-(3-methoxyphenyl)phenylacetonitrile (6.2 g, 16 mmol; prepared as described in Preparation 7) in t-butyl alcohol (150 mL) was added KOH (35 g, 620 mmol). The reaction flask was equipped with a reflux condenser and nitrogen inlet and stirred at 110° C. for 14 days. The mixture was allowed to cool to room temperature. Water (120 mL) and ether (100 mL) were added to the mixture. The organic phase was then separated, and the aqueous phase was extracted 2 times with ether (100 mL each). The organic layers were combined, dried over MgSO4, then filtered. The solvent was removed under reduced pressure and the crude material was then taken in DCM (250 mL) and cooled to 0° C. To this stirred solution was added 1.0 M of boron tribromide in DCM (30 mL, 30 mmol) and the mixture was stirred at 0° C. for 90 minutes. The mixture was then added to a stirred solution of 30% ammonia & ice. The mixture was then filtered through a pad of Celite®, then washed with a saturated aqueous NaCl solution (200 mL). The organic phase was dried over MgSO4, then filtered. The solvent was removed under reduced pressure. The crude material was then subjected to normal hydrogenation conditions to obtain the title compound. MS m/z: {M+H+] calcd for C18H20N2O2, 296.36; found 297.6.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:14][N:13]([CH2:15][CH2:16][C:17]([NH:19]C2C=CC=CC=2)=[O:18])[C:12](=[O:26])[CH2:11][N:10]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC=CC=1.C[Si](C)(C)N[Si](C)(C)C>>[CH2:1]([CH:8]1[CH2:14][N:13]([CH2:15][CH2:16][C:17]([NH2:19])=[O:18])[C:12](=[O:26])[CH2:11][N:10]([S:27]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)(=[O:29])=[O:28])[C:9]1=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCN1CC(Cc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(Cl)cc2)CC1=O)Nc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: Nc1ccccc1
Product: NC(=O)CCN1CC(Cc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(Cl)cc2)CC1=O

Procedure:
Instead of the starting material compound of Example 273, that is, aniline, 1,1,1,3,3,3-hexamethyldisilazane was used for the similar procedure as in Example 273 to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3](=[CH2:8])[C:4]([F:7])([F:6])[F:5].[CH3:11][O-:12].[Na+]>CO>[F:1][C:2]([F:10])([F:9])[C:3](=[CH2:8])[C:4]([F:7])([F:6])[F:5].[CH:11]([OH:12])=[CH2:2]
Reactant: C[O-]
Agent: C=C(C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CO
Product: C=CO

Procedure:
Hexafluoroisobutylene (HFIB)/Vinyl Alcohol (VOH) Copolymer. Fifty grams of the poly(HFIB/VOAc) prepared above, 500 ml of methyl alcohol, and 25 ml of 25 wt % sodium methoxide in methyl alcohol were refluxed for 6 hours. Over this period additional methyl alcohol was added as ˜860 ml of methyl alcohol were distilled off. Addition of resulting polymer solution to water gave a gummy precipitate. The water was decanted off and the precipitate taken back into 200 ml of methyl alcohol and reprecipitated with 500 ml of water in a Waring blender. Vacuum filtration, drying under pump vacuum and then for 24 hours in a 75° C. vacuum oven gave 37 g of poly(HFIB/VOH) as off white granules.
Reaction SMILES: C(O[C:4]([CH:6]1[C:14](=[O:15])[C:13]2[CH:12]=[N:11][CH:10]=[CH:9][C:8]=2[C:7]1=[O:16])=[O:5])C.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:17][C:4]([CH:6]2[C:14](=[O:15])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7]2=[O:16])=[O:5])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1C(=O)c2ccncc2C1=O
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)C1C(=O)c2ccncc2C1=O

