Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Cl.[I-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:22]=[C:23]([CH2:24][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(C(F)(F)F)c2)CCCC1=O
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
40% Methanolic Triton B (2.18 mL, 4.8 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (973 mg, 4.0 mM) in 10 mL of DMF at −10° C. After 30 minutes, 3-(trifluoromethyl)benzyl chloride (1.53 g, 6.0 mM) and sodium iodide (900 mg, 6.0 mM) were added and the resultant mixture stirred at room temperature for 25 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, 1 N HCl, H2O, sat NaHCO3, and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and dried in vacuo. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 1.02 g (63%) of the 9-[(3-trifluoromethylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan solid. 1H NMR (CDCl3) δ7.6 (d, 1H, J=8 Hz), 7.45-7.2 (m, 5H), 7.0 (d, 1H, J=8 Hz), 5.4 (s, 2H), 4.05 (s, 3H), 2.85 (t, 2H, J=6 Hz), 2.6 (t, 2H, J=6 Hz), and 2.2 (m, 2H). IR (KBr, cm−1) 1727 and 1652. MS (ES) m/e 400, 402.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([OH:13])[C:7]([OH:14])=[N:6]2)#[N:2].[N+:15]([O-])([OH:17])=[O:16]>>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:15]([O-:17])=[O:16])[N:9]=[C:8]([OH:13])[C:7]([OH:14])=[N:6]2)#[N:2]
Reactant: O=[N+]([O-])O
Reactant: N#Cc1ccc2nc(O)c(O)nc2c1
Product: N#Cc1cc2nc(O)c(O)nc2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
1 g 6-Cyano-2,3-dihydroxyquinoxaline is added gradually to 10 ml of ice-cooled fuming nitric acid. The mixture is stirred at 25° C. for 1 h. The reaction mixture is poured into ice-water giving 1 g of a crude product. Recrystallization (DMF-water) gives 0.9 g (75%) of 6-cyano-2,3-dihydroxy-7-nitroquinoxaline, m.p. >300° C. IR: peak at 2240 cm-1,
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12]C)=[CH:4][CH:3]=1.C(O)(=O)C.Br>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)c2ccccc12
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(Cl)c2ccccc12

Procedure:
The known compound 1-chloro-4-methoxynaphthalene is dissolved in 150 ml. of acetic acid and 150 ml. of 48 percent hydrobromic acid, and the mixture is heated at its reflux temperature for two hours. The mixture is diluted with 200 ml. of water and cooled to provide 1-chloro-4-hydroxynaphthalene as a crystalline solid.
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].N(OC(C)(C)C)=O.C(I)[I:22]>>[I:22][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(C(F)(F)F)ccc1N
Reactant: ICI
Agent: CC(C)(C)ON=O
Product: N#Cc1cc(C(F)(F)F)ccc1I
Temperature: 100 °C

Procedure:
2-Amino-5-(trifluoromethyl)benzonitrile (3.06 g, 16.45 mmol) was suspended in CH2I2 (36 mL) and t-butyl nitrite (3.9 mL, 32.9 mmol) was added dropwise by syringe. The reaction was heated slowly to 100° C. and was maintained at this temperature for 30 minutes. The reaction was then cooled to room temperature, diluted with hexanes (200 mL), loaded on a silica gel column, and purified with 100% hexanes to 15% EtOAc/hexanes. The resulting product, 2-iodo-5-(trifluoromethyl)benzonitrile was contaminated with minor impurities which were removed by silica gel chromatography with 25% CH2Cl2/hexanes. 2-Iodo-5-(trifluoromethyl)benzonitrile was obtained as a white solid. Rf=0.44 (15% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 8.10 (d, J=8.5 Hz, 1H), 7.85 (d, J=1.8 Hz, 1H), 7.52 (dd, J=8.5, 1.8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:24][CH2:25][C@@H:26]1[CH2:30][C@@H:29]([OH:31])[CH2:28][N:27]1[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C)C(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:24][CH2:25][C@@H:26]2[CH2:30][C@@H:29]([OH:31])[CH2:28][N:27]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:4]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:3]=1
Reactant: Oc1ccc(Br)cc1CCc1ccccc1
Reactant: CCOC(=O)N1C[C@H](O)C[C@H]1CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(Br)cc1CCc1ccccc1
Yield: 33.6 %

