Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](P(CCCC)CCCC)CCC.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:28]1([S:34]([CH2:37][C:38]2[C:43]([C:44]([OH:46])=[O:45])=[C:42]([OH:47])[C:41]([C:48]3[CH:52]=[CH:51][O:50][CH:49]=3)=[CH:40][CH:39]=2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C:53]([N:60]1[CH2:63][CH:62](O)[CH2:61]1)([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54]>C1COCC1.O.C(OCC)(=O)C>[C:28]1([S:34]([CH2:37][C:38]2[C:43]([C:44]([O:46][CH3:1])=[O:45])=[C:42]([C:41]([C:48]3[CH:52]=[CH:51][O:50][CH:49]=3)=[CH:40][CH:39]=2)[O:47][CH:62]2[CH2:63][N:60]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:61]2)(=[O:36])=[O:35])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: CCCCP(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 429.3 %

Procedure:
Tri-n-butylphosphine (0.087 g) was added dropwise to a solution of di-isopropyl azodicarboxylate (0.099 g) in dry THF (2 ml) at 0° C. The mixture was warmed to room temperature for 10 minutes then re-cooled to 0° C. A mixture of methyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 114, 0.05 g) and N-Boc-azetidin-3-ol (0.045 g) in THF (1 ml) was added dropwise and then the reaction mixture was warmed to room temperature for 10 minutes then heated to 55° C. for 6 hours. After cooling, ethyl acetate and water were added and the organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane (1:3) to give t-butyl 3-[3-(benzenesulphonylmethyl)-6-(furan-3-yl)-2-(methoxycarbonyl)phenoxy]azetidine-1-carboxylate (0.316 g) as a gum.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C(OCC(=O)C[O:26][C:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)C1C=CC=CC=1)CCCCCCCCCCCCCCC.[OH2:47]>CCCCCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH2:4]([O:47][CH:41]([CH2:42][O:26][C:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:40]=[CH2:27])[CH2:3][CH2:2][CH2:1][CH2:1][CH2:2][CH2:3][CH2:4][CH2:1][CH2:2][CH2:3][CH2:4][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: O
Reactant: CCCCCCCCCCCCCCCCOCC(=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1COCCO1
Product: C=CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82 %

Procedure:
A solution of n-butyllithium (47 ml, 113 mmol) in hexane was added to a suspension of methyltriphenylphosphonium bromide (40.0 g, 112 mmol) in 100 ml dry dioxane under N2 and the dark red solution was stirred at room temperature for 45 minutes. Compound 1 (35.1 g, 63.1 mmol) in 100 ml dry dioxane was added and the mixture was stirred for 2 hours. Water (10 ml) was added and the solution was partitioned between hexane and water. The aqueous layer was washed 2 times with hexane and the combined organic layers were dried over Na2SO4 and concentrated. The residue was crystallized from ethanol to afford 28.8 g (82%) of the title compound (2) as white needles, m.p. 34° ; NMR (CDCl3, (CH3)4Si); δ0.90 (t, 3H, J=6 Hz, --CH3), 1.25 (s, 26H, --CH2 --), 1.62 (m, 2H, --OCH2CH2R), 3.35 (t, 2H, J=7 Hz, --OCH2R), 3.62 (s, 2H, CH2OTr), 3.96 (s, 2 H, --CH2OR), 5.20 (d, 1 H, J=2 Hz, olefin), 5.40 (d, 1H, J=2 Hz, olefin), 7.2-7.5 (m, 15H, C(C6H5)85)3).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24](O)=[O:25].[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30].C(N(CC)CC)C.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH:30][C:24](=[O:25])[CH2:23][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:2]1=[O:1]
Reactant: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Reactant: Nc1ccccc1F
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21)Nc1ccccc1F
Temperature: 25 °C
Yield: 11.9 %

