Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][N:32]([C:2]3[C:3]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:4][C:5]4[C:10]([N:11]=3)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=4)[CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: Clc1cccc(N2CCNCC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4cccc(Cl)c4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
A solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 1-(3-chlorophenyl)piperazine (172.5 mg, 0.88 mmol, 2.00 equiv), and DIEA (170.3 mg, 1.32 mmol, 3.00 equiv) in DMF (4 mL) was placed in a 20-mL sealed tube and stirred overnight at 100° C. in an oil bath, then quenched with water. The resulting solution was extracted with 6×20 mL of ethyl acetate, the organic layers combined and dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under vacuum. Purification via silica gel column (PE/EA (30:1)) yielded 186.7 mg (89%) of methyl 3-(4-(3-chlorophenyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=2[CH3:18])[CH:4]=1>O1CCCC1.C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=2[CH3:18])[NH2:15])[CH:4]=1
Reactant: COc1ccnc(-c2cc([N+](=O)[O-])ccc2C)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccnc(-c2cc(N)ccc2C)c1
Yield: 99.6 %

Procedure:
A suspension of 2-(4-methoxypyridin-2-yl)-4-nitrotoluene (293 mg) in tetrahydrofuran (3 ml) and ethanol (3 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 0.1 g) under a hydrogen atmosphere for 3 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 3-(4-methoxypyridin-2-yl)-4-methylaniline (256 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][CH:29]([C:35]2([CH3:39])[CH2:38][CH2:37][CH2:36]2)[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.Cl>C(#N)C>[F:1][C:2]1[C:3]([NH:28][CH:29]([C:35]2([CH3:39])[CH2:36][CH2:37][CH2:38]2)[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: COC(=O)CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C1(C)CCC1
Agent: Cl
Solvent: CC#N
Product: COC(=O)CC(Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F)C1(C)CCC1
Temperature: 65 °C

Procedure:
To a racemic solution of methyl 3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-3-(1-methylcyclobutyl)propanoate, 119a, (3.3 g, 5.9 mmol) in acetonitrile (25 mL) was added HCl (26 mL of 4N solution in dioxane). The reaction mixture was heated to 65° C. for 4 hours. The solution was cooled to room temperature and the solvents were removed under reduced pressure. The mixture was flushed with acetonitrile after which aqueous sodium bicarbonate and ethyl acetate were added. The phases were separated and the aqueous layer washed with ethyl acetate. The combined organic phases were dried with Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (EtOAc/Hexanes) to afford the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.34 minutes (M+H) 403.11.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[C:13](=[O:14])[CH2:12][CH2:11][CH:10]1[C:15]#[N:16].[CH2:17](O)[CH2:18][OH:19].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:15]([CH:10]1[CH2:11][CH2:12][C:13]2([O:19][CH2:18][CH2:17][O:14]2)[CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])#[N:16]
Reactant: OCCO
Reactant: N#CC1CCC(=O)C1CCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: N#CC1CCC2(OCCO2)C1CCCCCCCO
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A mixture of 2-(7-hydroxyheptyl)-3-oxocyclopentanecarbonitrile (20 g.), ethylene glycol (5.6 g.), p-toluenesulphonic acid (1 g.) and benzene 160 ml.) was heated to reflux for 210 minutes with continuous removal of water. The mixture was cooled to ambient temperature, anhydrous sodium carbonate was added and, after filtration through a bed of sodium carbonate, the solvent was removed under reduced pressure. The residue was distilled under reduced pressure to give 7-cyano-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (19.3 g.), b.p. 166° C-182° C./0.1 mm.Hg. This material was used as a starting material in the next stage, as aliquot being redistilled to b.p. 177°-179° C./0.1 mm.Hg for elemental analysis:
Reaction SMILES: [I:1][C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][CH:3]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH4+].[Cl-]>CN(C=O)C.O>[CH2:15]([N:4]1[CH:3]=[C:2]([I:1])[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]1=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=c1[nH]cc(I)c2ccncc12
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cnccc2c(I)cn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
To a solution of 4-iodo-2,7-naphthyridin-1(2H)-one (0.544 g, 2.0 mmol) in anhydrous DMF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 0.104 g, 2.6 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 30 min and then benzyl bromide (0.410 g, 2.4 mmol) was added slowly. The reaction was stirred at 0° C. for 2 h, then allowed to warm to rt and stirred for 17 h. Saturated NH4Cl solution (5 mL) and water (5 mL) were added and the mixture was extracted with ethyl acetate (2×25 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 97:3 dichloromethane/methanol) to give 2-benzyl-4-iodo-2,7-naphthyridin-1(2H)-one (0.540 g, 75%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 8.84 (d, J=5.5 Hz, 1H), 7.68 (s, 1H), 7.45 (d, J=5.5 Hz, 1H), 7.30-7.41 (m, 5H), 5.19 (s, 2H); ESI MS m/z 363 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[CH2:16][C@H:17]([NH:21]C(OC(C)(C)C)=O)[C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:29]>O1CCOCC1>[ClH:29].[NH2:21][C@@H:17]([CH2:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18]([OH:20])=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(I)ccc1OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1cc(I)ccc1OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12 g (24.13 mmol) of 3-(2-benzyloxy-5-iodophenyl)-2(S)-tert-butoxycarbonylaminopropionic acid (Example (−)-6A) are added under argon into 60 ml of a 4M solution of hydrogen chloride in dioxane and stirred at RT for 2 h. The reaction solution is concentrated and dried under high vacuum.
Reaction SMILES: C([O:8][C:9]1[CH:40]=[CH:39][C:12]([O:13][CH2:14][C@@H:15]([OH:38])[CH2:16][NH:17][C@H:18]([CH2:36][OH:37])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.O1CCOCC1.[Pd]>[OH:37][CH2:36][C@@H:18]([NH:17][CH2:16][C@H:15]([OH:38])[CH2:14][O:13][C:12]1[CH:39]=[CH:40][C:9]([OH:8])=[CH:10][CH:11]=1)[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:28])=[CH:24][CH:25]=1
Reactant: O=C(Nc1ccccc1)Nc1ccc(C[C@@H](CO)NC[C@H](O)COc2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)Nc1ccc(C[C@@H](CO)NC[C@H](O)COc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
N-[4-[(2S)-2-[[(2S)-3-[4-(Benzyloxy)phenoxy]-2-hydroxypropyl]amino]-3-hydroxypropyl]phenyl]-N′-phenylurea (159 mg) was dissolved in a mixed solvent of methanol (2.5 ml) and 1,4-dioxane (2.5 ml) under heating. After cooling to room temperature, 10% palladium on activated carbon (50% wet, 159 mg) was added and the mixture was hydrogenated at 1 atm for 4 hours. The catalyst was removed by filtration and washed with methanol. The filtrate was concentrated in vacuo to give N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]propyl]phenyl]-N′-phenylurea (129 mg) as a white solid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15]1[S:16][CH:17]=[CH:18][C:19]=1Br.Cl>C(OCC)C.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15]1[S:16][CH:17]=[CH:18][C:19]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Brc1ccsc1-c1sccc1Br
Reactant: CCCCCC[Mg]Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CCCCCCc1ccsc1-c1sccc1CCCCCC
Yield: 100.1 %