Procedure:
500 mg of 4-bromo-2-(2-phenylethyl)phenol were dissolved in 10 ml of N,N-dimethylacetamide, allowed to react with 220 mg of potassium t-butoxide and 440 mg of (2S,4R)-2-(2-chloroethyl)-1-ethoxycarbonyl-4-hydroxypyrrolidine and extracted in the same manner as described in step (a) of Example 1. The resulting oily substance was purified by silica gel column chromatography, using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 280 mg (yield 34%) of the title compound as an oily substance.
Reaction SMILES: [Se](=O)=[O:2].[C:4]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:6])[CH3:5]>>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:4]([CH:5]=[O:2])=[O:6])[CH:8]=1
Reactant: CC(=O)c1cccnc1
Reactant: O=[Se]=O
Product: O=CC(=O)c1cccnc1
Yield: 90.3 %

Procedure:
3-Pyridylglyoxal (5.0 g, crude) was prepared from selenium dioxide (6.82 g, 61.4 mmol) and 3-acetyl pyridine (5.0 g, 41.0 mmol) according to the typical procedure used for Preparation 1.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][C:2]1=[N:6]O.[C:9]1(=O)[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10]1>C(O)(=O)C.[Zn]>[CH2:5]1[C:1]2[CH:2]([NH:6][CH:13]3[C:12]=2[C:11](=[O:15])[CH:10]=[CH:9][CH2:14]3)[CH2:3][CH2:4]1
Reactant: O=C1CCCC(=O)C1
Reactant: O=C1CCCC1=NO
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1C=CCC2NC3CCCC3=C12
Temperature: 25 °C

Procedure:
To a mechanically stirred solution of 1,2-cyclopentanedione-2-oxime (25.0 g, 0.22 mol) and 1,3-cyclohexanedione (25.0 g, 0.22 mol) in 70% acetic acid (250 mL) was added zinc dust (43.0 g, 0.66 g-atom) in about 5-g portions (moderately exothermic) over a 30 minute period. After the addition, the mixture was heated to reflux for 2 hours and was then cooled to room temperature. The solution was decanted from excess zinc and poured into ice water (250 mL). The mixture was extracted with dichloromethane (1×200 mL, 2×100 mL) and the combined extracts were washed with saturated sodium bicarbonate to neutrality, then washed with brine, and dried (Na2SO4). The solution was concentrated to about 1/4 the original volume, whereupon the title cyclopent[b]indolone (8.3 g) separated as a light tan solid: mp 236°-238° C. (recrystallized from ethyl acetate); IR (KBr) 3210 (NH), 1620 cm-1 (C=O); NMR (CDCl3) δ 2.07 (m, 2, CH2), 2.30-2.90 (m, 10, CH2), 10.17 (br s, 1, NH); MS m/e 175 (M+). Anal. Calcd for C11H13NO: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.36; H, 7.38; N, 7.84.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([N:6]([CH3:8])[CH3:7])=O.CO.Cl>C1COCC1>[CH3:8][N:6]([CH3:7])[CH2:4][CH2:3][C@@H:2]([NH2:1])[CH2:9][S:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN(C)C(=O)C[C@@H](N)CSc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CC[C@@H](N)CSc1ccccc1
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 1C (8.68 g) in THF (200 mL) was treated with BH3-dimethylsulfide (18.2 mL) at room temperature, stirred overnight, treated slowly with methanol (20 mL), followed by 2N HCl (50 mL), stirred overnight, and concentrated. The resulting residue was purified by silica gel chromatography eluting with 5% 7N NH3/CH3OH in dichloromethane to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[OH:17])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].Br[CH:37]([CH2:39][CH3:40])[CH3:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[O:17][CH:37]([CH2:39][CH3:40])[CH3:38])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: CCC(C)Br
Reactant: COc1ccc(CC2c3c(O)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Product: CCC(C)Oc1ccc(OC)c2c1C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccn1)CC2

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with 2-bromo-butane
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:30])[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[Br:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[N:39]1[C:43]2=[N:44][CH:45]=[N:46][C:47](Cl)=[C:42]2[CH:41]=[N:40]1>C1COCC1.CCOC(C)=O>[Br:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[N:39]1[C:43]2[N:44]=[CH:45][N:46]=[C:47]([O:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:30])[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:21]([CH3:23])[CH3:22])[CH:24]([CH3:26])[CH3:25])[C:5]([NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])[C:42]=2[CH:41]=[N:40]1
Reactant: Cc1cnc(NC(=O)[C@@H](O)CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)cn1
Reactant: Clc1cccc(Br)c1-n1ncc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)[C@H](CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)Oc2ncnc3c2cnn3-c2c(Cl)cccc2Br)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.5 %

