Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)#[N:2].I[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=[C:14]([C:6]3[CH:5]=[C:4]([CH2:3][C:1]#[N:2])[CH:9]=[CH:8][CH:7]=3)[C:22]=12
Reactant: N#CCc1cccc(B(O)O)c1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cccc(CC#N)c2)c2c(N)ncnc21
Temperature: 80 °C

Procedure:
A solution of (3-Cyanomethylphenyl)boronic acid (18 mg, 0.11 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA45. ESI-MS (M+H)+ m/z calcd 293.1, found 293.1.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:12])[CH:3]=1.CN([C:16]([O:20][N:21]1N=NC2C=CC=N[C:22]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CONC.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)C>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([N:21]([O:20][CH3:16])[CH3:22])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1F
Agent: CNOC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc(Cl)c(Cl)cc1F
Reaction time: 0.17 h
Yield: 82.6 %

Procedure:
4,5-Dichloro-2-fluoro-benzoic acid (50 mg, 0.24 mmol), HATU (100.0 mg, 0.26 mmol) and N-methoxymethanamine (hydrochloric acid) (23.33 mg, 0.24 mmol) were combined in DMF (1.0 mL) and treated with DIEA (83.33 μL, 0.48 mmol). After 10 min, the reaction was complete. The reaction was diluted with diethyl ether and washed with 50% sat. NaHCO3 (2×) and brine, dried over Na2SO4, filtered and concentrated. Silica gel chromatography using a gradient of ethyl acetate/hexanes from 0 to 30% provided 4,5-dichloro-2-fluoro-N-methoxy-N-methyl-benzamide (50 mg, 83%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J=6.3 Hz, 1H), 7.26 (d, J=8.6 Hz, 1H), 3.56 (s, 3H), 3.35 (s, 3H) ppm.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[O:12][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([NH:28][OH:29])=[O:27])=[CH:24][CH:25]=1)=[O:15])[CH3:3].C(O)(C)C.O.O.[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42]([OH:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1>O>[CH3:3][N:2]([CH2:4][C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[O:12][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([NH:28][OH:29])=[O:27])=[CH:24][CH:25]=1)=[O:15])[CH3:1].[S:42]([C:39]1[CH:40]=[CH:41][C:36]([CH3:46])=[CH:37][CH:38]=1)([O-:45])(=[O:44])=[O:43]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CN(C)Cc1c(C(=O)NCCOc2ccc(C(=O)NO)cc2)oc2ccccc12
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 75 °C