Procedure:
In a similar manner to Example 1a, 5,7-dioxo-6,7-dihydro-5H-[2]pyrindine-6-carboxylic acid phenylamide was obtained starting from 5,7-dioxo-6,7-dihydro-5H-[2]pyrindine-6-carboxylic acid ethyl ester and aniline. The desired product was obtained as a brownish orange powder. ESI−MS: m/z 267 (MH+); 1H-NMR (DMSO-d6): δ6.93 (1H, t, J=7.3 Hz), 7.26 (2H, t-like, 7.3 Hz), 7.33 (1H, dd, J=1.4 Hz, 4.6 Hz), 7.59 (2H, d, J=7.3 Hz), 8.51 (1H, d, J=1.4 Hz), 8.72 (1H, d, J=4.6 Hz), 10.78 (1H, brs).
Reaction SMILES: [CH3:1][C:2]1([CH3:45])[C:22]2[C:9](=[CH:10][C:11]3[C:12]([C:35]4[CH:44]=[CH:43][C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH:36]=4)(O)[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]([C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=4)(O)[C:20]=3[CH:21]=2)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[I-].[K+].[PH2]([O-])=O.[Na+]>C(O)(=O)C>[CH3:1][C:2]1([CH3:45])[C:22]2[C:9](=[CH:10][C:11]3[C:12]([C:35]4[CH:44]=[CH:43][C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH:36]=4)=[C:13]4[C:18](=[C:19]([C:24]5[CH:33]=[CH:32][C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[CH:25]=5)[C:20]=3[CH:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14]4)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)C(O)(c1ccc2ccccc2c1)c1ccccc1C3(O)c1ccc2ccccc2c1
Agent: O=[PH2][O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1(C)c2ccccc2-c2cc3c(-c4ccc5ccccc5c4)c4ccccc4c(-c4ccc5ccccc5c4)c3cc21
Reaction time: 5 h
Yield: 86.8 %

Procedure:
13,13-dimethyl-6,11-di(naphthalen-2-yl)-11,13-dihydro-6H-indeno[1,2-b]anthracene-6,11-diol (5 g, 1 eq, 0.0075 mol), potassium iodide (12.45 g, 10 eq, 0.075 mol), and sodium hypophosphite (6 g, 5 eq, 0.037 mol) were placed in a flask, acetic acid (200 ml) was added thereto, and the reaction mixture was stirred for five hours while heating. After the reaction was terminated, the reaction solution was added to an excess of distilled water. The resultant solid was washed, filtered and purified by column chromatography to give 13,13-dimethyl-6,11-di(naphthalen-2-yl)-13H-indeno[1,2-b]anthracene (3.56 g, yield=76%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)=[C:16]([F:31])[CH:15]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(#N)C.O>[F:31][C:16]1[CH:15]=[C:14]([CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:19]=[CH:18][C:17]=1[NH:20][C:21]1[N:22]=[CH:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][N:26]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ncc(C(F)(F)F)cn3)c(F)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Fc1cc(C2CNCCO2)ccc1Nc1ncc(C(F)(F)F)cn1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (RS)-2-[3-fluoro-4-(5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (110 mg) in acetonitrile (2 ml) and water (4 ml) was added trifluoroacetic acid (190 μl). The reaction mixture was then capped and the mixture was shaken at 80° C. for 4 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/EtOAc) to (RS)-(2-fluoro-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine (23 mg, 27%) as a white solid. MS (ISP): 343.1 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C[N:21]([CH:23]=O)C>C1COCC1.[NH4+].[Cl-].CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:1][C:2]2[CH:7]=[CH:6][C:5]([C:23]#[N:21])=[CH:4][CH:3]=2)[C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2=O)cc1
Reaction time: 5 h

Procedure:
To a solution of 3-oxo-piperazine-1-carboxylic acid benzyl ester (3.0 g, 12.8 mmol) and 4-bromomethyl tolylnitrile (2.76 g, 14.1 mmol) in 135 mL of THF and 15 mL of DMF at 0° C. is added a 60% dispersion in mineral oil of NaH (0.49 g, 12.8 mmol). After 5 hours, the solution is diluted with saturated NH4Cl and EtOAc. The organic layer is washed with H2O and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography over silcia gel eluting with 20% EtOAc/CH2Cl2. The title compound is obtained as a white solid (4.01 g, 11.4 mmol). 1H NMR (CDCl3, 300 MHz) δ7.62 (d, 2H), 7.39 (m, 7H), 5.14 (s, 2H), 4.68 (s, 2H), 4.27 (s, 2H), 3.73 (m, 2H), 3.30 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:13][C@H:14]2[CH2:18][N:17]([C@@H](C3C=CC=CC=3)C)[C:16](=O)[CH2:15]2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[C].[Pd].C(O)C>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:13][C@H:14]2[CH2:15][CH2:16][NH:17][CH2:18]2)[CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](c1ccccc1)N1C[C@H](CC2(NC(=O)OC(C)(C)C)CCC2)CC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(C[C@H]2CCNC2)CCC1

