Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[F:26][C:27]1[C:28](B(O)O)=[CH:29][C:30]([O:33][CH3:34])=[N:31][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:28]5[C:27]([F:26])=[CH:32][N:31]=[C:30]([O:33][CH3:34])[CH:29]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: COc1cc(B(O)O)c(F)cn1
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: CCOC(C)=O
Solvent: COCCOC
Product: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)c(F)cn1
Yield: 20.8 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.2 mmol) in 1,2-dimethoxyethane (2 mL) was added 5-fluoro-2-methoxypyridin-4-ylboronic acid (44 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium (0) (12 mg, 0.01 mmol), and 2 M sodium carbonate (0.20 mL, 0.4 mmol). The reaction mixture was irradiated in the microwave at 120° C. for twenty minutes. The reaction mixture was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The crude reaction mixture was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexanes) to yield the product (19 mg, 20%). ESI-MS m/z calc. 457.12. found 458.3 (M+1)+. Retention time 2.17 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Cl)=[CH:4][CH:3]=1.[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][N:12]=1.O>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]([C:14]2[CH:13]=[N:12][C:11]([F:10])=[CH:19][CH:18]=2)=[O:16])=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Cl)cc1
Reactant: O=C(Cl)c1ccc(F)nc1
Solvent: CCOCC
Solvent: O
Product: O=C(c1ccc(F)cc1)c1ccc(F)nc1

Procedure:
A 2 M solution of 4-fluorophenyl magnesium chloride (7 ml, 14 mmol) was slowly added at −30° C. to a solution of 6-fluoronicotinoyl chloride (3.35 g, 21 mmol,) in ether (30 ml). After complete addition, the cooling bath was removed and the reaction was allowed to reach 10° C. Hydrolysis was performed by addition of water, and the mixture is then diluted with ether. After separation of the layers, the ether solution was washed with brine, dried over Na2SO4 and evaporated in vacuum to yield a yellow solid. After purification by chromatography on silica gel (CH2Cl2/Hexane 85/15), the (4-fluorophenyl)(6-fluoro-3-pyridinyl)methanone 38 was obtained as a white solid (1.52 g, 50%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[CH2:28]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: N#Cc1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C#N)cc1
Temperature: 120 °C

Procedure:
In a 750 ml sulfonating flask, 30.0 g (0.252 mol) of 4-hydroxybenzonitrile, 84.0 g (0.252 mol) of 1-bromooctadecane and 48.7 g (0.353 mol) of finely ground potassium carbonate are introduced into 200 ml of N-methylpyrrolidone (NMP) under a nitrogen atmosphere and heated at 120° C., with stirring. After being stirred for 15 hours, the mixture is cooled to room temperature and poured into 2 liters of water, whereupon a light-beige solid precipitates out, which is filtered off and washed with water. After drying at 60° C. and 150 mbar, there are obtained 90.8 g (97% of theory) of a colourless crystalline solid of formula
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[O:8]=[C:9]1[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10]1>CO.C(Cl)Cl>[O:8]=[C:9]1[CH2:12][CH:11]([C:13]([O:15][CH3:1])=[O:14])[CH2:10]1
Reactant: O=C1CC(C(=O)O)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CC(=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trimethylsilyldiazomethane (21.0 mL of a 2 M solution in hexanes, 42.1 mmol) was added to a stirred solution of 3-oxocyclobutanecarboxylic acid (3.00 g, 26.3 mmol) in dry MeOH (11.1 mL) and dry CH2Cl2 (100 mL) at 25° C. under N2. The reaction was stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo to afford methyl 3-oxocyclobutanecarboxylate, as an oil. 1H NMR (500 MHz, CHCl3): δ 3.75 (s, 3H); 3.44-3.37 (m, 2H); 3.31-3.17 (m, 3H).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]([C:12](O)=[O:13])=[CH:10][N:9]=[C:8]2[N:15]([CH2:18][CH3:19])[N:16]=[CH:17][C:7]=12)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:22])=O>>[CH2:1]([NH:5][C:6]1[C:11]([C:12]([Cl:22])=[O:13])=[CH:10][N:9]=[C:8]2[N:15]([CH2:18][CH3:19])[N:16]=[CH:17][C:7]=12)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCNc1c(C(=O)O)cnc2c1cnn2CC
Product: CCCCNc1c(C(=O)Cl)cnc2c1cnn2CC

