Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[S:3]([CH2:6][C:7](OC)=[O:8])(=[O:5])=[O:4].[NH2:26][OH:27]>>[OH:27][NH:26][C:7](=[O:8])[CH2:6][S:3]([N:2]([CH3:1])[CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)(=[O:5])=[O:4]
Reactant: COC(=O)CS(=O)(=O)N(C)C/C=C/c1ccc(-c2ccccc2)cc1
Reactant: NO
Product: CN(C/C=C/c1ccc(-c2ccccc2)cc1)S(=O)(=O)CC(=O)NO

Procedure:
In a manner similar to Example 1 (b), methyl 2-({methyl[3-(1,1'-biphenyl-4-yl)-trans-prop-2-enyl]amino}sulfonyl)acetate was reacted with hydroxylamine to give the title compound as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([Cl:9])=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].Br[CH2:17][CH:18]1[CH2:21][CH2:20][CH2:19]1>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: BrCC1CCC1
Reactant: Oc1cc(Cl)ncc1Cl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Clc1cc(OCC2CCC2)c(Cl)cn1
Temperature: 80 °C
Reaction time: 20 h
Yield: 49.9 %

Procedure:
To a solution of 2,5-dichloro-4-pyridinol (CAN 847664-65-7, 660 mg, 4.02 mmol) in THF (20 mL) and DMF (20 mL) was added with stirring sodium tert-butoxide (1.16 g, 12.1 mmol) and (bromomethyl)-cyclobutane (CAN 17247-58-4, 2.26 mL, 20.1 mmol). The resulting mixture was stirred at 80° C. for 20 h, cooled and concentrated. The residue was partitioned between water and ethyl acetate; the organic portions were combined, dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography (silica, heptane/ethyl acetate gradient) to give the title compound (466 mg, 50%) as white solid. LC-MS (UV peak area, m/z) 97.8%, 232.0293 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:34])C(=O)C1>CN(C=O)C.C(OCC)(=O)C.O>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:11]=2[N:10]=[C:9]1[Cl:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(=O)[nH]c(=O)c2c1nc(Cl)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution of 7-benzyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (6.0 g, 16.13 mmol) in DMF (50 mL) was added NCS (3.23 g, 24.19 mmol) and the resulting mixture was stirred at room temperature for 8 h. The mixture was diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 7-benzyl-8-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (5.1 g, 77.9% yield) as light yellow oil. Product tlc [petroleum ether/ethyl acetate (15:1) iodine detection, Rf 0.6)
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]=[C:8]([NH:23][C:24]([C:26]1[C:31](Cl)=[N:30][CH:29]=[CH:28][N:27]=1)=[O:25])[CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1.Cl>CN(C=O)C>[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH2:12][CH2:11][O:10][CH2:9][C:8]1[NH:23][C:24](=[O:25])[C:26]2[C:31](=[N:30][CH:29]=[CH:28][N:27]=2)[N:7]=1
Reactant: N=C(COCCc1ccc2ccccc2c1)NC(=O)c1nccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(COCCc2ccc3ccccc3c2)nc2nccnc12
Temperature: 100 °C
Yield: 32 %

Procedure:
K2CO3 (442 mg) was added to a solution of 3-chloro-pyrazine-2-carboxylic acid [1-imino-2-(2-naphthalen-2-yl-ethoxy)-ethyl]-amide (590 mg) in DMF (5 ml) and heated to 100° C. for 3 h. The reaction mixture was acidified to pH=5 (aqueous HCl, 1N) and extracted with ethyl acetate. The organic layers were dried (Na2SO4), filtered, and the solvent was evaporated. 2-(2-Naphthalen-2-yl-ethoxymethyl)-3H-pteridin-4-one (170 mg, 32%) was obtained from the residue by column chromatography (silica gel, eluent gradient n-heptane/ethyl acetate=80/20-50/50). MS: m/e=331.0 [M−H−]. 1H NMR (d6-DMSO): δ 3.09 (t, 2H), 3.91 (t, 2H), 4.51 (s, 2H), 7.45-7.50 (m, 3H), 7.79-7.88 (m, 4H), 8.82 (d, 1H), 8.99 (d, 2H), 12.72 (bs, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([SnH](CCCC)CCCC)CCC>C1C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>[O:8]1[CH2:9][CH:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)C=CCOc1ccccc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CCOC(=O)CC1COc2ccccc21
Reaction time: 14 h
Yield: 95.1 %