Procedure:
Ethanol (30 ml) solution of 3-(R)-[1-(tert-butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]pyrrolidine (isomer B1) (516 mg, 1.44 mmol) was mixed with 10% palladium-carbon catalyst (53.8% moisture, 500 mg), and 5 hours of catalytic hydrogenation was carried out in an atmosphere of hydrogen at an outer temperature of 50° C. under atmospheric pressure. The reaction solution was filtered and the solvent was evaporated under a reduced pressure to obtain 366 mg (quantitative) of the title compound as colorless crystals.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[CH:15]([C:18]1[NH:19][C:20]([CH:41]([CH3:43])[CH3:42])=[C:21]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:22]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:17])[CH3:16]>C(Cl)Cl>[CH:41]([C:20]1[C:21]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:22]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:18]([CH:15]([CH3:17])[CH3:16])[N:19]=1)([CH3:43])[CH3:42]
Reactant: CCOC(=O)C1=C(C(C)C)NC(C(C)C)=C(C(=O)OCC)C1c1ccc(F)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.8 g (16.4 mmol) of 2,3-dichloro-5,6-dicyano-p-benzoquinone are added to a solution of 6.6 g (16.4 mmol) of the compound from Example 2 in 200 ml of methylene chloride p.a. and the mixture is stirred for 1 h at room temperature. It is then filtered with suction over kieselguhr, and the methylene chloride phase is extracted three times with 100 ml of water each time and dried over magnesium sulphate. After concentrating in vacuo, the residue is chromatographed on a column (100 g of silica gel 70-230 mesh, φ3.5 cm, using ethyl acetate/petroleum ether 1:9).
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:15][C:14](=C)[C:13]2=[O:17])=[CH:8][CH:7]=1.[O:18]=[O+][O-]>C(O)(C)C>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:15][C:14](=[O:18])[C:13]2=[O:17])=[CH:8][CH:7]=1
Reactant: C=C1CN(c2ccc(OC)cc2)C1=O
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1ccc(N2CC(=O)C2=O)cc1
Temperature: 25 °C

Procedure:
A 100 ml quantity of methylene chloride and 7.5 ml of isopropyl alcohol were added to 20 g of 1-(4-methoxyphenyl)3-methylene azetidine-2-one 9 and dissolved with stirring. The reaction mixture was cooled to -15° C. after which an ozone gas was introduced over a period of 30 minutes. The excess ozone gas was removed using nitrogen gas and 3 ml of thiodiethanol and 6 g of thiodicresol were added, while being warmed to room temperature and then stirred for 1 hour. The reaction mixture was filtered to remove the precipitated thiodiethanolsulfoxide and washed once with 5% aqueous sodium bicarbonate and twice with 50 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, giving 14 g of the title compound 10. The 1H-NMR spectrum of the compound was the same as that of an authentic sample. ##STR5##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:22]([CH3:39])[C:23](=[O:38])[CH2:24][N:25]3[C:30]4[CH:31]=[C:32]([Cl:36])[C:33]([Cl:35])=[CH:34][C:29]=4[O:28][CH2:27][C:26]3=[O:37])[CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:40]([S:42](Cl)(=[O:44])=[O:43])[CH3:41].C(N(CC)CC)C>ClCCl>[Cl:36][C:32]1[C:33]([Cl:35])=[CH:34][C:29]2[O:28][CH2:27][C:26](=[O:37])[N:25]([CH2:24][C:23]([N:22]([CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([NH:1][S:42]([CH2:40][CH3:41])(=[O:44])=[O:43])=[CH:7][CH:6]=4)=[CH:9][CH:10]=3)[CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH3:39])=[O:38])[C:30]=2[CH:31]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2ccc(N)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1ccc(-c2ccc(C(CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)cc1
Reaction time: 0.25 h
Yield: 23.1 %