Procedure:
26.2 g of 4-butylamino-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (0.1 mol) and 100 ml of thionyl chloride are refluxed for 4 hours. The thionyl chloride is removed by means of a water aspirator. The residue, containing the crude 4-butylamino-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carbonyl chloride, is recrystallized from benzene, and has a melting point of 142°-145°. Yield 23.5 g = 84% of theory.
Reaction SMILES: C(=O)([O-])O.[K+].C(OC(=O)C)(=O)C.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N+:22]([O-:24])=[O:23])=[C:18]([CH:21]=1)[CH:19]=O.[C:25]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N+:22]([O-:24])=[O:23])=[C:18]([CH:19]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:25]([O:33][CH2:34][CH3:35])=[O:32])[CH:21]=1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOC(=O)C(=Cc1cc(Cl)ccc1[N+](=O)[O-])C(=O)OCC
Temperature: 110 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
Potassium hydrogen carbonate (8.12 g) was added to an acetic acid anhydride (18 ml) solution of 5-chloro-2-nitrobenzaldehyde (9.99 g) and diethyl malonate (8.64 g), which was stirred at 110° C. for 2 hours. The reaction mixture was added to iced-water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/10) to obtain the entitled compound (15.10 g). 1H-NMR δ: 1.10(3H, t), 1.36(3H, t), 4.15(2H, q), 4.44(2H, q), 7.42(1H, d), 7.52(1H, dd), 8.11(1H, s), 8.18(1H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[C:8]([C:10](O)=[O:11])[O:9][C:5]=2[CH:4]=1.C(Cl)(=O)C([Cl:18])=O>O1CCCC1.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[C:8]([C:10]([Cl:18])=[O:11])[O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2cc(C(=O)O)oc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2cc(C(=O)Cl)oc2c1
Reaction time: 0.08 h

Procedure:
To a stirred solution of 6.0 g (0.031 mole) of 6-methoxy-2-benzofurancarboxylic acid (A. McGookin, A. Robertson, and W. B. Whalley, J. Chem. Soc. 787 (1940)) in 100 ml of tetrahydrofuran (under a nitrogen atmosphere) was added in one portion, 3.3 ml (4.8 g; 0.038 mole) of oxalyl chloride. The mixture was stirred for 5 minutes, then treated with 3 drops of N,N-dimethylformamide. After stirring at room temperature for 2 hours, the solvent was evaporated to leave a residue of crude 6-methoxy-2-benzofurancarbonyl chloride, mp 96°-99° (a mp of 101° is given by A. McGookin, etc., cited above). The residue was re-dissolved in 100 ml of dichloromethane, and the solution was filtered. The filtrate was added dropwise over 20 minutes to an ice-cooled solution of 3.6 g (0.037 mole) of N,0-dimethylhydroxylamine hydrochloride and 9.4 ml (7.7 g; 0.077 mole) of 1-methylpiperidine in 100 ml of dichloromethane. After stirring for 2 hours, the mixture was added to 400 ml of ice-cold 5% aqueous hydrochloric acid. The layers were separated, and the aqueous layer was extracted with fresh dichloromethane (3× 100 ml). The combined organic layers were washed with water (1× 200 ml), 3% aqueous sodium bicarbonate (2× 200 ml), and water again. The extracts were dried (anhydrous magnesium sulfate) and evaporated. Trituration of the residue with ether yielded 5.4 g (74% yield) of the analytically pure amide product, mp 73°-77°.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][CH:21]([CH3:27])[CH2:22][CH2:23][C:24](O)=[O:25]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:24](=[O:25])[CH2:23][CH2:22][CH:21]([CH3:27])[CH3:20])[N:11]=2)=[CH:13][CH:14]=1
Reactant: CC(C)CCC(=O)O
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: CC(C)CCC(=O)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 4-methylpentanoic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.42 (m, 1H), 7.88-8.04 (m, 2H), 7.72-7.75 (m, 1H), 7.59-7.69 (m, 4H), 2.34 (t, J=7.7 Hz, 2H), 1.57-1.68 (m, 1H), 1.49-1.54 (m, 2H), 0.92 (d, J=6.6 Hz, 6H); MS (ESI−) M/Z 368 (M−H)−.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[S:19][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:6]=2[CH:5]=1.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O>>[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:16]1[CH2:15][CH2:14][CH:13]([NH:12][C:11]2[C:6]3[CH:5]=[C:4]([Cl:3])[S:19][C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:18][CH2:17]1
Reactant: Clc1cc2c(NC3CCNCC3)ncnc2s1
Reactant: O=Cc1ccccc1F
Agent: Cl
Product: Fc1ccccc1CN1CCC(Nc2ncnc3sc(Cl)cc23)CC1