Procedure:
Hexylmagnesium bromide (100 ml, 2 M solution in diethyl ether, 200 mol) was added dropwise to a solution of 3,3′-dibromo-2,2′-bithiophene (15 g, 46.6 mmol) and Ni(dppp)Cl2 (0.5 g, 0.1 mmol) in 100 ml of diethyl ether at 0C. The reaction was slightly exotherm and a red brown coloration was observed. After stirred and heated for 24 h, the reaction mixture was cautiously poured into a mixture of crushed ice and diluted HCl solution and extracted with ether. The combined extracts were dried over anhydrous MgSO4 and filtered. After removal of the solvent, the residue was vacuum-distilled to give a clear viscous oil (15.6 g, 81%). 1H-NMR (CDCl3, ppm): δ7.25 (d, 2H, J=5 Hz), δ6.96 (d, 2H, J=5 Hz), 2.50 (t, 4H), 1.54 (m, 4H), 1.23 (m, 12H), 0.85 (t, 6H).
Reaction SMILES: C([C:4]1([CH:11]=[C:10]([CH:12]([CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:13])[CH2:9][C:7](C(=O)C)([OH:8])[CH:6]1[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:29]=1[C:30]([CH3:32])=[CH2:31])[OH:5])(=O)C.N>C1(C)C=CC=CC=1>[C:30]([C:29]1[CH:28]=[CH:27][N:26]=[CH:25][C:24]=1[C:6]1[C:4]([OH:5])=[CH:11][C:10]([CH:12]([CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:13])=[CH:9][C:7]=1[OH:8])([CH3:32])=[CH2:31]
Reactant: C=C(C)c1ccncc1C1C(O)(C(C)=O)C=C(C(C)C(C)CCCCC)CC1(O)C(C)=O
Agent: N
Solvent: Cc1ccccc1
Product: C=C(C)c1ccncc1-c1c(O)cc(C(C)C(C)CCCCC)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4.37 g. of 1,3-diacetyl-2-[4-isopropenyl-3-pyridyl]-5-(3-methyl-2-octyl)resorcinol in 50 ml. of toluene was placed in a high pressure bomb with 40 ml. of liquid ammonia. The mixture was shaken at room temperature overnight. The excess ammonia was allowed to escape; the residue was triturated with water and extracted with chloroform. The chloroform extracts were washed twice with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was recrystallized from ether-petroleum ether (30°-60°) to yield the pure product; m.p. 128°-129°.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:10]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:9]1)=[O:7])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:11]2([C:20]#[N:21])[CH:10]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[C:23]([F:29])[CH:24]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 79 %

