Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH2:14])[CH2:8][CH2:7]1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][NH:14][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[C:28]([O:27][CH3:26])[CH:29]=2)[CH2:10][CH2:11]1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: NCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(=O)NCCN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product from Example 3, Step b (2.00 g) was dissolved in TBF (100 ml) and triethylamine (2.10 g) added. The solution was then cooled with stirring to 0° C. and to it 3-methoxybenzoyl chloride was added dropwise as a solution in THF (10 ml). Reaction was left to warm to room temp and left for 24 hours then water was added and the organics extracted into ethyl acetate. The combined organics were dried with MgSO4 and the solvent removed by evaporation. The crude product was purified by flash chromatography to leave the sub-title product as a pale yellow oil (1.38 g).
Reaction SMILES: C(Br)C1C=CC=CC=1.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:14][C:15]=1[CH3:16].C(N(CC)CC)C.[H][H]>C(O)(C)C.[C].[Pd]>[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:17]2[CH2:18][NH:19][CH2:20][CH2:21][CH:22]=2)=[N:14][C:15]=1[CH3:16]
Reactant: [H][H]
Reactant: Cc1ccc(-c2cccnc2)nc1C
Agent: [Pd]
Agent: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1ccc(C2=CCCNC2)nc1C
Temperature: 50 °C
Reaction time: 5 h
Yield: 19.6 %

Procedure:
Benzyl bromide in an amount of 1.06 g was added to a solution of 1 g of 5,6-dimethyl-2,3′-bipyridine in 15 mL of isopropyl alcohol, and stirred for 5 hours at 50° C. to finish the reaction. To the reaction solution, 0.18 g of 10% palladium carbon and 0.59 g of triethylamine were added. This admixture was put in an autoclave, the autoclave's atmosphere was replaced twice with nitrogen gas under a nitrogen pressure of 196 kPa, and then hydrogen gas was blown into the autoclave over 3 hours at 80° C. under a hydrogen pressure of 196 kPa until the absorption of hydrogen gas in a volume of 400 mL was completed. After the replacement with nitrogen, the catalyst was filtered out and the resulting filtrate was concentrated under a reduced pressure of 1.33 kPa until the quantity thereof was reduced to 1.70 g. Further thereto, 50 mL of water and 10 g of a 25% aqueous solution of sodium hydroxide were added. The resulting solution was extracted with three 200 mL portions of ethyl acetate, and the organic layer was concentrated. The thus obtained solid was adsorbed to NH2-modified silica gel (produced by Biotage Japan, Ltd.), and eluted with ethyl acetate. The fraction obtained was concentrated, and the crystals thus deposited were dried to give 0.20 g of the entitled compound as light yellow crystals. Yield rate: 20%, EI-MS: (m/z) 188 (M+), melting point: 102-104° C.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5](=[O:20])[C:6]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:8])[CH3:7])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C(#N)C>[O:20]1[CH:1]=[N:3][N:4]=[C:5]1[C:6]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH3:7])[CH3:8]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)NNC=O
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(NC(=O)OCc1ccccc1)c1nnco1
Temperature: 25 °C
Reaction time: 4 h
Yield: 127.6 %

Procedure:
To a suspension of benzyl 1-(2-formylhydrazinyl)-2-methyl-1-oxopropan-2-ylcarbamate (0.9 g, 3 mmol) and PPh3 (CAN 603-35-0, 1.268 g, 5 mmol) in acetonitrile (20 mL) was added DIPEA (CAN 7087-68-5, 1.249 g, 10 mmol) and hexachloroethane (CAN 67-72-1, 0.991 g, 4 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 4 h. After evaporation of solvents, the residue was diluted with ethyl acetate (30 mL) and water (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate and evaporated. The remaining residue was then purified by column chromatography (silica gel, 30 g, eluting with 10% ethyl acetate in petroleum ether) to give the title compound (1 g, 30% purity, 36%) as colorless oil containing OPPh3 and PPh3; MS: m/e 262.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:25]([CH3:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Br:27]Br.O.[Cl-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:27][C:16]1[CH:15]=[CH:14][C:13]2[N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)(=[O:11])=[O:10])[CH:25]([CH3:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[CH:17]=1
Reactant: BrBr
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)N2c3ccc(Br)cc3-c3ccccc3C2C)cc1
Temperature: 25 °C
Yield: 48.5 %

