Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)/[C:20](=[N:24]/[OH:25])/[CH2:19][CH2:18]2)=[CH2:14].[C:26]1([C:32]2[O:36][N:35]=[C:34]([C:37](OC)=[O:38])[C:33]=2[C:41]([F:44])([F:43])[F:42])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[C:26]1([C:32]2[O:36][N:35]=[C:34]([C:37]3([OH:38])[O:25][N:24]=[C:20]4[C:21]5[C:17]([CH2:18][CH:19]34)=[CH:16][C:15]([CH:13]=[CH2:14])=[CH:23][CH:22]=5)[C:33]=2[C:41]([F:43])([F:44])[F:42])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: C=Cc1ccc2c(c1)CC/C2=N\O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=Cc1ccc2c(c1)CC1C2=NOC1(O)c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of diisopropylamine (0.441 mL, 3.10 mmol) in anhydrous THF (2 mL) was added n-BuLi (1.239 mL, 3.10 mmol) (2.5M solution in hexanes) dropwise at 0° C. under nitrogen. The pale yellow solution was then stirred at the same temperature for 20 min. before a solution of (E)-5-vinyl-2,3-dihydro-1H-inden-1-one oxime (Preparation 87B, 0.249 g, 1.438 mmol) in anhydrous THF (1 mL) was added dropwise at 0° C. under nitrogen. The mixture was stirred at 0° C. for 1 h and then a solution of methyl 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylate (Intermediate 1-5, 0.3 g, 1.106 mmol) in anhydrous THF (1 mL) was added dropwise at 0° C. The mixture was stirred at 0° C. for 70 min before being quenched with saturated aqueous ammonium chloride solution (3 mL) and water (3 mL). The mixture was extracted with EtOAc (2×30 mL). The EtOAc extracts were washed with brine (20 mL), dried over sodium sulfate and concentrated to yield a brown foamy solid. Flash chromatography purification (12 g silica gel column, 10→50% ethyl acetate in n-heptane) afforded 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-6-vinyl-3a,4-dihydro-3H-indeno[1,2-c]isoxazol-3-ol as a brown solid.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:11][CH2:10][O:9][C:8]2[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:7]=2[C:6]1=[O:17])=[O:4].[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>C1(C)C(C)=CC=CC=1>[S:20]1[CH:21]=[CH:22][N:23]=[C:19]1[NH:18][C:3]([CH:5]1[CH2:11][CH2:10][O:9][C:8]2[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:7]=2[C:6]1=[O:17])=[O:4]
Reactant: COC(=O)C1CCOc2cc(F)ccc2C1=O
Reactant: Nc1nccs1
Solvent: Cc1ccccc1C
Product: O=C(Nc1nccs1)C1CCOc2cc(F)ccc2C1=O
Temperature: 25 °C
Yield: 7 %

Procedure:
8-Fluoro-5-oxo-2,3,4,5-tetrahydro-benzo[b]oxepine-4-carboxylic acid methyl ester (0.6 mmol) and 2-aminothiazol (0.6 mmol) were dissolved in 2.5 ml xylene. Reaction was performed by microwave irradiation for 30 minutes at 140° C. The solution obtained from this reaction was cooled to room temperature and extracted by 2 mol/l hydrochloric acid and ethyl acetate. The ethyl acetate extract was dried over sodiumsulfate and the solvent removed in vacuo. After evaporation of the solvent in vacuo 8-Fluoro-5-oxo-2,3,4,5-tetrahydro-benzo[b]oxepine-4-carboxylic acid thiazol-2-ylamide was obtained as a white powder in a yield of 7%. LC-MS: 1.9 min, 307.0 (MH+) 1H-NMR: (DMSO-d6, 500 MHz): d [ppm]: 12.102 (s, 1H), 7.731 (t, 1H, J=7.3 Hz), 7.464 (d, 1H, J=3.2 Hz), 7.234 (d, 1H, J=3.6 Hz), 7.056 (m, 2H, J=7.8 Hz), 4.654 (m, 1H, J=2.6 Hz), 4.340 (m, 1H, J=7.6 Hz), 4.013 (m, 1H, J=7.2 Hz), 2.502 (m, 2H, J=1.8 Hz)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:45]([O:47]CC)=[CH2:46])CCC.Cl>O1CCOCC1.C1COCC1.C(OCC)(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:45]([C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)(=[O:47])[CH3:46]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a