Procedure:
In a manner similar to the method described in Example 1d, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 64b (1 g, 2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.88 g, 79%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([N:11]([CH3:26])[C:12]1[CH:13]=[CH:14][C:15]([F:25])=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:17]=1)[N:5]=2.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>N1C=CC=CC=1>[F:25][C:15]1[CH:14]=[CH:13][C:12]([N:11]([CH3:26])[C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:30]([CH:27]4[CH2:29][CH2:28]4)=[O:31])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]=1[NH:18][C:19](=[O:24])[C:20]([F:22])([F:21])[F:23]
Reactant: O=C(Cl)C1CC1
Reactant: CN(c1ccc(F)c(NC(=O)C(F)(F)F)c1)c1ccc2nc(N)sc2n1
Solvent: c1ccncc1
Product: CN(c1ccc(F)c(NC(=O)C(F)(F)F)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)(methyl)amino]-2-fluorophenyl}-2,2,2-trifluoroacetamide (385 mg, 1.00 mmol) in pyridine (10 mL) was added cyclopropanecarbonyl chloride (144 μL, 1.60 mmol) at 4° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate (10 mL). The obtained suspension was washed with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=80/20→0/100), and the obtained solution was concentrated under reduced pressure to give the title compound (250 mg, 59%) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:14])=[N:4][C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[N:6][C:7]=1Cl.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1COCC1>[Br:1][C:2]1[C:3]([NH2:14])=[N:4][C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[N:6][C:7]=1[S:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1nc(-n2cccn2)nc(Cl)c1Br
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(-n2cccn2)nc(Sc2ccccc2)c1Br

Procedure:
To a solution of 0.1 g (0.36 mmol) of 5-bromo-6-chloro-2-(1H-pyrazol-1-yl)pyrimidin-4-amine (Intermediate 5) in 4 ml of THF, 74 μl (0.73 mmol) of thiophenol and 0.178 g (0.55 mmol) of Cs2CO3 were added. The mixture was allowed to react under microwave conditions 15 min. at 100° C. Afterwards the reaction mixture was put on 10 ml of cool water. The formed white precipitate was filtered, washed several times with cold water and dried.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([N+:17]([O-])=O)[C:5]=1[O:6][CH:7]([CH3:11])[C:8](O)=[O:9])([OH:3])=[O:2].N>O>[Cl:16][C:14]1[CH:15]=[C:4]([C:1]([OH:3])=[O:2])[C:5]2[O:6][CH:7]([CH3:11])[C:8](=[O:9])[NH:17][C:12]=2[CH:13]=1
Reactant: CC(Oc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-])C(=O)O
Agent: N
Solvent: O
Product: CC1Oc2c(cc(Cl)cc2C(=O)O)NC1=O
Yield: 92.2 %

Procedure:
To a solution of 960 g of ferrous sulfate heptahydrate in 2 1 of hot water is added a solution of 130 g of 2-(2-carboxy-4-chloro-6-nitrophenoxy)propionic acid and 200 ml of aqueous concentrated ammonia solution in 480 ml of water under stirring. After stirring for 30 minutes, to the reaction mixture is twice added 480 ml of aqueous concentrated ammonia solution. While the reaction mixture becomes exothermic, stirring is continued for an hour. The resultant mixture is filtered through a celite layer under reduced pressure and washed with 2 1 of hot water twice. The filtrate is cooled and made acid with concentrated hydrochloric acid. The precipitated crystals are washed with water and dried to give 100 g of 6-chloro-3,4-dihydro-2 -methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid, melting at 319°-320° C. with decomposition.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.Cl[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1>>[CH3:8][C@H:4]1[NH:3][C@@H:2]([CH3:1])[CH2:7][N:6]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:5]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Clc1ccc2ccccc2n1
Product: C[C@@H]1CN(c2ccc3ccccc3n2)C[C@H](C)N1