Procedure:
1.66 kg of abexinostat (free base) are placed in 9.48 kg of a mixture of isopropanol/water (50/50 weight/weight) at ambient temperature. para-Toluenesulphonic acid monohydrate (0.83 kg) in 2.36 kg of water is added at ambient temperature. The mixture is then heated at 75° C. for 30 minutes before being cooled to 0° C. When crystallisation is complete, the suspension is filtered at 20° C. After drying, crystalline form I of abexinostat tosylate is obtained in a yield of about 85% and with a purity greater than 99%. The solid was characterised by the X-ray powder diffraction diagram, Raman spectrum and NMR spectrum as set out in Examples 3-5 and 6 hereinbelow.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[N:12]([O-])=O.[Na+].Cl[Sn]Cl.O>Cl>[NH:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[N:8][CH:7]=1)[NH2:12]
Reactant: O=N[O-]
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(C(F)(F)F)nc1
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
To a cold solution of 6-(trifluoromethyl)pyridin-3-amine (1.5 g, 9.25 mmol) in 4N HCl (60.0 mL) was added aqueous solution of NaNO2 (0.766 g, 11.11 mmol) at 0° C. The reaction mass was stirred at same temperature for 30 minutes. The reaction mass was added to a solution of SnCl2.H2O in 4N HCl at 80° C. and further continued stirring for 5-6 h at same temperature. The reaction mass was cooled, basified and extracted with DCM. The organic layer was dried and concentrated to afford 0.700 g of the product. 1H NMR (300 MHz, DMSO d6): δ 4.29 (br s, 2H), 7.1.8 (dd, J=8.6 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.68 (s, 1H), 8.13 (d, J=2.4 Hz, 1H); MS (m/z): 178.15 (M+H+).
Reaction SMILES: [Br:1][C:2]1[NH:13][C:5]2[C:6](=[O:12])[NH:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[C:3]=1[Br:14].[BH4-].[Na+]>CN(C=O)C.CO>[Br:1][C:2]1[NH:13][C:5]2[C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[C:3]=1[Br:14]
Reactant: O=C1NCCC(=O)c2c1[nH]c(Br)c2Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1NCCC(O)c2c1[nH]c(Br)c2Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,3-dibromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione (2.5 g, 7.74 mmol) in a mixture of DMF-MeOH (6 mL) is added NaBH4 (1.47 g, 38.7 mmol). The mixture is stirred at room temperature overnight. It is concentrated and water is added. The mixture is extracted with EtOAc, washed with brine and dried. After the solvent is removed, the residue is subjected to silica gel column chromatography and eluted with CH2Cl2-MeOH to give 2,3-dibromo-4-hydroxy-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one; 1H NMR (DMSO-d6) δ 1.74-1.84 (m, 1H), 2.01-2.10 (m, 1H), 3.00-3.10 (m, 1H), 3.42-3.50 (m, 1H), 4.63-4.68 (m, 1H), 5.06 (d, 1H, J=6.4 Hz), 7.92 (d, 1H, J=4.4 Hz); m/z [M++1] 324.9.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)=[O:8].[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[C:16]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:15]2[C:35]1[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=1.C1(CN)CC1>ClCCl>[C:41]([C:38]1[CH:37]=[CH:36][C:35]([C:15]2[C:14]3[C:18](=[CH:19][CH:20]=[C:12]([NH:11][C:6]([NH:1][CH2:2][CH:3]4[CH2:5][CH2:4]4)=[O:8])[CH:13]=3)[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[C:16]=2[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:40][CH:39]=1)([CH3:43])([CH3:42])[CH3:44]
Reactant: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(N)ccc2n1Cc1cccc(OC)c1
Reactant: c1ccncc1
Reactant: O=C(Cl)Cl
Agent: NCC1CC1
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(NC(=O)NCC3CC3)ccc2n1Cc1cccc(OC)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 26.3 %

