Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17]([O:19]CC)=[O:18])[N:10]=[CH:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CCO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:14])[F:15])=[C:11]([C:17]([OH:19])=[O:18])[N:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ncn(-c2ccc(Cl)cc2)c1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ncn(-c2ccc(Cl)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a solution of ethyl 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-imidazole-4-carboxylate (800 mg, 2.51 mmol) in EtOH (20 mL) was added a predissolved solution of sodium hydroxide (1004 mg, 25.1 mmol) in Water (5.00 mL). The reaction was stirred overnight at room temperature. The next day, the reaction was concentrated in vacuo, acidified with dilute HCl and extracted 2×EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated to give 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid (400 mg, 1.376 mmol, 54.8% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.3 (1H, br s), 8.19 (1H, dd), 7.68 (2H, d), 7.72 (2H, d).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:30])=[C:20]([CH:29]=1)[O:21][CH2:22][C:23]1[N:24]([CH3:28])[N:25]=[CH:26][N:27]=1>>[F:1][C:2]1[C:3]2[N:4]([C:12]([C:16]3[CH:17]=[CH:18][C:19]([F:30])=[C:20]([O:21][CH2:22][C:23]4[N:24]([CH3:28])[N:25]=[CH:26][N:27]=4)[CH:29]=3)=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9]
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Reactant: Cn1ncnc1COc1cc(Br)ccc1F
Product: Cn1ncnc1COc1cc(-c2cnc3c(F)c(C(C)(C)O)ccn23)ccc1F
Yield: 43 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 3-(5-bromo-2-fluorophenoxymethyl)-2-methyl-2H-[1,2,4]triazole as described in Example 6 to give 2-{8-fluoro-3-[4-fluoro-3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)phenyl]imidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (169 mg, 43%): δH (400 MHz, d6-DMSO) 1.58 (6H, d, J 1), 3.94 (3H, s), 5.53 (2H, s), 5.55 (1H, s), 7.21-7.29 (2H, m), 7.44 (1H, dd, J 11 and 9), 7.68 (1H, dd, J 8 and 2), 7.76 (1H, s), 7.98 (1H, s), 8.42 (1H, d, J 7); m/z (ES+) 400 [MH+].
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[CH2:15]([CH:17]([N:20]1[C:28]2[N:27]3[N:29]=[C:30]([CH3:34])[C:31]([CH:32]=O)=[C:26]3[N:25]=[C:24]([CH3:35])[C:23]=2[CH2:22][CH2:21]1)[CH2:18][CH3:19])[CH3:16].[C:36]1([NH2:43])[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH2:42].[OH-].[Na+]>C(#N)C>[NH:42]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:43]=[C:32]1[C:31]1[C:30]([CH3:34])=[N:29][N:27]2[C:28]3[N:20]([CH:17]([CH2:18][CH3:19])[CH2:15][CH3:16])[CH2:21][CH2:22][C:23]=3[C:24]([CH3:35])=[N:25][C:26]=12
Reactant: CCC(CC)N1CCc2c(C)nc3c(C=O)c(C)nn3c21
Reactant: Nc1ccccc1N
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCC(CC)N1CCc2c(C)nc3c(-c4nc5ccccc5[nH]4)c(C)nn3c21
Reaction time: 24 h
Yield: 17.5 %

Procedure:
DDQ (79 mg, 0.35 mmol) was added to a solution of 8-(1-ethylpropyl)-2,5-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidin-3-carbaldehyde (100 mg, 0.35 mmol) and 1,2-phenylenediamine (40 mg, 0.37 mmol) in acetonitrile (1 mL) at room temperature and the mixture was stirred for one day. Further, a 0.5N aqueous solution of sodium hydroxide was added thereto, followed by stirring for five hours. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by dry pack silica gel column chromatography (50% ethyl acetate/hexane), to give the title compound (23 mg) as pale yellow crystals.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([N:11]([CH2:13][CH2:14][CH2:15][CH3:16])[CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.Cl.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].ClCCl.N#N>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:6]3[N:7]=[C:8]([N:11]([CH2:13][CH2:14][CH2:15][CH3:16])[CH3:12])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: NCc1ccc(B(O)O)cc1
Reactant: CCCCN(C)c1ccc2ncc(Br)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: CCCCN(C)c1ccc2ncc(-c3ccc(CN)cc3)n2n1
Temperature: 85 °C