Procedure:
Prepared analogously to Example 38 from cis-2,6-dimethyl-piperazine and 2-chloroquinoline.
Reaction SMILES: C(O[C:4](=[O:11])[CH2:5][NH:6][CH2:7][CH:8]([CH3:10])[CH3:9])C.CCN(CC)CC.[CH3:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[N:29]=[C:30]=[S:31]>O.CC(C)=O>[CH3:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[N:29]=[C:30]1[N:6]([CH2:7][CH:8]([CH3:9])[CH3:10])[CH2:5][C:4](=[O:11])[S:31]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CCOC(=O)CNCC(C)C
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC(=O)CN1CC(C)C
Temperature: 40 °C
Yield: 20.3 %

Procedure:
A solution of N-isobutylglycine ethyl ester (0.41 g, 2.57 mmol) in water (5 mL) was treated with Et3N (0.71 mL, 5.15 mmol), followed by a solution of 2-methyl-4-nitrophenyl isothiocyanate (0.50 g, 2.57 mmol) in acetone (5 mL). The resulting mixture waxs heated at 40° C. for 2 h, then cooled to room temperature and concentrated under reduced pressure. The residue was separated between water (25 mL) and ethyl acetate (25 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidin-5-one (0.16 g, 88%): mp 152° C.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.[Cl-].[Na+]>[O:11]1[CH2:12][CH2:13][N:8]([C:7]2[C:2]([O:30][C:27]3[CH:26]=[CH:25][C:24]([NH:23][C:15]4[S:14][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=5[N:16]=4)=[CH:29][CH:28]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Clc1ncccc1N1CCOCC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: c1cnc(Oc2ccc(Nc3nc4ccccc4s3)cc2)c(N2CCOCC2)c1
Temperature: 25 °C

Procedure:
To a round bottomed flask was added 4-(2-chloropyridin-3-yl)morpholine (0.2076 g, 1.045 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (0.304 g, 1.254 mmol), and cesium carbonate (0.409 g, 1.254 mmol) in DMSO (3.48 mL) at 80° C. for two days. The reaction was allowed to cool to room temperature. The reaction mixture was diluted with a 50% sodium chloride solution and extracted with DCM. The organic extract was washed with water, brine, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (25M), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide N-(4-(3-morpholinopyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine. MS (ESI, pos. ion) m/z: 405 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][NH:18][CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22].CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][N:18]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CNCC4C3)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CN(S(C)(=O)=O)CC4C3)nc21
Reaction time: 0.08 h

Procedure:
1-(2,2-Dimethylpropyl)-5-(1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (84, 100 mg, 0.30 mmol, 1.0 equiv), and DIPEA (0.16 mL, 0.91 mmol, 3.0 equiv) were added to anhydrous methylene chloride (3 mL). Stirred for 5 min and methanesulfonyl chloride (26.3 μL, 0.33 mmol, 1.1 equiv) was added. After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 10-1 as a pale yellow oil. MS m/z (M+H): calculated=405.1957; observed=405.1969.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[Na].[CH2:13]([OH:17])[CH2:14][CH2:15][CH3:16]>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CCCCO
Agent: [Na]
Product: CCCCOc1nc(N)nc2[nH]cnc12

Procedure:
The title compound was prepared in a manner analogous to the preparation of the compound of Example 11a, using 2-amino-6-chloropurine (Sigma, lot #69F4064, 4.4 g, 25.9 mmol) and sodium (Aldrich, lot #9621CL, 3 g, 129.5 mmol) in 250 mL n-butanol to give 4.4 g (21.2 mmol, 82%). mp=165° C.
Reaction SMILES: N[C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.Cl.N([O-])=O.[Na+].[Cu](C#N)[C:20]#[N:21].[C-]#N.[Na+]>O.C(OCC)(=O)C>[Cl:11][C:10]1[C:2]([C:20]#[N:21])=[CH:3][C:4]([O:12][CH3:13])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7]
Reactant: N#C[Cu]C#N
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: [C-]#N
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C#N)c(Cl)cc1C(=O)O
Temperature: 5 °C
Yield: 72.9 %

Procedure:
To a solution of 4-amino-5-chloro-2-methoxybenzoic acid (4 g, 0.019 mol) in water (60 mL) was added hydrochloric acid (35%, 0.63 mL) and the mixture was stirred vigorously and cooled to 5° C. Then a solution of sodium nitrite (1.92 g, 0.027 mol) in water (6 mL) was added dropwise. The mixture was stirred for some minutes and then a previously formed solution of copper cyanide (2.32 g, 0.026 mol) and sodium cyanide (3.65 g, 0.074 mol) in water (20 mL) was added dropwise maintaining a low temperature. Once the addition was finished the reaction mixture was stirred 1 hour at room temperature. The pH of the aqueous phase was adjusted to 3 and ethyl acetate was added into the mixture and the organic layer was washed with water, dried, filtered and the solvent was removed under reduced pressure giving the title compound (2.93 g, 62%).