Procedure:
Pyridine (0.18 mL, 174 mg, 2.2 mmol) and phosgene (1.9 M in toluene, 0.66 mL, 1.2 mmol) were added to a cooled (0° C.) and stirred solution of ethyl 5-amino-3-(4-tert-butylphenyl)-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 160, 500 mg, 1.1 mmol) in dichloromethane (10 mL). The reaction was warmed to rt and stirred for 3 h. The solution was concentrated in vacuo leaving crude Example 172. A portion (260 mg, 0.54 mmol) of the intermediate was dissolved in dichloromethane (10 mL) and then (cyclopropylmethyl)amine (0.13 mL, 108 mg, 1.5 mmol) was added. The reaction was stirred at rt for 16 h and then diluted with dichloromethane (100 mL). The solution was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 3:1 hexane/ethyl acetate gave 160 mg (54%) of the desired product. The product had: 1H NMR (300 MHz, acetone-D6) δ 8.08 (d, 1 H), 7.09-7.45 (m, 7 H), 6.60-6.78 (m, 3 H), 6.33 (dd, 1 H), 5.76 (s, 2 H), 3.91 (q, 2 H), 3.68 (s, 3 H), 1.32 (s, 3 H), 0.87-0.96 (m, 1 H), 0.72 (t, 3 H), 0.31-0.41 (m, 2 H), 0.11-0.21 (m, 2 H).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][F:36])=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)C)(C)(C)C>ClCCl>[F:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH:23]=[CH:22][C:19]2[CH:20]=[CH:21][C:16]([NH:14][CH3:13])=[CH:17][CH:18]=2)=[CH:25][CH:26]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C=Cc2ccc(OCCOCCF)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(C=Cc2ccc(OCCOCCF)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
Trifluoroacetic acid (0.5 ml) was added slowly to a solution of compound 11a (7.0 mg, 0.017 mmol) in dichloromethane (1 ml). The mixture was then stirred at room temperature for 1 hour. After standard workup with dichloromethane, the residue was purified by silica gel preparative TLC (1.0% methanol in dichloromethane) to afford 12a (3 mg, 56%): 1H NMR δ 7.37 (m, 4H), 6.90 (m, 4H), 6.65 (d, 2H, J=8.4 Hz), 4.60 (d, t, 2H, J1=46 Hz, J2=4.0 Hz), 4.17 (t, 2H), 3.90 (t, 3H), 3.76 (t, 1H), 2.88 (s, 3H). Anal. (C19H22FNO2) C. H. N.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:12]2[S:29][C:28]([NH2:30])=[N:27][C:13]=2[N:14]=[C:15]([S:17][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH3:19])[N:16]=1.[NH2:31][C@H:32]([CH2:35][C:36]([F:39])([CH3:38])[CH3:37])[CH2:33][OH:34].O>CN1C(=O)CCC1>[NH2:30][C:28]1[S:29][C:12]2[C:11]([NH:31][C@H:32]([CH2:35][C:36]([F:39])([CH3:38])[CH3:37])[CH2:33][OH:34])=[N:16][C:15]([S:17][C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[CH3:19])=[N:14][C:13]=2[N:27]=1
Reactant: CC(C)(F)C[C@@H](N)CO
Reactant: C[C@H](Sc1nc(Cl)c2sc(N)nc2n1)c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: C[C@H](Sc1nc(N[C@@H](CO)CC(C)(C)F)c2sc(N)nc2n1)c1ccccc1F
Temperature: 120 °C
Reaction time: 22 h
Yield: 12.5 %

Procedure:
DIPEA (2.09 mL, 12.0 mmol) was added to 7-chloro-5-{[(1S)-1-(2-fluorophenyl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-2-amine (1.36 g, 4.0 mmol) and (2R)-2-amino-4-fluoro-4-methylpentan-1-ol (4 mmol) in NMP (3 mL). After stirring the reaction mixture at 120° C. for 22 h it was poured into water and the precipitate was collected by filtration. The solid was purified by flash column chromatography (a stepwise gradient of 5%-10% MeOH in CHCl3) and preparative HPLC to give the title compound (0.22 g, 13% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]3[CH:30]=[C:31]([C:34]([F:37])([F:36])[F:35])[CH:32]=[CH:33][C:19]=3[N:18]=2)[C:5](=[O:16])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=1.[B:38]1(B2OC(C)(C)C(C)(C)O2)[O:42]C(C)(C)C(C)(C)[O:39]1.C([O-])(=O)C.[K+]>CS(C)=O>[O:16]=[C:5]1[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=[C:2]([B:38]([OH:42])[OH:39])[CH:3]=[C:4]1[C:17]1[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]2[CH:30]=[C:31]([C:34]([F:37])([F:36])[F:35])[CH:32]=[CH:33][C:19]=2[N:18]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1nc(Cl)cc(-c2nc3ccc(C(F)(F)F)cc3n2COCC[Si](C)(C)C)c1=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCn1nc(B(O)O)cc(-c2nc3ccc(C(F)(F)F)cc3n2COCC[Si](C)(C)C)c1=O
Temperature: 95 °C