Procedure:
A stirred suspension of 5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.73 g, 2.0 mmol) was heated to 50° C. in glacial acetic acid 20 mL) and treated drop-wise over seven hours with excess bromine (1.92 g, 12 mmol). After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and the precipitate filtered. The organic phase filtrate was washed sequentially with a saturated, aqueous sodium thiosulfate solution, a 1 N hydrochloric acid solution, and water. The organic phase was further washed sequentially with a 2.5 N aqueous sodium hydroxide solution until a basic extract was obtained, water, and a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered through a short column of silica gel, and the solvent removed in vacuo to afford a crude yellow solid (0.75 g, 1.7 mmol, 85%). The crude solid was purified by preparative chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a mixture of methyl tert-butyl ether-hexane (15:85) at a flow rate of 40 mL/min to afford, after evaporation of the solvent, a solid. Crystallization of the solid from a mixture of diethyl ether-hexane yielded the title compound (0.43 g, 0.97 mmol, 48%) as a homogeneous, colorless, crystalline solid, m.p. 192-194° C.;
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].Cl[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=1.CCN(C(C)C)C(C)C.CCOC(C)=O>O1CCOCC1>[C:12]([O:11][C:9]([N:2]1[CH2:3][CH:4]2[CH2:8][N:7]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=3)[CH2:6][CH:5]2[CH2:1]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)nc1
Temperature: 75 °C
Yield: 75.6 %

Procedure:
To a solution of tert-butyl hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylate (1.11 g, 5.23 mmol) in dioxane were added ethyl 6-chloronicotinate (1.28 g, 6.9 mmol) and DIPEA (2 ml, 11.6 mmol). The mixture was heated at 75° C. for 3 days. The mixture was then poured into EtOAc (100 ml) and washed with saturated ammonium chloride (50 ml), water (50 ml) and brine (50 ml). The organic fraction was dried (MgSO4), concentrated and purified by flash column chromatography (5% MeOH-DCM) to yield the title compound (1.429 g, 75%). m/z 362.25 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 8.32 (1H, dd, J=0.6, 2.1 Hz), 8.03 (1H, dd, J=2.4, 9.0 Hz), 6.32 (1H, d, J=8.7 Hz), 4.34 (2H, q, J=6.9 Hz), 3.24-3.85 (8H, m), 3.03 (2H, m), 1.47 (9H, s), 1.38 (3H, t, J=7.2 Hz).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@@H:10]([C:25]([NH:27][C@@H:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[O:26])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]([O:23][CH3:24])=[O:22])[CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl[C:41]([O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:42]>N1C=CC=CC=1>[C:44]1([O:43][C:41]([NH:1][C@H:2]([C:7]([NH:9][C@@H:10]([C:25]([NH:27][C@@H:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[O:26])[CH2:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]([O:23][CH3:24])=[O:22])[CH:13]=2)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:42])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCCC[C@@H](NC(=O)[C@@H](Cc1cn(C(=O)OC)c2ccccc12)NC(=O)[C@@H](N)CC(C)C)C(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: CCCC[C@@H](NC(=O)[C@@H](Cc1cn(C(=O)OC)c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)Oc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 1.5 h

Procedure:
To a solution of H-Leu-DTrp(COOMe)-DNle-OtBu (320 mg, prepared in Example 21-(2)) in pyridine (2.3 ml) was added phenyl chloroformate at 0°-5° C. under argon atmosphere. The mixture was stirred at the same temperature for 1.5 h and concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with 10% aq. citric acid, sat. aq. NaHCO3 and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was purified by silica gel flash chromatography (Merck, Kieselgel 60) with ethyl acetate/hexane=2/1 for elution to give the product (337 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[N:7]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[C:30]([Cl:33])[CH:31]=3)[N:26](S(C3C=CC=CC=3)(=O)=O)[CH:25]=2)=[O:23])=[CH:18][N:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[C:1]([O:5][C:6](=[O:43])[N:7]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[C:30]([Cl:33])[CH:31]=3)[NH:26][CH:25]=2)=[O:23])=[CH:18][N:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1F)c1ccc(C(=O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1F)c1ccc(C(=O)c2c[nH]c3ncc(Cl)cc23)cn1
Yield: 85.7 %