Procedure:
To ethyl 4-(2-bromophenyloxy)but-2-enoate (6.10 g, 21.0 mmol) in benzene (200 mL) at reflux was added AIBN (0.07 g, 0.4 mmol) followed by dropwise addition of a benzene (~65 mL) solution containing tri-n-butyltin hydride (6.72 g, 23.1 mmol). After complete addition (one h) the reaction was refluxed an additional 2 h. The reaction was concentrated in vacuo and the residue treated with Et2O (~50 mL) and a 60% KF solution (~40 mL). The solution was stirred 14 h. The precipitate was removed by filtration and the Et2O phase decanted off. The remaining aqueous phase was extracted with Et2O (3×). The combined Et2O solutions were washed with saturated aqueous NaCl solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography (95:5 Hexane:EtOAc) afforded the title compound (4.12 g, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(C)(C)C>ClC(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][Br:10])[CH:3]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C)OOC(=O)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Br)cc(CBr)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5 ml (36.8 mmol) 5-bromo-m-xylene and 6.55 g (36.8 mmol) N-bromo-succinimide in 35 ml tetrachloromethane is added 0.138 ml (0.74 mmol) tert-butyl-perbenzoate. The mixture is irradiated using a heating lamp and stirred for 3 hrs at reflux temperature. The mixture is cooled to room temperature, filtered and evaporated. The product is isolated by chromatography on silica gel (flashmaster, hexane) to give the title compound as white crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1.Cl>C(O)C>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:2]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:26][CH:25]=2)[CH2:19][CH2:18]1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Agent: Cl
Solvent: CCO
Product: CN1CCN(Cc2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1

Procedure:
A solution of 4-chloro-7-trifluoromethylquinoline (400 mg, 0.0018 M), 1-methyl-4-[(4-aminophenyl)methyl]piperazine (400 mg, 0.0019 M) and 1.4 ml of ethanolic hydrogen chloride in 10 ml of ethanol is heated to reflux, under nitrogen for 15 minutes. The reaction mixture is quenched with ice, neutralized with aqueous 10% sodium hydroxide and extracted with methylene chloride. The methylene chloride solution is washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to a white solid. This solid, after recrystallization from ethyl acetate, gives 250 mg (32%) of white crystalline 4-[[4-[(4-methyl-1-piperazinyl)methyl]phenyl]amino]-7-(trifluoromethyl)quioline of melting point 218°-220° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH2:10][C@@H:11]3[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:12]3[C:13]=2[C:14]([O:16]CC=C)=[O:15])[CH:4]=1)[CH3:2].C(OCC)(=O)C.ClCCl.C(C(CCCC)C([O-])=O)C.[Na+:45].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>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.CC(C)=O.C(OCC)(=O)C>[CH2:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH2:10][C@@H:11]3[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:12]3[C:13]=2[C:14]([O-:16])=[O:15])[CH:4]=1)[CH3:2].[Na+:45]
Reactant: C=CCOC(=O)C1=C(c2cc(CC)n(C)n2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCc1cc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)nn1C
Temperature: 25 °C
Yield: 95.2 %