Procedure:
To a solution of N-[1-(4′-amino-4-biphenylyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (68 mg, 0.12 mmol) in dichloromethane (2 mL) was added ethanesulfonyl chloride (18.5 mg, 0.14 mmol). Triethylamine (24 mg, 0.24 mmol) was added, and the resultant mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by Gilson preparative HPLC (Xterra Prep RP, 30×100 mm, 45 mL/min, A: acetonitrile with 0.1% TFA B: water with 0.1% TFA, A: 25 to 55% over 15 min, UV detection at 214 nm) to give 18.3 mg (23%) of the title compound as an off white solid. MS (ES) m/e 661.1 [M+H]+.
Reaction SMILES: N1C=CC=C(CN)C=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][NH2:16].FC1C=CC(CN2[C@@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1.[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[C:63]([F:65])[CH:64]=1)[CH2:45][N:46]1[C@H:50]([CH3:51])[CH2:49][N:48]([C:52]2[S:53][C:54]([C:58](O)=[O:59])=[C:55]([CH3:57])[N:56]=2)[C:47]1=[O:61]>>[F:65][C:63]1[CH:62]=[C:44]([CH:43]=[C:42]([F:41])[CH:64]=1)[CH2:45][N:46]1[C@H:50]([CH3:51])[CH2:49][N:48]([C:52]2[S:53][C:54]([C:58]([NH:16][CH2:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=3)=[O:59])=[C:55]([CH3:57])[N:56]=2)[C:47]1=[O:61]
Reactant: NCc1ccccn1
Reactant: Cc1nc(N2C[C@@H](C)N(Cc3cc(F)cc(F)c3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2C[C@@H](C)N(Cc3cc(F)cc(F)c3)C2=O)sc1C(=O)NCc1ccccn1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with pyridin-2-ylmethanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (R)-2-(3-(3,5-difluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white solid: mp 147-148° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.55-8.50 (m, 2H), 7.79-7.73 (m, 1H), 7.31-7.24 (m, 2H), 7.19-7.08 (m, 3H), 4.60-4.37 (m, 4H), 4.27-4.20 (m, 1H), 3.88-3.81 (m, 1H), 3.60 (dd, J=10.1, 6.7 Hz, 1H), 2.50 (s, 3H), 1.23 (d, J=6.2 Hz, 3H); MS (ES+) m/z 458.0 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[C:7](=[O:20])[N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:10][CH2:11][CH:12]=1.CO.[NH2:24][O:25][K].C(O)(=O)C>C(OCC)(=O)C>[CH2:13]([N:8]1[CH2:9][CH2:10][CH2:11][CH:12]=[C:6]([CH2:5][CH2:4][C:3]([NH:24][OH:25])=[O:2])[C:7]1=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NO[K]
Reactant: COC(=O)CCC1=CCCCN(Cc2ccccc2)C1=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(CCC1=CCCCN(Cc2ccccc2)C1=O)NO
Temperature: 0 °C
Reaction time: 3 h
Yield: 42.4 %

Procedure:
108 mg of compound (d) prepared by the above Step 3 was dissolved in methanol solution (0.376 mmol) and then 1.7 M methanolic suspension solution containing NH2OK (1.315 ml, 2.63 mmol) was added thereto at 0° C. and the resulting mixture was stirred for 3 hrs at room temperature. The resulting mixture was neutralized with 0.02 ml of acetic acid, diluted with 10 ml of ethyl acetate solution, filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on Silica gel with methanol/chloroform (1:10) solvent mixture as an eluant to give 46 mg of the title compound (e1) (yield: 43%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CN(C)C=O>[N:13]1([CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-bromomethylbenzoate (14.75 g) in dimethylformamide (50 ml), cooled to 5° C., was added rapidly morpholine (13.8 ml). The mixture was stirred at room temperature for 2 h. The mixture was partitioned between diethyl ether and water. The organic layer was washed with water, dried (MgSO4), evaporated and purified by column chromatography eluting with ethyl acetate/iso-hexane (20:80) to give methyl 4-(morpholin-4-ylmethyl)benzoate (14.13 g) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1S(C)(=O)=O)[CH3:2].C1(C)C=CC=CC=1.C[O:33]CCOCCOC.[OH-].[Na+]>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1[OH:33])[CH3:2]
Reactant: COCCOCCOC
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Temperature: 120 °C
Reaction time: 15 h
Yield: 87 %

Procedure:
To a 100 mL volume four-necked flask, 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydropyridazin-3-one ((2-34)-(1)-39) (6.57 g), toluene (16.7 g), diethylene glycol dimethylether (3.6 g), and sodium hydroxide (2.86 g) were added under a nitrogen atmosphere, and stirred at 120° C. for 15 hours. Then, water (24.2 g) was added at room temperature. The organic layer was removed, and then the aqueous layer was mixed with 3.5 w/w % of hydrochloric acid (25 g) at the same temperature, and filtered. The residue was washed with water (12 g) and dried to give 4.7 g of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-39).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-])=O)=[C:8]([NH:11][C:12](=O)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[NH:4][C:3]1=[O:25].[CH2:27]([N:30]=[C:31]=[O:32])[CH2:28][CH3:29]>C1(C)C=CC=CC=1>[CH2:27]([NH:30][C:31]([N:4]1[C:5]2[CH:6]=[C:7]3[N:22]=[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)[NH:11][C:8]3=[CH:9][C:10]=2[C:2]([CH3:26])([CH3:1])[C:3]1=[O:25])=[O:32])[CH2:28][CH3:29]
Reactant: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])NC(=O)C3(C)C)cc1
Reactant: CCCN=C=O
Solvent: Cc1ccccc1
Product: CCCNC(=O)N1C(=O)C(C)(C)c2cc3[nH]c(-c4ccc(OC)cc4)nc3cc21
Temperature: 150 °C
Reaction time: 0.25 h