Procedure:
Sodium hydride (0.875 g, 21.87 mmol) was added to (S)-2-hydroxy-N-(5-methylpyrazin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate AZ2) (3.0 g, 7.29 mmol) in anhydrous THF (35 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then a solution of 1-(2-bromo-6-chlorophenyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (Intermediate BO2) (2.507 g, 7.29 mmol) in anhydrous THF (20 mL) was added dropwise over 1 minute. The mixture was stirred at 0° C. for 10 minutes and then allowed to warm to ambient temperature for 6 hours. It was then cooled to ˜0° C., the mixture poured into ice cold 1M citric acid and diluted with EtOAc (50 mL). It was stirred vigorously for 10 minutes. The organic phase was separated, washed with water and brine, dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (4.90 g, 93%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>CS(C)=O>[CH2:3]([O:10][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1ccncc1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc(COc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a suspension of sodium hydride (80% dispersed in oil, 876 mg, 29.2 mmol) in DMSO (10 ml) was added benzyl alcohol (3 ml, 29.2 mmol) and the mixture stirred at room temperature for 1 hour. To this was added 4-chloropyridine (3.3 g, 29.2 mmol) and the reaction stirred at room temperature overnight. The precipitated sodium chloride was removed by filtration and the filtrate diluted with water (100 ml) and extracted with ether (3×120 ml). The combined organic layers were dried (MgSO4) and evaporated in vacuo to yield the title compound as an oil (4.8 g, 95%); δH (CDCl3) 5.11 (2H, s, PhCH2O), 6.87 (2H, d, J 6.3 Hz, 3-H, 5-H), 7.29-7.42 (5H, m, Ph), and 8.42 (2H, d, J 6.3 Hz, 2-H, 6-H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[CH:3]=1.CI.[C:12]([O-])([O-])=O.[K+].[K+]>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:12])[C:4](=[O:9])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)cc(=O)[nH]1
Agent: [K+]
Solvent: CI
Product: Cc1cc(Br)cc(=O)n1C

Procedure:
4-bromo-1,6-dimethylpyridin-2(1H)-one was prepared by methylation of 4-bromo-6-methylpyridin-2(1H)-one with methyl iodide using K2CO3 following a procedure analogous to that described in Example 628 Step 1.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:25])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:18][CH3:19])=[CH:13][C:12]=2[N:20]([CH3:24])[CH2:21][C:22]#[CH:23])[CH2:5][CH2:4]1.[Cl:28][C:29]1[C:42]([N:43]=[C:44]=S)=[C:41]([Cl:46])[CH:40]=[CH:39][C:30]=1[CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].CC(C)N=C=NC(C)C>CN(C=O)C>[F:1][C:2]([F:26])([F:27])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[C:12]([N:20]([CH3:24])[CH2:21][C:22]#[CH:23])=[CH:13][C:14]3[N:18]([CH3:19])[C:44]([NH:43][C:42]4[C:41]([Cl:46])=[CH:40][CH:39]=[C:30]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]=4[Cl:28])=[N:17][C:15]=3[CH:16]=2)=[O:25])[CH2:5][CH2:4]1
Reactant: C#CCN(C)c1cc(NC)c(N)cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: C#CCN(C)c1cc2c(cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1)nc(Nc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1Cl)n2C

Procedure:
The title compound is prepared in analogy to 6c from N-(trans-4-trifluoromethyl-cyclohexyl)-2-[N-methyl-N-propargylamino]-4-methylamino-5-amino-benzoic acid amide (50 mg, 0.13 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (41 mg, 0.13 mmol), DIC (20 μL) and DMF (2.0 mL).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[N:8][C:7](O)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:7]1[N:8]=[N:9][C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc(C2CC2)nn1
Product: Clc1ccc(C2CC2)nn1
Yield: 89 %