Procedure:
Allyl (5R,6S)-2-(5-ethyl-1-methylpyrazol-3-yl)-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate (348 mg) in 1:1 ethyl acetate/dichloromethane (8 ml), under argon was treated successively with sodium 2-ethylhexanoate (198 mg), triphenylphosphine (27 mg) and tetrakis(triphenylphosphine)palladium (0), (38 mg). After a few seconds an off-white precipitate was formed. The reaction mixture was stirred at room temperature for 30 m. T.l.c. analysis (20% acetone/ethyl acetate showed no remaining starting material. The solvents were removed in vacuo and the residual solid stirred with diethyl ether (20 ml). The white solid was filtered off washed with ether and dried. This solid was dissolved in water (10 ml) and chromatographed on HP20SS resin eluting with 1-5% tetrahydrofuran/water (100 ml portions). The combined fractions containing the product (by h.p.l.c.), were concentrated and freeze-dried to give the title compound as an amorphous pale yellow solid, (314 mg, 95%); nmax (KBr) 1755, 1614, 1586 and 1386 cm−1; dH(D2O) 1.17 (3H, t, J7.5 Hz), 1.26 (3H, d, J6.4 Hz), 2.56 (2H, q, J7.5 Hz), 3.16 (2H, m), 3.44 (1H, dd, J2.8,6.0 Hz), 3.68 (3H, s), 4.21 (2H, m) and 6.47 (1H, s). m/z (Electrospray) 328 (MH+), 350 (MNa+), 633 (2MNa+, free acid), 655 (2MH+), 677 (2MNa+).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[N:10]=[C:9]1[CH:17]([N:21]1[CH:25]=[C:24]([CH2:26][CH2:27][N:28]2C(=O)C3C(=CC=CC=3)C2=O)[N:23]=[C:22]1[C:39]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=1)[CH:18]([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CCO>[NH2:28][CH2:27][CH2:26][C:24]1[N:23]=[C:22]([C:39]2[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=2)[N:21]([CH:17]([C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[N:10]=2)[CH:18]([CH3:20])[CH3:19])[CH:25]=1
Reactant: Cc1ccc(-c2nc(CCN3C(=O)c4ccccc4C3=O)cn2C(c2nc(C)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2nc(CCN)cn2C(c2nc(C)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.9 %

Procedure:
To 2-(2-{1-[1-(1-Benzyl-4,5-dimethyl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-2-methyl-propyl]-2-p-tolyl-1H-imidazol-4yl}-ethyl)-isoindole-1,3-dione (0.371 g, 0.619 mmol) in EtOH (14 mL) was added hydrazine monohydrate (0.138 g, 2.48 mmol) and the reaction was stirred at room temperature for 72 h. The reaction was filtered and the filtrate was concentrated to dryness. The residue was purified by flash chromatography on silica gel (90:9:1 CH2Cl2:MeOH:NH4OH) to give the title compound as a white solid (0.209 g, 72%). MS(ES)+m/e 470 [M+H]+.
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[N:20]1([CH2:25][CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][N:22]=[CH:21]1.[ClH:29]>C(O)(=O)C>[ClH:29].[N:20]1([CH2:25][CH2:26][CH2:27][N:28]2[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[CH2:6][N:5]2[C:4](=[O:14])[C:3]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]3[C:1]2=[O:19])[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: NCCCn1ccnc1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1ccc(CN2C(=O)c3ccccc3C2=O)n1CCCn1ccnc1

Procedure:
5.2 g (0.02 mol) of 6-phthalimido-2,5-hexanedione and 2.5 g (0.02 mol) of 3-(1-imidazolyl)-propylamine are stirred in 70 ml of acetic acid at 80° C. for 2 hours and the mixture is worked up as in Example 1. After ethanolic hydrochloric acid has been added, the product is filtered off and recrystallised from ethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:14]1=[O:25].Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:22]2[CH2:21][CH2:20][CH:19]([N:15]3[CH2:16][CH2:17][CH2:18][CH:13]([NH:12][C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=4[F:1])[C:14]3=[O:25])[CH2:24][CH2:23]2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CS(=O)(=O)c1ccc(NC2CCCN(C3CCNCC3)C2=O)c(F)c1
Reactant: CCc1cnc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(N3CCCC(Nc4ccc(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Temperature: 100 °C
Yield: 51.2 %