Procedure:
To a solution of (2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetic acid (0.53 g, 1.50 mmol), 2-fluoroaniline (0.2 mL, 2.1 mmol) and triethylamine (0.5 mL, 3.5 mmol) in chloroform (30 mL) was added 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (0.48 g, 1.94 mmol). The reaction mixture was heated at reflux for 26 h, allowed to cool to ambient temperature, diluted with ethyl acetate and washed sequentially with water, 10% w/v hydrochloric acid, water, 10% w/v aqueous sodium hydroxide, water and brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography and eluted with ethyl acetate/hexanes (1/3) to afford N-(2-fluorophenyl)-2-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetamide (0.08 g, 12%): mp 117-119° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.24-8.22 (m, 1H), 8.05-7.90 (m, 1H), 7.33-6.95 (m, 6H), 6.50-6.47 (m, 1H), 6.33-6.30 (m, 1H), 4.94-4.89 (m, 1H), 4.68-4.49 (m, 4H), 4.17-4.09 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 178.2, 164.6, 155.2, 144.7, 141.3, 138.4, 131.9, 129.1, 125.6, 124.9, 121.8, 120.4, 115.0, 114.8, 111.7, 108.9, 99.4, 80.0, 64.6, 63.8, 58.0, 45.1; MS (ES+) m/z 446.8 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][C:13]3=[O:20])=[CH:8]2)=[N:3]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:19][CH2:18][C:15]1[CH:16]=[CH:17][N:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[C:10]([CH3:11])[N:2]([CH3:1])[N:3]=3)[CH:8]=2)[C:13](=[O:20])[CH:14]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c2cc(-n3ccc(CO)cc3=O)ccc2nn1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c2cc(-n3ccc(COS(C)(=O)=O)cc3=O)ccc2nn1C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-(hydroxymethyl)pyridin-2(1H)-one (100 mg) in dichloromethane (5 ml) was added triethylamine (0.153 ml) at 0° C., and the mixture was stirred at the same temperature for 30 min. To the obtained reaction mixture was added methanesulfonyl chloride (0.057 ml) at 0° C., and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (120 mg).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.Cl.[NH2:7][C:8]1[N:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:33])[N:12]2[CH2:22][CH2:23][CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>CN1C(=O)CCC1>[NH2:7][C:8]1[N:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:33])[N:12]2[CH2:22][CH2:23][CH2:24][N:25]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCc3ccccc3)c2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3ccccc3)C(C)=O)c2n1
Reaction time: 2 h

Procedure:
Acetylchloride (0.08 ml) was added to a mixture of the product from step (viii) (250 mg) and triethylamine (0.6 ml) in NMP (5 ml) and stirred for 2 h. The mixture was purified by to RPHPLC, yield 85 mg.
Reaction SMILES: [B-](F)(F)(F)F.CN(C(O[N:14]1[C:19](=O)[CH2:18][CH2:17][C:15]1=O)=[N+](C)C)C.[OH:21][CH:22]([C:24]1[CH:25]=[C:26]([C:41](O)=[O:42])[CH:27]=[C:28]2[C:33]=1[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[CH:30][C:29]2=[O:40])[CH3:23].C(N(C(C)C)C(C)C)C.N1CCCC1>C(Cl)Cl>[OH:21][CH:22]([C:24]1[CH:25]=[C:26]([C:41]([N:14]2[CH2:15][CH2:17][CH2:18][CH2:19]2)=[O:42])[CH:27]=[C:28]2[C:33]=1[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[CH:30][C:29]2=[O:40])[CH3:23]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(O)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNC1
Product: CC(O)c1cc(C(=O)N2CCCC2)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
2-(2,5-dioxopyrrolidin-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (3.34 g, 11.09 mmol) at 25° C. was added portionwise to 8-(1-hydroxyethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (1.77 g, 5.54 mmol) and N-ethyl-N-isopropylpropan-2-amine (2.028 mL, 11.64 mmol) suspended in DCM (15 mL) under nitrogen. The resulting mixture was stirred at 25° C. for 5 hrs. Pyrrolidine (1.388 mL, 16.63 mmol) was then added to the mixture and the resulting mixture was stirred at 25° C. overnight. The mixture was poured onto a silica gel column and purified by flash chromatography eluting with 2 to 7% methanolic ammonia (7 N) in DCM. The solvent was evaporated to dryness, the residue was triturated in ethylacetate (10 mL), collected by filtration and dried to afford 8-(1-hydroxyethyl)-2-morpholino-6-(pyrrolidine-1-carbonyl)-4H-chromen-4-one (1.66 g, 80%) as a beige solid. Mass Spectrum: M+H+ 373.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)[NH2:7])(=[O:3])[CH3:2].Cl[C:15]1[N:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[N:16]=1.Cl.Cl.C(C1C=C(NC(NC(N)=N)=N)C=C(C(=O)C)C=1)(=O)C>O>[C:1]([C:4]1[CH:5]=[C:6]([NH:7][C:15]2[N:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[N:16]=2)[CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(N)cc(C(C)=O)c1
Reactant: Nc1nc(N)nc(Cl)n1
Agent: CC(=O)c1cc(NC(=N)NC(=N)N)cc(C(C)=O)c1
Agent: Cl
Solvent: O
Product: CC(=O)c1cc(Nc2nc(N)nc(N)n2)cc(C(C)=O)c1
Yield: 62.5 %