mixture of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (5.0 g, 14.6 mmol), palladium diacetate (240 mg, 1.46 mmol) and triphenylphosphine (376 mg, 2.92 mmol) in dioxane (100 mL) was added tributyl(1-ethoxyvinyl)stannane (5.3 mL, 16.1 mL) under N2, and the reaction mixture was stirred at 80° C. overnight. The reaction was cooled to RT and diluted with THF (100 mL), followed by the addition of 2 N HCl (100 mL). The mixture was stirred at RT for 30 mins, and LCMS showed the reaction was completed. The reaction mixture was diluted with ethyl acetate (200 mL). The organic phase was separated, washed with water (3×100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to afford the title compound (3.0 g, 67%). MS (ES+) C15H22N4O3 requires: 306, found: 251 [M-56+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][CH:20]=1)[C:7]1[N:8]([CH3:17])[C:9]3[CH:10]=[C:11]([CH3:16])[CH:12]=[C:13]([CH3:15])[C:14]=3[C:6]=1[CH2:5]2.[Li]CCCC.[CH3:26][Si:27](Cl)([CH3:29])[CH3:28]>CCOCC>[F:1][C:2]1[CH:3]=[C:4]2[C:18]([CH:7]([Si:27]([CH3:29])([CH3:28])[CH3:26])[C:6]3[C:14]4[C:13]([CH3:15])=[CH:12][C:11]([CH3:16])=[CH:10][C:9]=4[N:8]([CH3:17])[C:5]=32)=[CH:19][CH:20]=1
Reactant: Cc1cc(C)c2c3c(n(C)c2c1)-c1ccc(F)cc1C3
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cc(C)c2c3c(n(C)c2c1)-c1cc(F)ccc1C3[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A round bottom flask containing 48b (1.11 g, 4.17 mmol) in dry ether (27 mL) was immersed in a 25° C. water bath. n-BuLi (1.5 M in THF, 3.33 mL, 5.00 mmol) was added via syringe pump over one hour, generating a brown solution. Following addition of base, the reaction mixture was stirred at 25° C. for an additional 30 minutes and then cooled to −78° C. TMSCl (1.11 mL, 8.76 mmol) was added rapidly via syringe and the solution was subsequently warmed to room temperature. The reaction was diluted with ether, filtered, and concentrated in vacuo. Crude product was purified by flash column chromatography (20:1 hexanes-ethyl acetate followed by a second column 40:1 to 26:1 hexanes—ethyl acetate) to yield 49b as an orange solid in 78% yield (1.09 g, 3.24 mmol). 1H NMR (400 MHz, CDCl3): δ 7.57-7.60 (dd, 1H, J=8.4, 5.2 Hz), 7.19-7.22 (dd, 1H, J=9.6, 2.4 Hz), 7.00-7.04 (m, 2H), 6.78 (s, 1H), 4.01 (s, 3H), 3.97 (s, 1H), 2.61 (s, 3H), 2.49 (s, 3H), −0.15 (s, 9H); 13C NMR (150 MHz, CDCl3): δ 159.7 (d, J=289.5 Hz), 152.2 (d, J=10.1 Hz), 142.1, 141.2, 131.17, 129.4, 129.0, 122.7, 121.9, 121.7, 117.2 (d, J=10.5 Hz), 111.7 (d, J=27.9 Hz), 111.6 (d, J=29.7 Hz), 107.0, 38.2, 31.0, 21.8, 20.1, −2.2; 19F NMR (CD3CD, 376 MHz): δ −118.6 (m) FTIR: cm−1 2952, 1583, 1445, 1357, 1248, 1198, 1037, 838. EI-HRMS: Calcd. for C21H24FNSi+ [M]+: 337.1662. found 337.1664.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH2:22][CH2:23][C:24](=[O:27])[NH:25][N:26]=2)=[CH:17][CH:16]=1)=[O:13])=O)(C)(C)C.Cl>C(O)C>[NH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH2:22][CH2:23][C:24](=[O:27])[NH:25][N:26]=2)=[CH:19][CH:20]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)Cc1ccc(C2=NNC(=O)CC2)cc1
Agent: Cl
Solvent: CCO
Product: NCCNC(=O)Cc1ccc(C2=NNC(=O)CC2)cc1

Procedure:
A mixture of 6.8 g (18 mmol) of 6-[4-((2-tert.butoxycarbonylaminoethyl)aminocarbonylmethyl)phenyl]4,5-dihydro-3(2H)-pyridazinone, 25 ml of ethanol and 50 ml of 2N hydrochloric acid is refluxed for about 2 minutes, then the ethanol is distilled off, the aqueous solution is made alkaline with concentrated ammonia solution and finally the precipitate is suction filtered. This product is purified by chromatography on 200 g of silica gel (eluant: dichloromethane/methanol/ammonia=70:30:1).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:12]3[CH2:18][C:17]4[CH:19]=[C:20]([C:23]5[CH:24]=[C:25]([N+:30]([O-])=O)[C:26]([NH2:29])=[N:27][CH:28]=5)[CH:21]=[CH:22][C:16]=4[O:15][CH2:14][CH2:13]3)[C:4]=2[CH2:3]1>[Pd].CO>[CH3:1][C:2]1([CH3:33])[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:12]3[CH2:18][C:17]4[CH:19]=[C:20]([C:23]5[CH:24]=[C:25]([NH2:30])[C:26]([NH2:29])=[N:27][CH:28]=5)[CH:21]=[CH:22][C:16]=4[O:15][CH2:14][CH2:13]3)[C:4]=2[CH2:3]1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(N)c([N+](=O)[O-])c5)cc4C3)c2C1
Agent: [Pd]
Solvent: CO
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(N)c(N)c5)cc4C3)c2C1
Reaction time: 18 h
Yield: 99.5 %

Procedure:
A mixture of 5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-3-nitropyridin-2-amine (0.63 g, 1.4 mmol), 10% palladium on charcoal (0.50 g) in 30 mL of methanol was shaken in a Parr hydrogenation at 38 psi for 18 hours. The reaction mixture was filtered through a pad of celite and concentrated to give to give 5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]pyridine-2,3-diamine (0.58 g, 99% yield). MS (EI) for C24H28N6O: 417 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6](=[O:8])[CH:5]=[C:4]([S:9][CH2:10][C:11]2[CH2:12][S:13][C@@H:14]3[C@H:34]([NH:35]C(=O)CC4C=CC=CC=4)[C:33](=[O:45])[N:15]3[C:16]=2[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:3]=1.CN1CCOCC1.P(Cl)(Cl)(Cl)(Cl)Cl.CO>ClCCl.O>[NH2:35][C@@H:34]1[C:33](=[O:45])[N:15]2[C:16]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])=[C:11]([CH2:10][S:9][C:4]3[CH:3]=[C:2]([CH3:1])[O:7][C:6](=[O:8])[CH:5]=3)[CH2:12][S:13][C@H:14]12
Reactant: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)cc(=O)o1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](N)[C@H]3SC2)cc(=O)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A stirred solution of diphenylmethyl 3-(6-methyl-2-oxo-2H-pyran-4-ylthiomethyl)-7β-phenylacetamidoceph-3-em-4-carboxylate (1.55 g) in dichloromethane (20 ml) was cooled to -15° to -20° C. and N-methylmorpholine (0.54 ml) was added followed by a solution of phosphorus pentachloride in dichloromethane (19 ml of a solution containing 40 mg ml-1). The mixture was maintained at the same temperature for 0.5 h and then methanol (4.9 ml) was added and the mixture stirred at room temperature for 0.5 h. Water (6.6 ml) was then added and the mixture was vigorously stirred for 0.5 h. Most of the dichloromethane was removed on a rotary evaporator and the residue was stirred with water and ethyl acetate. The pH of the aqueous phase was adjusted to 6.2 with 1N aqueous ammonia. The organic phase was separated, washed with water and brine, dried over magnesium sulphate and evaporated. The product (1.20 g) was isolated by column chromatography using gradient elution (Kieselgel 1:1 hexane:ethyl acetate going to neat ethyl acetate). υmax (CHCl3) 1785, 1710cm-1 δ(CDCl3) 1.79 (2H, S). 2.18 (3H, S) 3.42 (1H, d, J 18.2Hz), 3.61 (1H, d, J 18.3Hz), 3.80 (1H, d, J 12.2Hz), 3.90 (1H, d, J 12.2Hz), 4.80 (1H, d, J 5.2Hz), 4.96 (1H, d, J 5.1Hz), 5.66 (1H, d, J ca 1Hz), 5.78 (1H, d, J ca 1Hz), 7.00 (1H, s), 7.2-7.45 (10H, m). [Mass spectrum: +ve ion (3NOBA, Na+) MNa+ 543].