Procedure:
To a mixture of (3-bromo-imidazo[1,2-b]pyridazin-6-yl)-butyl-methyl-amine (377.7 mg, 1.3 mmol), 4-aminomethylphenylboronic acid hydrochloride [75705-21-4] (302.4 mg, 1.6 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (612.7 mg, 2.7 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [95464-05-4] (110.4 mg, 0.1 mmol) contained in a 25 mL round bottomed flask was added a solution of 30% (v/v) water in 1,2-dimethoxyethane (15 mL) and a magnetic stir bar. The reaction pot was fitted to a reflux condenser, lowered into an ambient temperature oil bath, and the system taken through 10 evacuation/N2 blanket cycles while being rapidly stirred. The rapidly stirred, N2 blanketed, reaction was heated to an oil bath temperature of 85° C. for 17 h then cooled and partitioned between brine (pH adjusted to 10 with 3N aqueous sodium hydroxide) and ethyl acetate. The phase separated extract was dried (CaSO4), evaporated and flash chromatographed (silica gel, eluted with 1% NH4OH in 10% (v/v) methanol/ethyl acetate) to isolate a brown solid which was triturated in heptane to precipitate a brown solid. Trituration solvent was then evaporated to provide [3-(4-aminomethyl-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-butyl-methyl-amine as 41.8 mg white solid, mp. 99-101° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (t, J=7.33 Hz, 3H) 1.30-1.42 (m, 2H) 1.47-1.70 (m, 2H) 1.90 (br. s., 1H) 3.10 (s, 3H) 3.51-3.57 (m, 2H) 3.75 (s, 2H) 7.05 (d, J=9.85 Hz, 1H) 7.42 (d, J=8.34 Hz, 2H) 7.85 (d, J=10.11 Hz, 1H) 7.92 (s, 1H) 8.14 (d, J=8.34 Hz, 2H). LRMS (ESI) m/z 310.3 [(M+H)]+, calc'd for C18H23N6: 309.42.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21]CC3C=CC=CC=3)=[CH:17][CH:16]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C(O)C.[Pd]>[C:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(OCc3ccccc3)cc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)cc2)C1
Temperature: 38 °C
Reaction time: 16 h

Procedure:
To a solution of the intermediate (c), N-Boc-(R)-2-(4-benzyloxybenzyl)morpholine (4.92 g, 12.8 mmol) in ethanol (100 mL), was added 10% palladium on charcoal (1.3 g, 1.28 mmol) and the flask flushed with hydrogen. The mixture was stirred at 38° C. for 16 h then filtered through celite and concentrated to afford the product intermediate (b), N-BOC-(R)-2-(4-hydroxybenzyl)morpholine, as a brown oil (3.7 g, 99%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1B(O)O>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:33]2[CH:34]=[CH:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:32]=2)[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2ccccc2c1
Yield: 71.6 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol), tetrakis(triphenylphosphine) palladium(0) (0.058 mg; 0.05 mmol), N,N-Diisopropylethylamine (0.345 mL; 2 mmol) and naphthalen-2-ylboronic acid (0.258 g; 1.5 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.147 g (71%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH:9]1([C:13](O)=O)[CH2:12][CH2:11][CH2:10]1.N>>[CH:9]1([C:13]2[NH:8][C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[N:1]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: O=C(O)C1CCC1
Reactant: Nc1ccncc1N
Agent: N
Product: c1cc2[nH]c(C3CCC3)nc2cn1
Temperature: 110 °C
Yield: 72.2 %

Procedure:
[step 1] 3,4-Diaminopyridine (2.0 g, 18.4 mmol) was mixed with polyphosphoric acid (20g), cyclobutanecarboxylic acid (2.63 mL, 27.5 mmol) was added, and the mixture was stirred with heating at 110° C. for 3 hr. The mixture was added dropwise to 5% aqueous ammonia solution under ice-cooling, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the obtained residue was added ethyl acetate (7 mL), and the precipitated crystals were collected by suction filtration to give 2-cyclobutyl-1H-imidazo[4,5-c]pyridine (2.3 g, 73%).
Reaction SMILES: [CH3:1][CH:2]([CH2:14]/[C:15](=[CH:23]/[C:24](/[CH3:39])=[CH:25]/[CH:26]([CH3:38])[CH2:27][CH:28]([CH3:37])[CH2:29][CH:30]([CH3:36])[CH2:31][CH:32]([CH3:35])[CH2:33][CH3:34])/[C:16]([O:18]C(C)(C)C)=[O:17])[C:3]([O:5][CH2:6][C:7]([O:9]C(C)(C)C)=[O:8])=[O:4].FC(F)(F)C(O)=O>ClCCl>[C:7]([CH2:6][O:5][C:3](=[O:4])[CH:2]([CH3:1])[CH2:14]/[C:15](=[CH:23]/[C:24](/[CH3:39])=[CH:25]/[CH:26]([CH3:38])[CH2:27][CH:28]([CH3:37])[CH2:29][CH:30]([CH3:36])[CH2:31][CH:32]([CH3:35])[CH2:33][CH3:34])/[C:16]([OH:18])=[O:17])([OH:9])=[O:8]
Reactant: CCC(C)CC(C)CC(C)CC(C)/C=C(C)/C=C(/CC(C)C(=O)OCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)CC(C)CC(C)CC(C)/C=C(C)/C=C(/CC(C)C(=O)OCC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.6 %