Procedure:
To [5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(2-fluoro-benzyl)-carbamic acid tert-butyl ester (583, 60.0 mg, 0.097 mmol) in tetrahydrofuran (1.0 mL) was added aqueous potassium carbonate (1.0 M, 1.0 mL). The reaction was irradiated with microwave on 300 watts, 100° C. for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give crude compound (584, 0.040 g, 64%) that was used in the next step without further purification.
Reaction SMILES: [CH:1]1[C:10]2[N:9]3[CH:11]=[CH:12][CH:13]=[C:8]3[C:7]3([CH2:18][CH2:17][N:16](C(OCC4C=CC=CC=4)=O)[CH2:15][CH2:14]3)[O:6][C:5]=2[N:4]=[CH:3][CH:2]=1.CC(O)=O>CO.[Pd]>[CH:1]1[C:10]2[N:9]3[CH:11]=[CH:12][CH:13]=[C:8]3[C:7]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:6][C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)Oc1ncccc1-n1cccc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: c1cnc2c(c1)-n1cccc1C1(CCNCC1)O2

Procedure:
A solution of benzyl spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate (220 mg, 0.586 mmol), AcOH (33 μL, 0.59 mmol) and Pd/C (22 mg, 0.21 mmol) in MeOH (2 mL) was stirred under a balloon on H2 for 6 hours. The mixture was filtered through celite and the filtrate was evaporated to give spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine] (ESI-MS m/z calc. 241.1, found 242.5 (M+1)+; Retention time: 0.46 minutes (3 min run)). The residue was then taken up in THF (3 mL) before Na2CO3 (1.2 mL of 2.0 M, 2.4 mmol) was added. Boc2O (156 mg, 0.70 mmol) was added and the mixture was stirred at room temperature for 12 hours. N,N-dimethylethylenediamine (0.5 mL) was added and the mixture was stirred at room temperature for 30 min. The mixture was poured into water and was extracted with EtOAc (3×). The organics were combined, washed with 0.1N HCl (3×), brine, dried (Na2SO4) and filtered through a plug of silica to give tert-butyl spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate (134 mg, 67%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([Cl:44])[CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([Cl:44])[CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(Cl)c(Cl)c2)CC1
Yield: 6.7 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.51 g) as starting compound, potassium carbonate (0.77 g) and 6-bromo-1-(3,4-dichlorophenyl)-1-hexanone (0.45 g) were reacted and treated in the same manner as in Example 172 to give 50 mg of 4-amino-5-chloro-N-((1-(6-(3,4-dichlorophenyl)-6-oxohexyl)piperidin-4-yl)-methyl)-2-methoxybenzamide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([Cl:12])=[C:4]([NH2:13])[N:3]=1.Br[CH2:15][C:16](=O)[CH2:17][CH3:18]>>[NH2:13][C:4]1[N:3]2[CH:15]=[C:16]([CH2:17][CH3:18])[N:1]=[C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[Cl:12]
Reactant: COC(=O)c1cc(Cl)c(N)nc1N
Reactant: CCC(=O)CBr
Product: CCc1cn2c(N)c(Cl)cc(C(=O)OC)c2n1

Procedure:
The title compounds were prepared according to the procedure described in the step 4 in Example 2 from methyl 2,6-diamino-5-chloro-3-pyridinecarboxylate (Example 2, Step 3) and 1-bromo-2-butanone.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16]N(C3C=CC(OC(C)C)=CC=3)CN(C3C=CC(OC(C)C)=CC=3)[CH2:12]2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].ClC(OC(Cl)(Cl)Cl)=[O:39].[CH2:45]([NH:52][C:53]([NH:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[S:54])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[OH-].[Na+]>>[CH2:45]([N:52]=[C:53]1[N:55]([CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:16](=[O:39])[N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=2)[CH2:12][S:54]1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: S=C(NCc1ccccc1)NCc1ccccc1
Reactant: CC(C)Oc1ccc(N2CN(c3ccc(OC(C)C)cc3)CN(c3ccc(OC(C)C)cc3)C2)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Oc1ccc(N2CSC(=NCc3ccccc3)N(Cc3ccccc3)C2=O)cc1
Yield: 84.2 %