Procedure:
Compound No. 13: A suspension of 3,5-diacetylaniline (1.95 g) in water (10 mL) was treated with 2-chloro-4,6-diamino-1,3,5-triazine (1.455 g) and concentrated HCl (0.1 mL) and heated at reflux for 20 min. After cooling the hydrochloride of Compound No. 13 separated as a white powder. This was filtered out, dissolved in 60 mL of boiling aqueous 75% methanol and treated with triethylamine (1.5 mL). On cooling, off-white flakes separated. Filtration and drying gave 1.79 g of 2-(3,5-diacetylphenyl)amino-4,6-diamino-1,3,5-triazine, mp 271-2° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16].C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>CCO.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.O>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C(O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(O)c1cccc(-c2cccc(F)c2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of (3-fluorophenyl)boronic acid (790 mg, 3.57 mmol, 1.0 eq), 3-bromobenzoic acid (790 mg, 3.93 mmol, 1.1 eq) and Na2CO3 (142 mg, 1.03 mmol, 2.5 eq) in a mixture of EtOH (2.5 mL), DMF (10 mL) and H2O (2.5 mL) was added Pd(PPh3)4 (170 mg, 0.18 mmol, 0.05 eq). The mixture was stirred at 100° C. overnight. Water was added and the aqueous layer was extracted with EtOAc and the organic extract was discarded. The aqueous layer was acidified to pH 4-5 with 1M HCl and extracted with EtOAc. The combined organic extracts were filtered through silica gel and evaporated in vacuo to give the title compound as a white solid (440 mg, 56%).
Reaction SMILES: [CH2:1](/[C:3](/[N:9]=N/C(OC(C)(C)C)=O)=[CH:4]\[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[C:18]1([NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1N.O.O1CCC[CH2:28]1>>[CH2:1]([C:3]1[C:4]([C:5]([O:7][CH2:8][CH3:28])=[O:6])=[N:25][C:18]2[C:23]([N:9]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:2]
Reactant: CCC(=C\C(=O)OC)/N=N/C(=O)OC(C)(C)C
Reactant: Nc1ccccc1N
Reactant: C1CCOC1
Solvent: O
Product: CCOC(=O)c1nc2ccccc2nc1CC
Reaction time: 22 h

Procedure:
Preparation was performed in a similar manner as Example 1.001 (a). To a solution of tert-butyl (E)-[(1E)-1-ethyl-3-methoxy-3-oxoprop-1-en-1-yl]diazenecarboxylate (see Synlett. 2003, 8, 1183; 1.50 g, 6.19 mmol) in tetrahydrofuran (30 mL) was added 1,2-phenylenediamine (683 mg, 6.19 mmol) at room temperature. After being stirred for 22 hour, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was combined and dried over magnesium sulfate, filtrated and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=6:1) to give ethyl 3-ethylquinoxaline-2-carboxylate. MS (APCI): m/z 217 (M+H).
Reaction SMILES: ClCCl.[OH:4][N:5]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([C:12](=[O:14])[NH2:13])[C:6]1([CH3:16])[CH3:15].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(N(CC)CC)C>[C:17]([O:4][N:5]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([C:12](=[O:14])[NH2:13])[C:6]1([CH3:16])[CH3:15])(=[O:19])[CH3:18]
Reactant: CC1(C)CC(C(N)=O)C(C)(C)N1O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)ON1C(C)(C)CC(C(N)=O)C1(C)C
Yield: 85.2 %