Procedure:
(Step 2) To 1-(2-tert-butoxy-2-oxoethyl) 5-tert-butyl (Z)-2-methyl-4-{(E)-2,4,6,8,10-pentamethyldodec-2-enylidene}pentanedioate (14.7 mg, 0.027 mmol) obtained in Step 1, dichloromethane (2 mL) and trifluoroacetic acid (0.2 mL, 2.6 mmol) were added, and the resulting mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by thin-layer column chromatography (methanol/chloroform=1/9), whereby Compound 9 (8.6 mg, 74%) was obtained.
Reaction SMILES: C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[CH3:38][N:39]=[C:40]=[O:41].[I:42][C:43]#[C:44][CH2:45][O:46][CH2:47][CH2:48][OH:49]>C(Cl)CCl>[CH3:38][NH:39][C:40](=[O:41])[O:49][CH2:48][CH2:47][O:46][CH2:45][C:44]#[C:43][I:42]
Reactant: CN=C=O
Reactant: OCCOCC#CI
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: ClCCCl
Product: CNC(=O)OCCOCC#CI
Yield: 96.7 %

Procedure:
One milliliter of dibutyltin dilaurate was added under agitation as catalyst to a solution of 3.3 gm (0.058 mol) of methyl isocyanate and 12.8 gm (0.057 mol) of 2-(3-iodo-2-propynyloxy)-ethanol in 50 ml ethylene chloride. Due to the exothermic reaction, the temperature rose gradually from room temperature to 30° C. After a reaction time of 16 hours, the solvent was removed by distillation under vacuum, and the yellowish oil obtained was extracted with n-hexane to separate the catalyst, the hexane phase being discarded. Then, the residual solvent was removed under vacuum,, and 15.6 gm of 2-(3-iodo-2-propynyloxy)-ethyl N-methyl-carbamate (97% of theory) were obtained as a clear, yellowish oil, which crystallized into a colorless solid (melting point: 52°-55° C). Solubility: dissolves readily in ethanol or acetone; almost insoluble in water.
Reaction SMILES: CC1C=CC(S([O-])(=O)=O)=CC=1.[NH2:12][C:13]([C:15]1[C:23]2[C:19](=[CH:20][N:21]([C:24]3[CH:29]=[CH:28][C:27]([C@@H:30]4[CH2:35][CH2:34][CH2:33][NH2+:32][CH2:31]4)=[CH:26][CH:25]=3)[N:22]=2)[CH:18]=[CH:17][CH:16]=1)=[O:14].[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40]>C(O)C>[C:36]([O-:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([O-:41])=[O:40].[NH2:12][C:13]([C:15]1[C:23]2[C:19](=[CH:20][N:21]([C:24]3[CH:29]=[CH:28][C:27]([C@@H:30]4[CH2:35][CH2:34][CH2:33][NH2+:32][CH2:31]4)=[CH:26][CH:25]=3)[N:22]=2)[CH:18]=[CH:17][CH:16]=1)=[O:14].[NH2:12][C:13]([C:15]1[C:23]2[C:19](=[CH:20][N:21]([C:24]3[CH:29]=[CH:28][C:27]([C@@H:30]4[CH2:35][CH2:34][CH2:33][NH2+:32][CH2:31]4)=[CH:26][CH:25]=3)[N:22]=2)[CH:18]=[CH:17][CH:16]=1)=[O:14]
Reactant: O=C(O)/C=C/C(=O)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: NC(=O)c1cccc2cn(-c3ccc([C@@H]4CCC[NH2+]C4)cc3)nc12
Solvent: CCO
Product: O=C([O-])/C=C/C(=O)[O-]
Temperature: 40 °C
Reaction time: 24 h