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[CH2:15](O)[CH:16]=[CH2:17]>>[OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:17][CH:16]=[CH2:15])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: C=CCO
Reactant: O=C(O)c1ccc(CO)c([N+](=O)[O-])c1
Product: C=CCOC(=O)c1ccc(CO)c([N+](=O)[O-])c1

Procedure:
In a 100 mL round bottom flask was placed 4-hydroxymethyl-3-nitrobenzoic acid (1.97 g, 10 mmol). Allyl alcohol (20 mL) was added, followed by p-toluensesulfonic acid (0.190 g, 1 mmol). The mixture was heated to reflux for 24 hr., at which time all the volatiles were removed in vacuo. The residue was taken up in EtOAc and washed with sat'd KHCO3. The organic layer was dried over MgSO4 and concentrated to afford the title compound as a cream colored solid; 2.4 g (100%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[C:24](OC(C)(C)C)(=[O:29])[CH2:25][C:26]([CH3:28])=[O:27]>C1(C)C=CC=CC=1>[O:27]=[C:26]([CH3:28])[CH2:25][C:24]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[O:29]
Reactant: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Yield: 88.8 %

Procedure:
A solution of 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (1.0 g, 3.12 mmol) and t-butyl acetoacetate (0.494 g, 3.12 mmol) in 8 mL of toluene was heated at 90° C. for 2 h, then cooled. The resulting solid was filtered and air-dried to give 1.12 g (89%) of 3-oxo-N-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)-butanamide as a tan solid (B10); mp 159-164° C. 1H NMR (CDCl3) δ 9.35 (s, 1H), 8.55 (s, 1H), 8.19-8.09 (d, J=8.7 Hz, 2H), 7.83-7.74 (d, J=9.1 Hz, 2H), 7.74-7.63 (d, J=8.7 Hz, 2H), 7.43-7.32 (d, J=8.3 Hz, 2H), 3.62 (s, 2H), 2.34 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 205.34, 163.43, 163.02, 148.34, 141.49, 138.84, 135.55, 127.37, 126.50, 122.37, 121.67, 121.16, 120.03, 49.56, 31.36; ESIMS m/z 581 ([M+H]+).
Reaction SMILES: S(O)(O)(=O)=O.[C:6]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[NH:8])[NH2:7].[CH:15]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([S:25](Cl)(=[O:27])=[O:26])[C:19]=2[CH:18]=[CH:17][N:16]=1.[OH-].[Na+].Cl>O.O1CCCC1>[C:6]([N:9]1[CH2:14][CH2:13][N:12]([S:25]([C:20]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:24]=3[CH:23]=[CH:22][CH:21]=2)(=[O:26])=[O:27])[CH2:11][CH2:10]1)(=[NH:7])[NH2:8]
Reactant: N=C(N)N1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N=C(N)N1CCN(S(=O)(=O)c2cccc3cnccc23)CC1
Reaction time: 1 h
Yield: 87.9 %

Procedure:
In 30 ml of water was dissolved 3.9 g of 1-amidinopiperazine sulfate, and 60 ml of tetrahydrofuran solution containing 4.1 g of 5-isoquinolinesulfonyl chloride and 1N sodium hydroxide was added dropwise under cooling with ice so that the pH of the solution maintain the range from 8 to 8.5. After the dropwise addition, the mixture solution was stirred for one hour. The crystalline residue was discarded, and the pH of the aqueous layer was adjusted to 1 with an aqueous diluted hydrochloric acid solution. The crystalline residue was discarded, and the pH of the aqueous layer was adjusted to 13 with a 5N aqueous sodium hydroxide solution. The crystals precipitated were separated by filtration, and the crystalline residue obtained was dissolved with an aqueous diluted hydrochloric acid solution. The pH of the solution was adjusted to 13.5 with a 2N aqueous sodium hydroxide solution. The crystals precipitated were separated by filtration, the crystalline residue was washed with water, methanol and ethylether and condensed to dryness to give 4.84 g of 4-amidino-1-(5-isoquinolinesulfonyl)piperazine, i.e., Compound (44) in a yield of 84%.