Procedure:
The title compound was prepared (65 mg, 37%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine dihydrochloride (160 mg, 0.47 mmol) and 2-fluorobenzaldehyde (58 mg, 0.47 mmol) by following the general procedure described for Preparation 11. 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.37 (t, 1H), 7.25 (m, 1H), 7.13 (t, 1H), 7.07 (t, 1H), 6.97 (s, 1H), 4.85 (d, 1H), 4.16 (m, 1H), 3.63 (s, 2H), 2.92 (d, 2H), 2.29 (t, 2H), 2.08 (d, 2H), 1.61 (m, 2H); MS (ESI) m/z: Calculated for C18H19ClFN4S, 377.1; Observed: 377.2 (M++1).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=O)(C)(C)C.[ClH:24].O1CCOCC1>C(Cl)Cl>[ClH:24].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl 6-(tert-butoxycarbonylamino)hexanoate (1 eq) in DCM (0.17 M) was added 4M HCl in dioxane (30 eq). The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated en vaccuo. The crude material was dissolved in DCM and precipitated in diethyl ether to give the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].I[CH:12]([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:12]([CH3:14])[CH3:13])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CC(C)I
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Cl)cc1C=O
Yield: 78.8 %

Procedure:
5-Chloro-2-hydroxy-benzaldehyde (3 g, 19.16 mmol),2-Iodo-propane (4.88 g, 28.74 mmol) and K2CO3 (4 g, 28.74 mmol) was mixed in anhydrous DMF. The reaction tube was placed into the cavity of a focused monomode microwave reactor and the contents of the flask were irradiated for 30 min at 100° C. Then the solution was filtered and the filtration was concentrated to obtain the crude product (3 g). The crude product was used into next step reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3=[CH:19][CH:20]=[CH:21][C:22]([C:23]([NH2:25])=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[Na+].P(Cl)(Cl)(Cl)=O>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3=[CH:19][CH:20]=[CH:21][C:22]([C:23]#[N:25])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cccc2c1nc(Nc1cccc(Cl)c1)c1ccncc12
Agent: [Cl-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: N#Cc1cccc2c1nc(Nc1cccc(Cl)c1)c1ccncc12
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-7-carboxamide (12 mg, 0.034 mmol) was suspended in dichloroethane (0.2 ml). Sodium chloride (70 mg) was added followed by Phosphorus oxychloride (20 ul). The mixture was stirred at 80° C. for 1.5 hours. An extra amount of Phosphorus oxychloride (50 ul) was added and the mixture was heated at 80° C. for 8 hours. The volatiles were removed in vacuo. Water was added and the solid was filtered. The material was purified by preparative TLC on silica gel (5% MeOH in CH2Cl2) to provide 6 mg of 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-7-carbonitrile. LCMS (ES): >95% pure, m/z 331 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[S:13][CH2:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.CS(O[CH2:33][C:34]1([CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:36][CH2:35]1)(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:33][C:34]1([CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:35][CH2:36]1)[CH:6]=[C:5]2[S:13][CH2:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CSc2c[nH]c(=O)c3ccc(Br)cc23)C1
Reactant: CC(C)(C)[Si](C)(C)OCC1(COS(C)(=O)=O)CC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](CSc2cn(CC3(CO[Si](C)(C)C(C)(C)C)CC3)c(=O)c3ccc(Br)cc23)C1
Yield: 40.3 %

Procedure:
tert-Butyl (3S)-3-{[(6-bromo-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfanyl]methyl}-piperidine-1-carboxylate (Example 63c, 190 mg) was reacted with [1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methyl methanesulfonate (136 mg) by the method of Example 58c to afford the subtitle compound (110 mg) as a colourless oil.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[N:5][N:4]=[C:3]1[S:13][CH3:14].O.[C:16]([OH:20])(=[O:19])[CH:17]=[O:18]>C(OCC)(=O)C>[CH3:14][S:13][C:3]1[N:2]([NH:1][CH:17]([OH:18])[C:16]([OH:20])=[O:19])[C:7](=[O:8])[C:6]([C:9]([CH3:11])([CH3:10])[CH3:12])=[N:5][N:4]=1
Reactant: CSc1nnc(C(C)(C)C)c(=O)n1N
Reactant: O=CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1nnc(C(C)(C)C)c(=O)n1NC(O)C(=O)O
Reaction time: 3 h
Yield: 87.4 %