Procedure:
50 mg of tert-butyl(3S)-3-{4-[7-(aminocarbonyl)-2H-indazol-2-yl]phenyl}piperidine-1-carboxylate (Example 1, D3) as a compound stock solution was reacted with 1 mole equivalent of fumaric acid, added as a 0.405 Molar solution in ethanol. Excess solvent was removed under centrifugal evaporation and 1 mL of ethanol added at ambient room temperature (˜25° C.). The resultant solution stirred at 40° C. for 24 hours. The experiment was left to gently evaporate under atmospheric conditions where a colorless solid was observed. This solid was analyzed using x-ray powder diffraction, proton NMR, DSC and TGA to confirm the formation of the title salt.
Reaction SMILES: Br[C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:9][N:10]=2)[CH:7]=1.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:3]2[C:2]([C:33]3[CH:32]=[CH:31][C:30]([Cl:29])=[CH:35][C:34]=3[Cl:36])=[CH:7][N:6]3[C:8]([CH2:11][C:12]4[CH:13]=[N:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)=[CH:23][CH:24]=1
Reactant: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(Br)cn23)cn1
Reactant: OB(O)c1ccc(Cl)cc1Cl
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4Cl)cn23)cn1
Temperature: 100 °C
Yield: 51.5 %

Procedure:
To a degassed solution of 6-bromo-7-(4-chlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (9.5 mg, 0.02 mmol), 2,4-dichlorophenylboronic acid (8.0 mg, 0.041 mmol) and K2CO3 (8.5 mg, 0.061 mmol) in 1,4-dioxane (0.3 mL) and H2O (0.1 mL) was added Pd(PPh3)4 (2.3 mg, 0.002 mmol) under argon at 20° C. The reaction mixture was heated at 100° C. for 2 h under argon, then allowed to cool to 20° C. The reaction was concentrated in vacuo, and the residue was purified using reverse phase preparative HPLC (Conditions: Phemomenex Luna 5μC18 30×75 mm; Eluted with 0% to 100% B, 10 min gradient, 100% B hold for 2 min, (A=90% H2O, 10% CH3CN, 0.1% trifluoroacetic acid and B=10% H2O, 90% CH3CN, 0.1% trifluoroacetic acid); Flow rate at 40 mL/min, UV detection at 220 nm) to afford 5.5 mg (55%) of the title compound as a white solid. LC/MS (method B): retention time=2.03 min, [M+H]+=533.2.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:19])([F:18])[CH:9]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][C:11](O)=[O:12].S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[F:7][C:8]([F:18])([F:19])[CH:9]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][OH:12]
Reactant: CCCCC(CC(=O)O)C(F)(F)F
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCCCC(CCO)C(F)(F)F
Reaction time: 4 h
Yield: 62.4 %

Procedure:
In a two-necked round-bottomed flask replaced with nitrogen, 0.09 g of lithium aluminum hydride and dry ether were placed and cooled with ice, and a solution of 0.5 g of (+)-3-trifluoromethyl-1-heptanoic acid in 3 ml of dry ether was added dropwise thereto. The mixture was stirred for 4 hours on an ice bath for reaction, and a saturated sodium sulfate aqueous solution was added thereto, followed by decantation to recover the ether layer. The ether solution was dried on sodium sulfate, followed by distilling-off of the solvent and distillation by means of a Kugelrohr distiller in the range of 96° C./33 mmHg-104° C./34 mmHg to obtain 290 mg (yield: 66%) of (-)-3-trifluoromethyl-1-heptanol. [α]D21 -2.3 (c 1, CHCl3)
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:3]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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]>[C:15]1([O:14][CH2:13][CH2:12][CH2:11][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[C:3]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1c(Br)c2ccccc2n1CCCOc1cccc2ccccc12
Reactant: C1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(N2CCCCC2)c2ccccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 31C (100 mg), piperidine (57 mg), tris(dibenzylideneacetone)dipalladium(0) (20 mg), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (26 mg) and Cs2CO3 (216 mg) in toluene (2 mL) was heated at 100° C. for 48 hours. The mixture was diluted with ethyl acetate and was washed with water and brine. The organic phase was dried (Na2SO4) filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel with 0-10% ethyl acetate/hexanes.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)=[C:9]([Cl:28])[CH:8]=1>N1C=CC=CC=1>[Cl:28][C:9]1[CH:8]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=[CH:11][C:10]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][CH:22]=2)[CH2:15][CH2:14]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(CCN2CCN(c3ccc(N)cc3Cl)CC2)cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(CCN2CCN(c3ccc(NS(C)(=O)=O)cc3Cl)CC2)cc1
Yield: 64.2 %