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl.CN(C=O)C>[O:1]([C:8]1[N:13]=[C:12]([C:14]([Cl:20])=[O:16])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccnc(Oc2ccccc2)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccnc(Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-phenoxy-pyrimidine-4-carboxylic acid, 17, (0.19 g, 0.89 mmol) in methylene chloride (10 mL) containing a few drops of DMF is added oxalyl chloride (0.1 mL). The solution is stirred for 2 hours at room temperature and concentrated in vacuo to afford the desired product which is used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].Cl[C:7]1[C:20]2[C:19](=O)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[NH:12][C:11]=2[C:10]([N+]([O-])=O)=[CH:9][CH:8]=1>CO.C1COCC1>[CH3:23][O:22][C:16]1[C:17]2[N:4]([CH2:3][CH2:2][OH:1])[N:5]=[C:19]3[C:18]=2[C:13]([NH:12][C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:20]=23)=[CH:14][CH:15]=1
Reactant: NNCCO
Reactant: COc1ccc2[nH]c3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c3c(nn(CCO)c13)-c1ccccc1N2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3.6 g of 2-hydroxyethyl hydrazine in 5 ml of methanol and 20 ml of THF was added over 1.5 hours to a mixture of 6.09 g of 1-chloro-7-methoxy-4-nitro-9(10H)-acridinone in 75 ml of methanol and 55 ml of THF, and the resulting suspension was stirred 20 hours at room temperature. The precipitate was coliected and recrystallized from DMSC-methanol, providing 9=methoxypyrazolo[3,4,5-kl]acridine-2(6H)ethanol, mp 275°-276 C.
Reaction SMILES: [CH2:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:10][CH2:11]O)[C:4]1=[O:13])[CH3:2].CCN(CC)CC.CS(Cl)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>C(Cl)Cl.CN(C=O)C>[N:34]([CH2:11][CH2:10][N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C:3]([CH2:1][CH3:2])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:4]1=[O:13])=[N+:35]=[N-:36]
Reactant: CCC1(c2cccc(OC)c2)CCCCN(CCO)C1=O
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1(c2cccc(OC)c2)CCCCN(CCN=[N+]=[N-])C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-ethyl-1-(2-hydroxy-ethyl)-3-(3-methoxyphenyl)-azepan-2-one (as described above in Step A) (0.6 g, 2.05 mmol) in CH2Cl2 (15 mL) at 0° C. was added NEt3 (0.85 mL, 6.15 mmol) and methanesulfonyl chloride (0.19 mL, 2.45 mmol). The mixture was stirred for 30 min at 25° C. then NaN3 (0.27 g, 4.1 mmol) in DMF (3 mL) was added. The reaction was stirred for 18 hr then partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with brine and dried (MgSO4) Filtration and concentration to dryness gave the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH:7]([NH:17][C:18](=[O:28])[C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=1[CH3:27])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[CH:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:30][CH2:31][O:32][C:33](/[C:35](/Cl)=[N:36]\[OH:37])=[O:34].CCN(CC)CC.C(OCC)(=O)C>C(Cl)Cl>[CH2:31]([O:32][C:33]([C:35]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH:7]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:29])[NH:17][C:18](=[O:28])[C:19]3[C:20]([CH3:27])=[CH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])=[CH:14][CH:13]=2)[O:37][N:36]=1)=[O:34])[CH3:30]
Reactant: C#Cc1ccc(CC(NC(=O)c2c(C)cc(C)cc2C)C(=O)OC(C)(C)C)cc1
Reactant: CCOC(=O)/C(Cl)=N\O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2ccc(CC(NC(=O)c3c(C)cc(C)cc3C)C(=O)OC(C)(C)C)cc2)on1
Temperature: 0 °C
Yield: 65.4 %

Procedure:
195 mg (0.498 mmol) of (3) and 377 mg (2.49 mmol) of ethyl chlorooximido acetate were dissolved in 4 ml of DCM and cooled to 0° C. 417 μl (2.99 mmol) of Et3N dissolved in 4 ml of DCM were added slowly (1 drop/7 seconds). After 3 h additional 3 eq. of ethyl chlorooximidoacetate and Et3N were added. The reaction mixture was poured into ethyl acetate, washed with saturated NaHCO3, brine and dried over Na2SO4. The solvent was removed at the evaporator. The product was purified by column chromatography on silica gel using ethyl acetate/hexane to give 165 mg of (4).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:19]=[C:20]1[NH:29][C:28](=S)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1>CN(C)C=O>[O:19]=[C:20]1[N:29]=[C:28]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=c1[nH]c(=S)c2ccccc2[nH]1
Solvent: CN(C)C=O
Product: O=c1nc(NCCCOc2cccc(CN3CCCCC3)c2)c2ccccc2[nH]1

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (2.98 g) and 2-oxo-4-thiono-1,2,3,4-tetrahydroquinazoline (1.78 g) (J. Heterocyclic Chem. 11 (5) p749 (1974)) were stirred in dimethylformamide (5 ml) for 5 days. The reaction mixture was filtered, washing through with cold dimethylformamide and diethyl ether. The filtrate was slowly evaporated to yield the title product as a white crystalline solid (1.38 g), m.p. 219°-221° C. (recrystallised from isopropanol).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:20]=[N:19][C:18]2[C:13](=[C:14]([Cl:21])[CH:15]=[CH:16][CH:17]=2)[N:12]=1>C1COCC1>[Cl:21][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[N:12]=[C:11]([O:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH:20]=[N:19]2
Reactant: Oc1ccccc1
Reactant: Clc1cnc2cccc(Cl)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cccc2ncc(Oc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
NaH (60% w/w in mineral oil; 269 mg, 6.72 mmol) was added to a solution of phenol (633 mg, 6.72 mmol) in THF (4.5 ml) at 0° C.; the resulting mixture was stirred for 15 min before 2,8-dichloroquinoxaline (177a, 892 mg, 4.48 mmol, Pharmabridge, Inc., Doylestown, Pa.) in THF (10 ml) was added at 0° C. The mixture was slowly warmed to RT and stirred for 16 h. The crude material was quenched with MeOH and was purified by silica gel (100% hexanes to 20% EtOAc/hexanes) to provide 8-chloro-2-phenoxyquinoxaline (61% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 257.2 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:26])[CH2:7][CH:8]([CH3:25])[C:9]([C:11]1[N:16]2[N:17]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[N:19]=[C:15]2[C:14]([O:23][CH3:24])=[CH:13][CH:12]=1)=[O:10])(C)(C)C>FC(F)(F)C(O)=O>[CH:20]1([C:18]2[N:19]=[C:15]3[C:14]([O:23][CH3:24])=[CH:13][CH:12]=[C:11]([C:9](=[O:10])[CH:8]([CH3:25])[CH2:7][C:6]([OH:26])=[O:5])[N:16]3[N:17]=2)[CH2:22][CH2:21]1
Reactant: COc1ccc(C(=O)C(C)CC(=O)OC(C)(C)C)n2nc(C3CC3)nc12
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)C(C)CC(=O)O)n2nc(C3CC3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere 4-(2-Cyclopropyl-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-3-methyl-4-oxo-butyric acid tert-butyl ester (0.29 g) was dissolved in Trifluoroacetic acid (0.6 mL) and stirred at RT for 2 h after which the mixture was concentrated in vacuo. The crude product was suspended in 1 N NaOH (5 mL) and washed with Et2O (×2). The aqueous phase was adjusted to pH 1 with 4N HCl (1.5 mL) The aqueous phase was extracted with DCM (×2). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to afford 4-(2-Cyclopropyl-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-3-methyl-4-oxo-butyric acid as a crude product.