Procedure:
20 ml of dichloromethane and 3 ml of triethylamine were added to 0.50 g (2.7 mmol) of 1-hydroxy-3-carbamoyl-2,2,5,5-tetramethylpyrrolidine. 0.38 ml (4.0 mmol) of acetic anhydride was added dropwise to the mixture with stirring and ice-cooling, the mixture was stirred for 3 hours. The reaction mixture was washed with water, 3% diluted hydrochloric acid, water, 5% sodium hydrogencarbonate aqueous solution, and water, in this order. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate to obtain 0.53 g (2.3 mmol) of white crystals (yield: 86%).
Reaction SMILES: [C:1]1(C(Cl)[C:8]([C:10]2[C:18]3[C:13](=CC=CC=3)[N:12](C)C=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:21]([CH2:28][CH2:29]O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[O:9]1[CH:8]=[CH:10][CH:18]=[CH:13][NH:12]1.[C:22]1([N:21]2[C:6]3[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=3)[CH:29]=[CH:28]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cn1cc(C(=O)C(Cl)c2ccccc2)c2ccccc21
Reactant: OCCNc1ccccc1
Solvent: CCO
Product: C1=CNOC=C1
Product: c1ccc(-n2ccc3ccccc32)cc1
Temperature: 80 °C
Yield: 76 %

Procedure:
0.283 g of 3-(2-phenyl-2-chloro acetyl) N-methylindole (1 mmole) (H. Nakamura and T. Goto, Heterocyles, 10, 167-170 (1978) and 0.274 g of 2-anilino ethanol (2.0 mmole) were dissolved in 3 ml of dry ethanol and heated in a sealed tube at 80° C. for 8 hours. On cooling the product crystallized out as pale yellow needles which was filtered and dried to yield 0.21 g of N-phenyl indole oxazine Compound 17.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=4)=[CH:20][C:15]=3[O:14][N:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:31][NH2:32]>C1COCC1.O.CCOC(C)=O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:32][CH3:31])[N:23]=4)=[CH:20][C:15]=3[O:14][N:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1noc2cc(Oc3ccnc(Cl)n3)ccc12
Reactant: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1nccc(Oc2ccc3c(C(=O)Nc4cccc(C(F)(F)F)c4)noc3c2)n1
Reaction time: 20 h

Procedure:
50 mg (0.115 mMol) 6-(2-chloro-pyrimidin-4-yloxy)-benzo[d]isoxazole-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide are dissolved in 5 ml THF. Then 250 μl methylamine (2 M in THF; 0.50 mMol) are added and the solution is stirred in a sealed tube for 20 h. The mixture is diluted with water and EtOAc, the aq. layer separated off and extracted with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (reversed phase; Gilson) gives the title compound: MS: [M+1]+=430; HPLC: tRet=14.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[Cl:21][C:22]1[C:30]2[N:29]=[C:28]([CH3:31])[NH:27][C:26]=2[CH:25]=[CH:24][C:23]=1[O:32][C:33]1[CH:38]=[C:37](Cl)[N:36]=[CH:35][N:34]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[Cl:21][C:22]1[C:30]2[N:29]=[C:28]([CH3:31])[NH:27][C:26]=2[CH:25]=[CH:24][C:23]=1[O:32][C:33]1[N:34]=[CH:35][N:36]=[C:37]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[CH:38]=1
Reactant: Cc1nc2c(Cl)c(Oc3cc(Cl)ncn3)ccc2[nH]1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4ccc5[nH]c(C)nc5c4Cl)ncn3)CC1)C(=O)N2