Procedure:
A mixture of 6-cyclopropylpyridazin-3-ol (182 mg, 1.3 mmol) in POCl3 (15 mL) was refluxed for 1 hour, and concentrated. The residue was treated with ethyl acetate (60 mL) and sat. NaHCO3 aqueous solution (10 mL) at 0° C. The organic layer was dried over Na2SO4 and concentrated to afford 3-chloro-6-cyclopropylpyridazine (185 mg, 89%). 1H NMR (400 MHz, CD3OD): δ1.11 (m, 2H), 1.20 (m, 2H), 2.25 (m, 1H), 7.52 (d, 1H), 7.67 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C([Li])CCC.[CH3:17][CH2:18][C:19](=[O:22])[CH2:20][CH3:21]>C(OCC)C>[S:4]1[CH:5]=[CH:6][C:2]([C:19]([OH:22])([CH2:20][CH3:21])[CH2:18][CH3:17])=[C:3]1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: Brc1ccsc1-c1cccs1
Reactant: CCC(=O)CC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCC(O)(CC)c1ccsc1-c1cccs1
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
3-Bromo-2,2′-bithiophene (IIIa) (3.00 g, 12 mmol) in dry diethylether (100 mL) was added slowly to a solution of n-butyllithium (1.6 M in hexane, 7.50 mL, 12 mmol) in dry diethylether (100 mL) at −78° C. over 2 h under N2. The mixture was stirred for 15 minutes at the same temperature. Freshly distilled 3-pentanone (1.29 mL, 12 mmol) was added via a syringe to the mixture at −78° C., followed by stirring overnight at room temperature. The reaction was quenched with an aqueous NH4Cl-solution (2.5 M, 50 mL) and water (50 mL) at 0° C. The organic phase was separated and the aqueous phase was extracted with diethylether. The combined organic phases were washed with brine, dried over MgSO4 and evaporated under reduced pressure to give a crude oil. The oily residue was purified by column chromatography (eluent hexane/EtOAc 90:10) to afford the title compound (IIa) as a green oil (1.7 g, 56%). 1H-NMR (CDCl3): δ=7.35 (dd, J=5.2 Hz, J=1.2 Hz, 1H), 7.24 (d, J=5.4 Hz, 1H), 7.10 (dd, J=3.6 Hz, J=1.2 Hz, 1H), 7.00 (dd, J=5.2 Hz, J=3.6 Hz, 1H), 6.95 (d, J=5.4 Hz, 1H), 1.75 (q, J=7.7 Hz, 4H), 0.80 (t, J=7.4 Hz, 6H). 13C-NMR (CDCl3): δ=145.33, 136.11, 129.99, 129.76, 128.97, 127.87, 127.40, 125.54, 79.29, 35.79, 8.80.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]=[C:6]1[CH2:10][C@H:9]([CH3:11])[C@H:8]([CH3:12])[CH2:7]1)[CH3:2].[N+:14]([CH3:17])([O-:16])=[O:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1([CH2:17][N+:14]([O-:16])=[O:15])[CH2:7][C@@H:8]([CH3:12])[C@H:9]([CH3:11])[CH2:10]1)[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=C1C[C@@H](C)[C@@H](C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(C[N+](=O)[O-])C[C@@H](C)[C@H](C)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.3 %

Procedure:
The unsaturated ester (2) (1.384 g, 7.60 mmol) was dissolved in tetrahydrofuran (10 mL) and stirred at 70° C. with nitromethane (0.82 mL, 15.2 mmol) and tetrabutylammonium fluoride (1.0M in tetrahydrofuran, 11.4 mL, 11.4 mmol). After 6 hours, the mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and washed with 2N HCl (30 mL) followed by brine (50 mL). The organic phase was collected, dried (MgSO4), and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate:heptane 5:95) to give 0.837 g (45%) of a clear oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6](C)=[N:5]1)([CH3:3])[CH3:2].[CH3:25][O:26][C@H:27]1[CH2:31][CH2:30][NH:29][C@@H:28]1[C:32]([NH2:34])=[O:33]>C(N(CC)CC)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:29]5[CH2:30][CH2:31][C@H:27]([O:26][CH3:25])[C@H:28]5[C:32]([NH2:34])=[O:33])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(O)cc2OCC3)n(C(C)C)n1
Reactant: CO[C@H]1CCN[C@@H]1C(N)=O
Solvent: CCN(CC)CC
Product: CO[C@H]1CCN(c2cc3c(cn2)-c2nc(-c4ncnn4C(C)C)cn2CCO3)[C@@H]1C(N)=O
Yield: 27 %

Procedure:
Following the procedure for Example 339, 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol and (2S,3S)-3-methoxy-pyrrolidine-2-carboxylic acid amide with added triethylamine were reacted. The crude product was washed with water, filtered then triturated in diethyl ether and methanol to give 408 as a white solid (40 mg, 27%). LCMS: RT=2.68 min, [M+H]+=439. 1H NMR 400 MHz (CDCl3) δ: 9.31 (1 H, s), 7.86 (1 H, s), 7.59 (1 H, s), 6.99 (1 H, br, s), 6.08 (1 H, s), 6.03 (1 H, m), 5.37 (1 H, br, s), 4.67 (1 H, s), 4.53-4.49 (2 H, m), 4.40-4.39 (2 H, m), 4.29 (1 H, m), 3.62-3.57 (1 H, m), 3.52-3.51 (1 H, m), 3.39 (3 H, s), 2.23 (2 H, m), 1.57 (6 H, dd, J=6.68, 3.32 Hz)
Reaction SMILES: [CH:1]([CH:3]([CH:13]=O)[C:4]1[N:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][CH:5]=1)=O.Cl.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:1]=[C:3]([C:4]3[N:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][CH:5]=3)[CH:13]=[N:25]2)=[CH:20][CH:19]=1
Reactant: O=CC(C=O)c1cccc(C(=O)O)n1
Reactant: COc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(-n2cc(-c3cccc(C(=O)O)n3)cn2)cc1
Yield: 60.7 %