Procedure:
3-(2-Fluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one (0.300 g, 0.812 mmol), 2-chloro-5-ethylpyrimidine (0.116 g, 0.812 mmol) and DIEA (0.210 g, 1.62 mmol) were dissolved in DMF (5 mL) and heated at 100° C. overnight. The reaction was concentrated and purified over silica gel (50-100% EtOAc in hexanes) to provide 1′-(5-ethylpyrimidin-2-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one (0.198 g, 0.416 mmol, 51.3% yield) as white solid. Mass spectrum (apci) m/z=476.2 (M+H).
Reaction SMILES: [C:1]1([CH3:29])[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][C:10]2[N:28]=[C:13]3[CH:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:27])([F:26])[F:25])[CH2:15][CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:3][CH:2]=1.C(OCC)(=[O:32])C.O>CO.O>[C:1]1([CH3:29])[CH:6]=[CH:5][C:4]([S:7]([CH2:8][CH2:9][C:10]2[N:28]=[C:13]3[CH:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:26])([F:27])[F:25])[CH2:15][CH2:16][CH2:17][N:12]3[N:11]=2)=[O:32])=[CH:3][CH:2]=1
Reactant: Cc1ccc(SCCc2nc3n(n2)CCCC3c2ccccc2C(F)(F)F)cc1
Reactant: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)CCc2nc3n(n2)CCCC3c2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-p-Tolylsulfanylethyl)-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine (8.8 g) was dissolved in a mixed solvent of methanol-water (2:1 v/v) (300 ml). Sodium periodide (6.78 g) was added under cooling with an ice water bath, and the reaction solution was stirred at room temperature overnight. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the organic layer was concentrated under reduced pressure to obtain the title compound (8.87 g). The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N+:31]#[C-:32])S(C2C=CC(C)=CC=2)(=O)=O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CCO>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:31]=[CH:32][O:12][C:11]=2[C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH2:1])[S:3][C:4]=3[CH:10]=2)=[CH:16][CH:15]=1
Reactant: Nc1nc2ccc(C=O)cc2s1
Reactant: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1nc2ccc(-c3ocnc3-c3ccc(F)cc3)cc2s1
Temperature: 25 °C
Yield: 86.1 %

Procedure:
A solution of 2-aminobenzo[d]thiazole-6-carbaldehyde (0.91 g, 5.11 mmol, 1.0 eq.), 1-((4-fluorophenyl)(isocyano)methylsulfonyl)-4-methylbenzene (2.20 g, 7.60 mmol, 1.5 eq.), and K2CO3 (1.34 g, 9.70 mmol, 1.9 eq.) in EtOH (51 mL) was refluxed for 4 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo, and the residue was taken up in CH2Cl2 and saturated aqueous NaHCO3. After separation of the layers, the aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel chromatography using CH2Cl2:MeOH (40:1) as eluent afforded 6-(4-(4-fluorophenyl)oxazol-5-yl)benzo[d]thiazol-2-amine as a tan solid (1.37 g, 86% yield).
Reaction SMILES: [C:1]([O:5][P:6]([O-:13])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:31][CH2:32][CH2:33]Br>C(COC)OC>[P:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:13][CH2:33][CH2:32][Br:31])=[O:7]
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Reactant: BrCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: COCCOC
Product: CC(C)(C)OP(=O)(OCCBr)OC(C)(C)C
Temperature: 25 °C
Yield: 46.2 %