Procedure:
A solution of N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-4-methoxy-benzamide (200 mg) and propyl isocyanate (59 μl) in dry toluene (2 ml) is stirred in a microwave apparatus at 150° C. for 900 s. The resulting solid is collected by filtration, dissolved in acetic acid (3 ml) and iron (200 mg; powder) is added and the mixture is again stirred in a microwave apparatus at 150° C. for 900 s to achieve reduction of the nitro function and ring closure. The mixture is filtered and concentrated in vacuo. The desired compound (65 mg) is obtained by preparative RP-HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)=[N:10]1.Cl.CN.C1C=[C:36]2[N:38]=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O.C(N(CC)CC)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:38][CH3:36])=[O:25])=[CH:27][CH:28]=2)=[N:10]1
Reactant: On1nnc2ccccc21
Reactant: COc1nccc2c1c(-c1ccc(C(=O)O)cc1)nn2-c1c(F)cccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(-c2nn(-c3c(F)cccc3F)c3ccnc(OC)c23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of 4-(1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzoic acid (2.59 g), methylamine hydrochloride (688 mg), HOBt monohydrate (1.56 g) and triethylamine (1.89 mL) in DMF (20 mL) was added EDCI hydrochloride (1.95 g) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the white precipitate was filtered, washed with water and hexane, and dried in vacuum to give the title compound (2.68 g).
Reaction SMILES: C([C:5]1[N:14](CC2C=CC(N3C=C(Cl)C(Cl)=C3C#N)=CC=2)[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)CCC.C[Sn](N=[N+]=[N-])(C)C.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:13][C:12]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:14][CH:5]=[N:6][C:7]=12
Reactant: CCCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(Cl)c(Cl)c2C#N)cc1
Agent: C[Sn](C)(C)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: Cc1ccnc2[nH]cnc12
Temperature: 120 °C
Reaction time: 22 h
Yield: 346.7 %

Procedure:
A mixture of 2-butyl-3-[4-(3,4-dichloro-2-cyano-1-pyrrolyl)benzyl]-7-methyl-3H-imidazo[4,5-b]pyridine (490 mg) and trimethyltin azide (690 mg) in xylene (5 ml) was stirred at 120° C. for 22 hours. After cooled to ambient temperature, the mixture was treated with aqueous 1N sodium hydroxide (10 ml) for 4 hours. The suspension was filtered. The filtrate was washed with diisopropyl ether, adjusted to pH 4 with aqueous 1N-hydrochloric acid, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution by methanol/dichloromethane=1/8) to give 2-butyl-3-[4-[3,4-dichloro-2-(1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]benzyl]-7-methyl-3H-imidazo[4,5-b]pyridine (516 mg) as an amorphous solid.
Reaction SMILES: F[C:2]1[C:7]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)=[C:6]([CH3:13])[CH:5]=[CH:4][N:3]=1.[NH3:14]>>[CH3:13][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:14])[C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1
Reactant: N
Reactant: Cc1ccnc(F)c1-n1cccc1
Product: Cc1ccnc(N)c1-n1cccc1
Temperature: 150 °C
Yield: 76 %

Procedure:
2-Fluoro-4-methyl-3-(1H-pyrrol-1-yl)pyridine (3.9 g, 22.1 mmol) was dissolved in 80 mL of ammonia solution (7N in MeOH) in a sealed tube (350 mL). The mixture was heated at 150° C. for 2 days protected with a blast shield. The mixture was cooled to room temperature, then cooled in the ice for minutes. The filtrate was evaporated to dryness and purified by flash chromatography (EtOAc/Hexanes=1:1, Rf=0.5) to give 2.9 g (76%) white solid. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=5.1 Hz, 1H) 6.67 (t, J=2.1 Hz, 2H), 6.60 (d, J=5.2 Hz, 1H), 6.41 (t, J=2.1 Hz, 2H), 4.52 (s, 2H), 2.02 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.1, 147.2, 145.9, 121.5, 121.1, 116.0, 110.0, 16.7. HRMS (m/z): calcd for C10H12N3 (M+H) 174.1031. found 174.1026. Peet & Sunder (1986) Heterocycles 24:3213-3221.