Procedure:
The title compound (0.52 g), was prepared similarly to the procedure of Example 1(C) from methanesulphonyl chloride (0.44 g), 1-(4-amino-2-chlorophenyl)-4-(4-aminophenethyl)piperazine (0.55 g), and pyridine (10 ml).
Reaction SMILES: C[CH2:2][N:3]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.CN.[CH3:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][C:36]=1[N:41]1[CH2:45][CH2:44][N:43]([C:46]2[CH:54]=[CH:53][C:49]([C:50]([OH:52])=O)=[CH:48][CH:47]=2)[C:42]1=[O:55]>CN(C=O)C>[CH3:2][NH:3][C:50](=[O:52])[C:49]1[CH:48]=[CH:47][C:46]([N:43]2[CH2:44][CH2:45][N:41]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][C:35]=3[CH3:34])[C:42]2=[O:55])=[CH:54][CH:53]=1
Reactant: Cc1ccncc1N1CCN(c2ccc(C(=O)O)cc2)C1=O
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N2CCN(c3cnccc3C)C2=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.1 %

Procedure:
EDCI (176.4 mg, 0.9205 mmol), HOBt (5.8 mg, 0.2525 mmol), DIPEA (0.3 mL, 2.3006 mmol) and methylamine hydrochloride (62 mg, 0.9205 mmol) were added to a stirred solution of 4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzoic acid (228 mg, 0.7668 mmol) in dry DMF (10 mL) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was partitioned between water and ethylacetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography on silica gel (5% MeOH in DCM) afforded 155 mg of the product (65.4% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:4]([C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[O:22]([NH2:24])[CH3:23].C([O-])(=O)C.[Na+]>C(O)C>[F:1][C:2]1[C:3]([CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:4]([C:8](=[N:24][O:22][CH3:23])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CON
Reactant: CCOC(=O)C(=O)c1cccc(F)c1COC(C)(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=NOC)c1cccc(F)c1COC(C)(C)C
Temperature: 60 °C
Yield: 98.8 %

Procedure:
To a solution of 79 g (0.28 mole) of ethyl 3-fluoro-2-[(1,1-dimethylethoxy)methyl]-α-oxo-benzeneacetate in 300 mL of ethyl alcohol was added 100 mL (0.39 mole, 30% aq) of methoxylamine HCl followed by 33 g (0.4 mole) of sodium acetate. The mixture was then heated at 60° C. for three hours. After cooling to room temperature, the salts were filtered and the mixture was concentrated in vacuo. Water and EtOAc were added, the layers separated, and the organics were washed with saturated NaHCO3, brine and dried over MgSO4. After filtration, the solution was concentrated in vacuo to give 86.1 g of ethyl 3-fluoro-2-[(1,1-dimethylethoxy)methyl]-α-(methoxyimino)-benzeneacetate as a lightly tinted oil, 1:2 ratio of oxime isomers by gas chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[CH:20](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[F:19][C:17]1[CH:18]=[C:2]2[C:3]([C:4](=[O:5])[N:6]([CH:7]3[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]3=[O:14])[CH:20]=[N:1]2)=[CH:15][CH:16]=1
Reactant: Nc1cc(F)ccc1C(=O)NC1CCC(=O)NC1=O
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C1CCC(n2cnc3cc(F)ccc3c2=O)C(=O)N1
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-4-fluoro-benzamide (0.9 g, 3.4 mmol) and trimethyl orthoformate (4 mL) and p-toluene sulfonic acid (110 mg) was heated to 160° C. in a microwave oven for 15 minutes. To the mixture, was added methanol (10 mL), and the mixture was stirred for 10 minutes. The suspension was filtered and washed with methanol to give 3-(7-fluoro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (650 mg, 70% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 2.45 min (96.1%); mp: 296-298° C.; 1H NMR (DMSO-d6) δ 2.13-2.19 (m, 1H, CHH), 2.63-2.73 (m, 2H, 2CHH), 2.82-2.93 (m, 1H, CHH), 5.50 (br, 1H, NCH), 7.46 (dt, J=3, 9 Hz, 1H, Ar), 7.53 (dd, J=3, 10 Hz, 1H, Ar), 8.22 (dd, J=6, 9 Hz, 1H, Ar), 8.42 (s, 1H, CH), 11.18 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.45, 30.88, 56.43, 112.3 (d, JC-F=22 Hz), 115.91 (d, JC-F=23 Hz), 118.38, 129.32 (d, JC-F=11 Hz), 148.71, 149.65 (d, JC-F=14 Hz), 159.00, 165.70 (d, JC-F=252 Hz), 169.76, 172.41; LCMS: MH=276; Anal Calcd for C13H10N3O3F: C, 56.73; H, 3.66; N, 15.27. Found: C. 56.39; H, 3.60; N, 15.16.