Procedure:
21.4 g (0.1 mol) of 4-amino-6-tert.-butyl-3-methylthio-1,2,4-triazin-5-one and 10.1 g (0.11 mol) of glyoxylic acid monohydrate were stirred in 250 ml of ethyl acetate for 12 hours at room temperature, whereby a clear solution was produced. The mixture was then left to stand; after about 3 hours, the product began to crystallize out. It was filtered off and the filtrate was concentrated, whereupon further material crystallized out. The combined filter residues were washed with ether and dried. 25.2 g (87.5% of theory) of N-(3-methylthio-6-tert.-butyl-1,2,4-triazin-5-on-4-yl)- α-hydroxy-glycine of melting point 161° C (decomposition) were obtained.
Reaction SMILES: [O-]CC.[Na+].[Cl:5]/[C:6](=[C:9](\[Cl:12])/[CH:10]=[O:11])/[CH:7]=[O:8].Cl.[CH3:14][NH2:15].O>C(O)(=O)C>[Cl:5][C:6]1[C:7]([N:15]([CH3:14])[C:10](=[O:11])[C:9]=1[Cl:12])=[O:8]
Reactant: CN
Reactant: O=C/C(Cl)=C(/Cl)C=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN1C(=O)C(Cl)=C(Cl)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
Sodium ethoxide (3.56 g, 50 mmol) was added to a solution containing 2,3-dichloromaleic hydride (5.56 g, 33.3 mmol) and methylamine hydrochloride (3.50 g, 55.0 mmol) in 40 mL of acetic acid. The mixture was stirred under a CaCl2 drying tube at 25° C. for 16 hours and then refluxed for 4 hours. The cooled mixture was poured into water (350 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were washed with 100 mL portions of saturated aqueous NaHCO3, water and brine and dried (MgSO4). The solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give 3.82 g (64%) of 2,3-dichloro N-methylmaleimide as white crystals. Concentration of the mother liquor and chromatography of the residue by radial preparative layer chromatography (Chromatotron, Harrison Research), gave an additional 0.81 g of 2,3-dichloro N-methylmaleimide, raising the yield to 77%.
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([C:8]([O:10][C:11]2[C:20]3[C:15](=[C:16]([O:21][C:22](=[O:32])[C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=4)[CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CN(C=O)C.[Pd]>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([O:21][C:16]2[C:15]3[C:20](=[C:11]([O:10][C:8](=[O:9])[C:7]4[CH:33]=[CH:34][C:4]([NH2:1])=[CH:5][CH:6]=4)[CH:12]=[CH:13][CH:14]=3)[CH:19]=[CH:18][CH:17]=2)=[O:32])=[CH:28][CH:27]=1
Reactant: [H][H]
Reactant: O=C(Oc1cccc2c(OC(=O)c3ccc([N+](=O)[O-])cc3)cccc12)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)Oc2cccc3c(OC(=O)c4ccc(N)cc4)cccc23)cc1
Reaction time: 0.17 h
Yield: 82.9 %

Procedure:
22.2 g of 5-[(4-nitrobenzoyl)oxy]-1-naphthyl 4-nitrobenzoate (48.4 mM) were suspended in 400 ml of DMF and 2.5 g of palladium on charcoal (10%) were added. The resulting mixture was hydrogenated at atmospheric pressure until the theoretical amount of hydrogen was consumed. The mixture was then filtered, the cake was washed with DMF and the filtrate was poured onto 4 L of water. The resulting suspension was stirred for 10 min. and the solids ware filtered off, washed with water and dried to give 16.0 g (40.2 mM, 83.0%) of 5-[(4-aminobenzoyl)oxy]-1-naphthyl 4-aminobenzoate as beige crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[Br:13]Br>C(Cl)Cl>[Br:13][C:9]1[CH:10]=[C:11]([CH3:12])[C:2]([OH:1])=[CH:3][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C)c(O)c1
Reactant: BrBr
Solvent: ClCCl
Product: COC(=O)c1cc(O)c(C)cc1Br
Reaction time: 8 h

Procedure:
A solution of 1 g (6 mmoles) of the ester from step a. dissolved in 10 ml of dry CH2Cl2 and cooled in an ice bath was treated dropwise with 0.96 g (6 mmoles) of Br2 in 2 ml CH2Cl2. The reaction flask was sealed and stored at -15° overnight. Gentle swirling of the reaction solution induced crystallization of fine white needles that were collected by filtration and washed with cold CH2Cl2 /hexanes.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[NH2:17])\[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]#N)[CH:22]=[CH:23][C:24]=1[Cl:25].C(O)C.Cl>C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]2[O:1][N:2]=[C:3]([CH2:4][O:5][C:6]3[CH:7]=[C:8]4[C:13](=[CH:14][CH:15]=3)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]4)[N:17]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: N/C(COc1ccc2c(c1)CCC(=O)N2)=N/O
Reactant: N#CNc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1CCc2cc(OCc3noc(Nc4ccc(Cl)c(Cl)c4)n3)ccc2N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 7 %