Procedure:
A solution of 6-(diformylmethyl)-pyridin-2-carboxylic acid (315 mg, 1.63 mmol), 4-methoxyphenylhydrazine hydrochloride (285 mg, 1.63 mmol) and sodium acetate (134 mg, 1.63 mmol) in acetic acid (5 mL) is heated to 110° C. for 18 h. After being allowed to cool, the solution is filtered. The solid product is washed with ethyl acetate and diethyl ether, and dried under vacuum to afford the title product (294 mg, 0.99 mmol, 61%) as a beige powder. m.p. 122-123° C. 1H NMR (300 MHz, DMSO-d6): δ 9.11 (1H, s), 8.38 (1H, s), 7.99 (2H, d, J=4.7 Hz), 7.86 (1H, t, J=4.4 Hz), 7.80 (2H, d, J=9.1 Hz), 7.08 (2H, d, J=9.1 Hz), 3.80 (3H, s), 1H missing. MS (ES+): m/e 297 (18), 296 (100). MS (ES−): m/e 295 (14), 294 (100).
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH:11]=[O:12])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.Cl([O-])=[O:14].[Na+].P([O-])(O)(O)=O.[Na+]>CC(O)(C)C.CC(=CC)C.O>[O:1]1[C:10]2[CH:9]=[C:8]([C:11]([OH:14])=[O:12])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1cc2c(cn1)OCCO2
Temperature: 25 °C
Reaction time: 19 h
Yield: 51.2 %

Procedure:
To a solution of 2,3-dihydro-[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (722 mg, 4.37 mmol) in 2-methyl-2-propanol (95 mL) and 2-methyl-2-butene (22 mL) was added dropwise a solution of sodium chlorite (80%, 4.55 g, 40.22 mmol) and sodium dihydrogenphosphate (3.65 g, 26.45 mmol) in water (35 mL). The resulting solution was stirred at rt for 19 h. The volatiles were removed under reduced pressure. The residue was diluted with water (20 mL) and pH was adjusted to 3 by addition of 1N HCl. The aq. layer was extracted with DCM-MeOH 9-1 (25×30 mL). The combined extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was triturated in ether and filtered to give the title acid as a white solid (0.405 g, 51% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([C:18]([O:22]COCCOC)=[C:19]([F:21])[F:20])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.Cl[Si](C)(C)C.C(=O)(O)[O-].[Na+]>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([C:18](=[O:22])[CH:19]([F:20])[F:21])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCCOCOC(=C(F)F)c1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccc2ccc3ncc(Cl)cc3c(=O)c2c1)C(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) solution of 3-chloro-7-{2,2-difluoro-1-[(2-methoxyethoxy)methoxy]vinyl}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (50 mg, 0.12 mmol) in a mixture of methanol (0.6 mL) and dichloromethane (0.6 mL) was added chlorotrimethylsilane (0.08 mL, 0.61 mmol). The mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was then poured into an aqueous sodium bicarbonate solution and extracted with ethyl acetate three times. The combined organics were dried over magnesium sulfate, filtered, concentrated in vacuo, and purified via flash chromatography (silica, 0-60% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, CD3OD) δ 8.84 (d 1H), 8.52 (d, 1H), 8.41 (s, 1H), 7.93 (dd, 1H), 7.76 (d, 1H), 7.42 (d, 1H), 7.33 (d, 1H), 5.79 (t, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][N:9]([NH2:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([OH:22])([CH3:21])[CH3:20])[N:14]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[OH:22][C:19]([C:15]1[N:14]=[C:13]([CH2:12][N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[CH:30]=4)[C:3]=3[NH:10][N:9]2[NH2:11])[CH:18]=[CH:17][CH:16]=1)([CH3:21])[CH3:20]
Reactant: COc1cccc(B(O)O)c1
Reactant: CC(C)(O)c1cccc(CN2c3ncnc(Cl)c3NN2N)n1
Product: COc1cccc(-c2ncnc3c2NN(N)N3Cc2cccc(C(C)(C)O)n2)c1
Yield: 37 %

Procedure:
Prepared as described in Example 20 from 7-chloro-3-(6-[1-hydroxy-1-methylethyl]pyridine-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-2-amine and 3-methoxyphenylboronic acid (0.08 g, 0.56 mmol) to give the title compound (68 mg, 37%) as a yellow solid.