Procedure:
Similarly, 2.0 g (0.004 mole) of 1,3,5-tris(p-isopropoxyphenyl)-hexahydro-s-triazine, 1.2 g (0.006 mole) of trichloromethyl chloroformate, 3.1 g (0.012 mole) of 1,3-dibenzylthiourea, and 11 g of a 10% aqueous sodium hydroxide solution were used to obtain 1.5 g (28% yield) of 2-benzylimino-3-benzyl-5-(p-isopropoxyphenyl)-tetrahydro-1,3,5-thiadiazin-4-one (compound No. 375) of the formula, ##STR174## as white crystals melting at 141°-142° C.
Reaction SMILES: [OH-:1].[K+].C(S[C:11]1[CH:16]=[N:15][NH:14][C:13](=[O:17])[N:12]=1)C1C=CC=CC=1.S(O)(O)(=O)=O.[NH2:23]O>C(O)C.O>[OH:1][NH:23][C:11]1[CH:16]=[N:15][NH:14][C:13](=[O:17])[N:12]=1
Reactant: [OH-]
Reactant: NO
Reactant: O=c1nc(SCc2ccccc2)cn[nH]1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=c1nc(NO)cn[nH]1
Temperature: 25 °C
Yield: 115.9 %

Procedure:
To a solution of potassium hydroxide (2.02 g) in a mixture of ethanol (50 ml) and water (10 ml), 5-benzylthio-2,3-dihydro-1,2,4-triazin-3-one (6.58 g) and hydroxylamine sulfate (2.95 g) were added, and the resultant mixture was refluxed for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was recrystallized from water to give 5-hydroxyamino-3-oxo-2,3-dihydro-1,2,4-triazine (Ic) (3.34 g) as pale yellow crystals. Yield, 87.1%.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:31])=[C:13]([C:26](OCC)=[O:27])[C:14](=[O:25])[N:15]2[CH2:18][C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][CH2:34][CH2:35][NH2:36]>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:31])=[C:13]([C:26]([NH:36][CH2:35][CH2:34][O:33][CH3:32])=[O:27])[C:14](=[O:25])[N:15]2[CH2:18][C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2nccn2C)c1=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2nccn2C)c1=O

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-1-[(1-methyl-1H-imidazol-2-yl)methyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 6. The product was obtained as a beige powder: 1H NMR (CDCl3) δ 10.14 (1H, br), 8.58 (2H, br), 7.32-7.15 (5H, m), 7.12 (1H, br), 6.88 (1H, br s), 5.97 (2H, br), 4.22 (2H, s), 3.70 (3H, s), 3.67 (2H, q, J˜5 Hz), 3.60 (2H, t, J˜5 Hz), 3.42 (3H, s); ES+ MS: 483 (M+H+, 100).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13]CC#N)=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:24]([OH:27])(=[O:26])[CH3:25].S(=O)(=O)(O)O>O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:25][C:24]([OH:27])=[O:26])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)O
Reactant: CC1(c2ccccc2)Cc2cc(OCC#N)c(Cl)c(Cl)c2C1=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(c2ccccc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C

Procedure:
A mixture of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetonitrile (3.0 g.), Example 19, Step A, acetic acid (20 ml.), water (5 ml.) and concentrated sulfuric acid (5 ml.) is refluxed for 2 hours then poured into ice-water (100 ml.) affording 2.5 g. of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid which melts at 168°-169° C. after recrystallization from acetic acid.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:9])/[CH2:4][O:5][CH2:6][CH2:7][CH3:8].Cl[C:11](=O)[C:12]([O:14][CH3:15])=[O:13]>C1COCC1>[CH2:6]([O:5][CH2:4][C:3]1[N:9]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[O:1][N:2]=1)[CH2:7][CH3:8]
Reactant: COC(=O)C(=O)Cl
Reactant: CCCOC/C(N)=N/O
Solvent: C1CCOC1
Product: CCCOCc1noc(C(=O)OC)n1
Reaction time: 0.17 h