Procedure:
Tetra-n-butylammonium di-tert-butyl phosphate (4.0 g, 8.87 mmol) and 1,2-dibromoethane (5.0 g, 26.7 mmol) in dimethoxyethane (20 ml) were stirred and refluxed for 4 hr. then cooled to room temperature and filtered. The filtrate was concentrated, diluted with diethyl ether, washed with 20% aqueous potassium carbonate solution, dried over magnesium sulphate and evaporated to leave a colourless oil. The crude product was purified by silica gel chromatography eluting with a 20-50% mixture of ethyl acetate in iso-hexane to give 2-bromoethyl di-tert-butyl phosphate (1.3 g, 46% yield) as a colourless oil:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.Cl.[CH3:15][O:16][NH2:17].C(=O)([O-])O.[Na+]>C(O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:17][O:16][CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CON
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=NOC)c1csc(N)n1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
In 10 ml of 50% aqueous ethanol is dissolved 200 mg of ethyl 2-aminothiazol-4-yl-glyoxylate, followed by the addition of 166 mg of O-methylhydroxylamine hydrochloride and, then, 168 mg of sodium hydrogen carbonate. The mixture is stirred in a closed vessel at 70° C. for 5 hours. The reaction mixture is concentrated under reduced pressure and the residue is diluted with 10 ml of water and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried. The ethyl acetate is then distilled off to obtain ethyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate as crystals. Based on NMR and other data, this product is found to be an 83:17 mixture of syn- and anti-isomers.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[NH:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[C:16]([CH2:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O)#[N:17].N1CCCCC1.O>C(Cl)(Cl)Cl.CN(C)C=O>[OH:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5](=[O:15])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([O:19][CH2:18][C:16]#[N:17])[CH:21]=1
Reactant: N#CCOc1cccc(C=O)c1
Reactant: CC(=O)c1c(O)c2ccccc2[nH]c1=O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1cccc(C=CC(=O)c2c(O)c3ccccc3[nH]c2=O)c1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
In a mixture of 3000 ml of chloroform and 600 ml of dimethylformamide were dissolved 60.00 g of 3-acetyl-4-hydroxy-2(1H)-quinolinone, 142.20 g of 3-(cyanomethoxy)benzaldehyde and 17.64 g of piperidine, and the solution was heated overnight under reflux while water was removed with a Soxhlet extractor filled with molecular sieves. After cooled to room temperature, precipitated crystals were filtered, and washed with 750 ml of tetrahydrofuran and 900 ml of t-butyl methyl ether to obtain 77.59 g of 4-hydroxy-3-[3-[3-(cyanomethoxy)phenyl]-1-oxo-2-propenyl]-2(1H)-quinolinone [Compound No. (10e)] as a yellow crystal.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[CH2:10]([O:12][C:13](=[O:33])[CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:19](=[O:31])[C:18]2=[O:32])[CH3:11]>O1CCCC1>[C:27]([O:26][C:24]([NH:20][C:21]1[CH:22]=[CH:23][C:15]([CH2:14][C:13]([O:12][CH2:10][CH3:11])=[O:33])=[CH:16][C:17]=1[C:18](=[O:32])[C:19]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[O:31])=[O:25])([CH3:29])([CH3:28])[CH3:30]
Reactant: c1ccc2c(c1)CNC2
Reactant: CCOC(=O)Cc1ccc2c(c1)C(=O)C(=O)N2C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(NC(=O)OC(C)(C)C)c(C(=O)C(=O)N2Cc3ccccc3C2)c1
Temperature: 23 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
2.2 g of isoindoline are added to 5.9 g of tert-butyl 5-(2-ethoxy-2-oxoethyl)-2,3-dioxoindoline-1-carboxylate in 100 ml of tetrahydrofuran, and the mixture is subsequently stirred at 23° C. for 1 h. The solvent is removed in vacuo, and the residue is purified by column chromatography, giving 4.9 g of ethyl 2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]acetate;
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:12][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11]
Reactant: O=C1CCc2c(O)cccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc2c1CCC2=O
Temperature: 50 °C
Reaction time: 72 h
Yield: 98.8 %

Procedure:
4-Hydroxy-1-indanone (5.0 g, 33.7 mmol) was dissolved in acetone (170 mL) and then potassium carbonate (9.0 g, 138.21 mmol) and MeI (9.6 g, 67.5 mmol) were added. The resulting suspension was heated to 50° C. and stirred for 3 days at which time the reaction mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and water. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (5.4 g, 98%) as a yellow solid. GC-MS m/z[M+H]+ 163.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][C:21]1[N:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:27][C:23]3[CH:22]=[C:21]([CH3:20])[N:26]=[CH:25][N:24]=3)=[N:3][CH:4]=[C:5]([F:19])[C:6]=2[N:10]=1
Reactant: Fc1cnc(Br)c2sc(-c3c(Cl)cccc3Cl)nc12
Reactant: Cc1cc(N)ncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2ncc(F)c3nc(-c4c(Cl)cccc4Cl)sc23)ncn1
Temperature: 80 °C
Yield: 58.3 %

Procedure:
A mixture of 4-bromo-2-(2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridine (0.113 g, 0.30 mmol), 6-methylpyrimidin-4-ylamine (0.036 g, 0.33 mmol), XantPhos (0.018 g, 0.030 mmol) and Cs2CO3 (0.247 g, 0.75 mmol) in dioxane (2.5 mL) was degassed with a stream of argon. Pd2(dba)3 (0.014 g, 0.015 mmol) was added and the reaction mixture was heated in a sealed vial at 80° C. for 3 hours. After cooling to room temperature, the crude reaction mixture was filtered through Celite® washing with EtOAc and the filtrate was concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-100% EtOAc in pentane and then triturated with diethyl ether to afford the title compound as an off-white solid (71 mg, 58% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.68 (s, 1H), 8.61 (d, J=1.1 Hz, 1H), 8.49 (d, J=1.9 Hz, 1H), 7.77-7.72 (m, 2H), 7.71-7.66 (m, 1H), 7.42 (s, 1H), 2.38 (s, 3H). LCMS (Method C): RT=3.73 min, m/z: 406 [M+H+].