Procedure:
To a solution of (E)-N′-hydroxy-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetimidamide (0.1 g, 0.425 mmol) in ethyl acetate (10 mL) was added a 0.5M solution of zinc chloride (0.073 mL, 0.510 mmol) followed by N-(3,4-dichlorophenyl)cyanamide (0.080 g, 0.425 mmol) and stirred at room temperature for 12 h. Then reaction mixture was concentrated. Ethanol (10.00 mL) was added along with HCl (0.1 mL, 3.29 mmol) and the reaction mixture was heated at 80° C. for 6 h. The reaction mixture was concentrated and basified with sodium bicarbonate solution, then the resulting solid was filtered and was washed with acetonitrile to give 6-((5-((3,4-dichlorophenyl)amino)-1,2,4-oxadiazol-3-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one as a white solid (12 mg, 6.8% yield). 1H NMR 400 MHz, DMSO-d6: δ 2.41 (t, J=15.20 Hz, 2H), 2.84 (t, J=15.20 Hz, 2H), 4.94 (s, 2H), 6.77-6.79 (m, 1H), 6.84-6.87 (m, 1H), 6.93 (d, J=2.80 Hz, 1H), 7.30 (s, 1H), 7.37 (s, 1H), 7.80 (s, 1H), 9.91 (s, 1H). LCMS: RT 1.963 min; LCMS (ES-API), m/z 403.0 [M−H]−.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([C:21]([OH:23])=O)[C:18]([CH3:24])=[C:17]3[C:13]=2[C:14]2[CH:28]=[C:27]([CH3:29])[CH:26]=[N:25][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH:34][C:21]([C:19]1[C:18]([CH3:24])=[C:17]2[C:13]([C:14]3[CH:28]=[C:27]([CH3:29])[CH:26]=[N:25][C:15]=3[NH:16]2)=[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:7]=2)[CH:20]=1)=[O:23]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C(=O)O)c(C)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1cccc(-c2cc(C(=O)NCCN(C)C)c(C)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxylic acid (3.0 g, 73 mmol), N,N-Dimethylethylene diamine (g, mmol), HATU (g, mmol), triethylamine (g, mmol) and DMF (mL) was stirred at room temperature for two days. The reaction mixture was poured over ice affording a precipitate, The resulting suspension was filtered, rinsed with H2O and dried in vacuo to g (%). 1H NMR (400 MHz, DMSO-d6): δ 12.04 (s, 1H), 8.28-8.31 (m, 2H), 8.12 (s, 1H), 8.01-8.05 (m, 2H), 7.89 (t, 1H), 7.52 (s, 1H), 7.12 (s, 1H), 3.43 (q, 2H), 2.63 (s, 3H), 2.27 (s, 3H), 2.20 (s, 6H), 1.17 (t, 3H). MS (ES) [m+H] calc'd for C26H30N4O3S, 479; found 479.4.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([N:11]1[C:23]2[CH:22]=[CH:21][C:20]([CH:24]=O)=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[C:15]([CH:26]=O)[CH:16]=2)[CH3:10]>C1(C)C=CC=CC=1.C1COCC1>[C:1]1([NH:7][N:8]=[CH:24][C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[N:11]([CH2:9][CH3:10])[C:12]2[CH:13]=[CH:14][C:15]([CH:26]=[N:8][NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:16][C:17]3=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: CCn1c2ccc(C=O)cc2c2cc(C=O)ccc21
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCn1c2ccc(C=NNc3ccccc3)cc2c2cc(C=NNc3ccccc3)ccc21
Temperature: 25 °C

Procedure:
Phenylhydrazine (0.2 mole, commercially available from Aldrich, Milwaukee, Wis.) and N-ethyl-3,6-diformylcarbazole (0.1 mole) were dissolved in 100 ml of a 1:1 v/v mixture of toluene and THF in 250 ml 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The solution was refluxed for 2 hours. Thin layer chromatography indicated the disappearance of the starting materials. At the end of the reaction, the mixture was cooled to room temperature. The N-ethyl-3,6-diformylcarbazole bis(N-phenylhydrazone) crystals formed upon standing were filtered off, washed with isopropanol and dried in a vacuum oven at 50° C. for 6 hours. Without further purification, the product was used for the next step.