Procedure:
100 mg (0.36 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 110 mg (0.37 mmol) 4-chloro-5-(6-chloropyrimidin-4-yloxy)-2-methyl-1H-benzo[d]-imidazole and 0.14 mL (0.81 mmol) DIPEA in 2.0 mL DMF were stirred for 3 h at RT and for 4 h at 40° C. The reaction mixture was mixed with water. The precipitate formed was suction filtered, washed and dried. The filtrate was again suction filtered, washed and dried.
Reaction SMILES: [OH-].[Na+:2].C(O)C.O1CCCC1.Cl.[NH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[C:26]3[C:25](=[O:36])[N:24]([CH3:37])[C:23](=[O:38])[N:22]([CH3:39])[C:21]=3[C:20]=2[C:40]([O:42]C)=[O:41])[CH2:14]1>O>[NH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[C:26]3[C:25](=[O:36])[N:24]([CH3:37])[C:23](=[O:38])[N:22]([CH3:39])[C:21]=3[C:20]=2[C:40]([O-:42])=[O:41])[CH2:14]1.[Na+:2]
Reactant: COC(=O)c1c(N2CCC[C@@H](N)C2)n(Cc2ccccc2Cl)c2c(=O)n(C)c(=O)n(C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cn1c(=O)c2c(c(C(=O)[O-])c(N3CCC[C@@H](N)C3)n2Cc2ccccc2Cl)n(C)c1=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A 1N aqueous sodium hydroxide solution (1 ml), ethanol (1 ml) and tetrahydrofuran (1 ml) were added to methyl 6-[(3R)-3-aminopiperidin-1-yl]-5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate hydrochloride (53 mg), and the resulting mixture was stirred at 80° C. for 3 hours. After the reaction solution was cooled to 25° C., water was added thereto, followed by washing with ethyl acetate, and the aqueous layer was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (41 mg) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][C:8]=2[C:16]([F:17])([F:18])[F:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC(=O)c1ccc(C2=CCCCC2)c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1ccc(C2CCCCC2)c(C(F)(F)F)c1
Yield: 95.9 %

Procedure:
4-(1-Cyclohexen-1-yl)-3-(trifluoromethyl)benzamide (D32) (850 mg, 3.16 mmol) was dissolved in methanol (63 ml) and hydrogenated using an H-Cube, using palladium on carbon at 40° C. with a flow rate of 2 mL/min. The solvent was removed in vacuo to give the title compound as a white solid (822 mg). MS (ES): C14H16F3NO requires 271; found 272 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=O)[NH:13][C:14](=[O:33])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:27]OS(C)(=O)=O)[CH:17]=2)=[CH:3]1.[C-:35]#[N:36].[Na+].[OH2:38]>CS(C)=O>[C:35]([CH2:27][CH2:26][CH2:25][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:15]2[C:14](=[O:33])[NH:13][C:12](=[O:38])[C:11]=2[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:17]1)#[N:36]
Reactant: Cn1cc(C2=C(c3cn(CCCOS(C)(=O)=O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: [C-]#N
Reactant: O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1cc(C2=C(c3cn(CCCC#N)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 50 °C

Procedure:
450 mg of the product of Example 58 in 20 ml of DMSO were treated with 116 mg of sodium cyanide. The mixture was heated at 50° C. for 8 hours, then cooled and poured into water. The mixture was extracted with ethyl acetate and the extracts were dried. Concentration and chromatography on silica gel with toluene/ acetic acid (9:1) gave a solid which was triturated with diethyl ether, filtered off and dried. There were obtained 69 mg of 3-[1-(3-cyanopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 245°-247° C.
Reaction SMILES: [Cl-].[NH4+:2].[OH-].[NH4+].[CH3:5][O:6][N:7]=[C:8]([C:11]#[N:12])[C:9]#[N:10].[CH2:13]([OH:15])[CH3:14]>>[C:13]([O-:6])(=[O:15])[CH3:14].[C:9]([C:8](=[N:7][O:6][CH3:5])[C:11]([NH2:2])=[NH2+:12])#[N:10]
Reactant: CON=C(C#N)C#N
Reactant: [NH4+]
Reactant: CCO
Agent: [Cl-]
Agent: [OH-]
Product: CC(=O)[O-]
Product: CON=C(C#N)C(N)=[NH2+]
Reaction time: 10 h

Procedure:
To a mixed solution of ammonium chloride(14.2 g) dissolved in ethanol (90 ml) and conc. ammonium hydroxide aqueous solution (178 ml) was added 2-(methoxyimino)malononitrile(29 g) at -5°~0° C., and the mixture was stirred for 10 hours at these temperatures. The reaction mixture was extracted 3 times with methylene chloride (respectively, 450 ml, 100 ml and 100 ml), dehydrated, filtered, and concentrated. The residue was dissolved in ethyl acetate, and crystalized with acetic acid to give the above-indicated compound (20.5 g) in pale brown.