Procedure:
6-Chloro-4-[6-trifluormethyl-1-(2-trimethylsilanylethoxymethyl)-1H-benzimidazol-2-yl]-2-(2-trimethylsilanylethoxymethyl)-2H-pyridazin-3-one (prepared in analogy to example 15b), bis(pinacolato)diboron, (1,1′-bis(diphenylphosphine)ferrocene)-palladium(II) chloride-dichloromethane complex and potassium acetate are dissolved in DMSO. The solution is degassed with argon and heated at 95° C. for 2.5 hours. The reaction solution is filtered through silica gel, and the latter is washed with dichloromethane. The solvent is removed in a rotary evaporator, and the crude product is purified by RP-HPLC (0-100% acetonitrile in water (+0.01% trifluoroacetic acid)). MS (ES+) m/z 585 (M+H).
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)[C:10](O)=[O:11])=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH:17]1[CH:18]=[C:14]([CH2:13][C@H:9]([NH:8][CH3:6])[CH2:10][OH:11])[N:15]=[CH:16]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@H](CO)Cc1c[nH]cn1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-3-(1H-imidazol-4-yl)propanoic acid (1.0 g, 3.92 mmol) in THF (20 mL) was added LAH (2 M, 10 mL, 20 mmol) at 0-5° C. The reaction mixture was stirred at 0-5° C. for 30 min and heat to reflux for 2 h. The reaction mixture was cooled to 0-5° C. and quenched with water (0.8 mL), NaOH (0.8 mL), and water (2.4 mL). The resulting suspension was stirred RT for 30 min and filtered. The filtrate was concentrated to give (S)-3-(1H-imidazol-4-yl)-2-(methylamino)propan-1-ol (400 mg, crude), which was used without further purification. LRMS (M-Boc+H+) m/z 156.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]3[S:22][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:20][CH:19]=3)[CH2:12][CH2:11]2)=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[N+]([C:32]1[CH:33]=C(S([O-])(=O)=O)C=C[CH:37]=1)([O-])=O.[Na+].OCC(CO)O.[OH-].[Na+]>CS(O)(=O)=O.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]3[S:22][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:20][CH:19]=3)[CH2:12][CH2:11]2)=[C:5]2[C:6]([CH:37]=[CH:32][CH:33]=[N:9]2)=[CH:7][CH:8]=1
Reactant: COc1cccc(N)c1N1CCCN(Cc2cnc(-c3ccccc3)s2)CC1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: OCC(O)CO
Product: COc1ccc2cccnc2c1N1CCCN(Cc2cnc(-c3ccccc3)s2)CC1
Temperature: 130 °C
Yield: 87.2 %

Procedure:
A mixture of 3-methoxy-2-[4-(2-phenylthiazol-5-ylmethyl)-[1,4]diazepan-1-yl]-phenylamine (210 mg, 0.53 mmol, 1 equiv), sodium 3-nitrophenylsulfonate (78 mg, 0.65 equiv), FeSO4.7H2O (7.5 mg, 0.05 equiv) and glycerol (122 mg, 2.5 equiv) in 2 mL of methanesulfonic acid was heated at 130° C. for 2 hours. After cooling down to room temperature, the mixture was diluted with water, neutralized with 10 N NaOH to pH ˜10. Ethyl acetate was added and the mixture was filtered through celite. The organic layer was subjected to reverse phase HPLC purification. The combined fractions with the desired product were evaporated to remove acetonitrile, treated with saturated sodium bicarbonate and extracted with ethyl acetate to give the pure title compound (130 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 8.85 (dd, 1H, J=4.1, 2 Hz), 8.05 (dd, 1H, J=7.8, 2 Hz), 7.95 (d, 1H, J=2 Hz), 7.90 (d, 1H, J=2 Hz), 7.50 (d, 1H, 8.6 Hz), 7.42-7.35 (m, 3H), 7.30-7.20 (m, 3H), 7.20 (dd, 1H, J=7.8, 4.1 Hz), 4.08 (s, 2H), 3.85 (s, 3H), 3.62-3.50 (m, 4H), 3.10-3.00 (m, 2H), 3.00-2.80 (m, 2H), 2.20-2.00 (m, 2H). MS (ES) m/z 431.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:11][CH2:12][N:13]([C:19]4[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=4)[CH2:14][CH2:15]3)[S:8][C:4]=2[CH:3]=1
Reactant: Brc1ccc2nc(OC3CCNCC3)sc2c1
Reactant: Fc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cnc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)nc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
To a solution of 6-bromo-2-(piperidin-4-yloxy)benzo[d]thiazole (1 g, 3.19 mmol) and 2-chloro-5-fluoropyrimidine (0.508 g, 3.83 mmol) in DMF (15 mL) was added potassium carbonate (1.32 g, 9.58 mmol). The reaction mixture was stirred at 100° C. for 4 h. The reaction mixture was cooled to rt, diluted with water (40 mL), and extracted with EtOAc (3×20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 40% EtOAc) to afford 6-bromo-2-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazole (1.112 g, 2.72 mmol, 85% yield) as a white solid.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5]([NH:7][C:8](=[N:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])SC)#[N:6]>C(#N)C>[CH2:1]([NH:4][C:8]([NH:7][C:5]#[N:6])=[N:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])[CH:2]=[CH2:3]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: C=CCN
Solvent: CC#N
Product: C=CCNC(=NCCSCc1[nH]cnc1C)NC#N