Procedure:
To a solution of (1Z)—N′-hydroxy-2-propoxyethanimidamide (3.1 g) in absolute THF under Ar atmosphere is added CaH2 (1.09 g) and molecular sieves (4 A°). The mixture is stirred for 10 min and subsequently methyl chloro(oxo)acetate (3.16 g) is added and the reaction mixture is stirred for 3 h under reflux conditions. The mixture is filtered through celite and the filtrate is evaporated to dryness under vacuo. The resulting residue is purified by flash column chromatography (silica gel, eluent: cyclohexane/EtOAc, 3/2 (v/v)) to give the title compound as an oil.
Reaction SMILES: [N+]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([O-])=O.[C:14](CC(OCC)=O)#[N:15].[OH-].[K+].C[N:25](C)C=O>>[NH2:25][C:9]1[CH:8]=[CH:7][C:6]2[N:5]=[CH:4][CH:13]=[CH:12][C:11]=2[C:10]=1[C:14]#[N:15]
Reactant: CN(C)C=O
Reactant: CCOC(=O)CC#N
Reactant: O=[N+]([O-])c1ccc2ccccc2n1
Agent: [K+]
Agent: [OH-]
Product: N#Cc1c(N)ccc2ncccc12
Temperature: 25 °C
Reaction time: 22 h
Yield: 70 %

Procedure:
Nitroquinoline (5 g, 28.71 mmol) was added to a stirred solution of ethyl cyanoacetate (9.74 g, 86.13 mmol) and potassium hydroxide (4.83 g, 86.13 mmol) in N,N-dimethylformamide (87 mL). The mixture was stirred at room temperature for 22 hours. Then the solvent was removed in vacuo and the residue was hydrolyzed with chlorohydric acid (10%) at reflux for 3 hours. The mixture was basified with sodium hydroxide (10%) and extracted three times with chloroform. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/methanol 95/5) to give the desired product (16a) (3.4 g, 20.1 mmol, 70%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7](Cl)(=[O:11])/[CH:8]=[CH:9]/[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH2:18]Cl>>[CH3:18][C:1]1[CH:6]=[CH:5][C:4]([C:7](=[O:11])/[CH:8]=[CH:9]/[CH3:10])=[CH:3][CH:2]=1
Reactant: ClCCl
Reactant: c1ccccc1
Reactant: C/C=C/C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: C/C=C/C(=O)c1ccc(C)cc1

Procedure:
Benzene (1 mL), crotonoyl chloride (236 mg), and aluminium chloride (160 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (126 mg).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[C:5](=[O:14])[N:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)[CH:3]=1.C(Cl)Cl.B(Br)(Br)Br>O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[C:5](=[O:14])[N:4]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:3]=1
Reactant: COc1ccc(-n2cc(Br)c3cc(OC)ccc3c2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=c1c2ccc(O)cc2c(Br)cn1-c1ccc(O)cc1
Temperature: 25 °C
Yield: 49.4 %

Procedure:
4-Bromo-6-methoxy-2-(4-methoxyphenyl)isoquinolin-1(2H)-one (0.22 g, 0.61 mmol) was placed in a dry 150 mL single-necked flask fitted with a stirring bar and septa. Methylene chloride (30 mL) was added via a syringe. Boron tribromide (1.83 mL of 1.0 M methylene chloride solution) was added dropwise with stirring under argon atmosphere at room temperature. The reaction mixture was allowed to stir at room temperature for 20 hours. Then, 20 mL of water was added to quench the reaction. The mixture was extracted with 50 mL of ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was subjected to flash column chromatography (silica gel, CH2Cl2/MeOH=9/1 v/v) to give a white solid product, 0.10 g, 49.4% yield. MS: 334.2 [M+H]+. 1H NMR (DMSO-d6, 300 MHz): δ 10.58 (s, 1H), 9.83 (s, 1H), 8.12 (d, 1H, J=8.7 Hz), 7.71 (s, 1H), 7.22 (d, 2H, J=8.7 Hz), 7.09 (d, 1H, J=21. Hz), 7.04 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 6.84 (d, 2H, J=8.7 Hz).