Procedure:
Reaction of allylamine and N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea by the procedure of Example 11 afforded the title compound, m.p. 113°-114° C. (from acetonitrile)
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C1([O-])C=CC=CC=1.[C:21]([C:25]1[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:28]=[CH:27][C:26]=1[OH:35])([CH3:24])([CH3:23])[CH3:22].[OH-].[Na+].[N:38]1C=CC=CC=1>C1(C)C=CC=CC=1.O>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[N:6]=[N:38][C:27]1[CH:28]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:30]=[C:25]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:26]=1[OH:35])([CH3:13])[CH3:12]
Reactant: c1ccncc1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: [Na+]
Agent: [O-]c1ccccc1
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1N=Nc1cc(C(C)(C)C)cc(C(C)(C)C)c1O

Procedure:
This phenol was prepared, as described for above, from a theoretical yield of 7.4 mmol of diazotized 2,6-diisopropylaniline and a phenolate solution comprised of 2,4-Ditertbutylphenol (1.42 g), water (15 mL), NaOH (0.5 g), pyridine (3 mL), and toluene (6 mL) Yield=0.98 g (36%).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C:3]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH:7]([C:12]([O:14]CC)=O)[CH2:6]1)=[O:4].Cl.[C:20]([NH2:26])(=[NH:25])[CH2:21][CH2:22][CH2:23][CH3:24].C[O-].[Na+]>C(O)C.CO>[CH2:21]([C:20]1[NH:26][C:12](=[O:14])[C:7]2[CH2:6][N:5]([C:3](=[O:4])[C:2]([CH3:1])([CH3:17])[CH3:18])[CH2:10][CH2:9][C:8]=2[N:25]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCOC(=O)C1CN(C(=O)C(C)(C)C)CCC1=O
Reactant: CCCCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCCCc1nc2c(c(=O)[nH]1)CN(C(=O)C(C)(C)C)CC2
Yield: 67.4 %

Procedure:
A mixture of 1.3 g of ethyl 1-(2,2-dimethyl-1-oxopropyl)-4-oxo-3-piperidinecarboxylate and 0.75 g of valeramidine hydrochloride in 10 ml of anhydrous ethyl alcohol is treated with 5.3 ml of a 1M solution of sodium methoxide in methanol. The resulting mixture is stirred and heated at reflux for one hour. The reaction mixture is allowed to cool over 30 minutes then filtered. The filtrate is evaporated to a gummy residue and stirred with 40 ml of ether for 30 minutes, filtered and the cake washed with ether. The cake is dried at 56° C. under vacuum to afford 1.0 g of the desired product as a colorless solid, m.p. 167°-172° C.
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[Cl:16])(=[O:4])[CH3:3].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=1[Cl:31])=[O:23]>>[ClH:16].[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)=[O:23])=[C:25]([Cl:31])[CH:26]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)Oc1ccc2ncnc(Cl)c2c1
Reactant: Nc1ccc(C(=O)c2cccs2)c(Cl)c1
Agent: Cl
Product: CC(=O)Oc1ccc2ncnc(Nc3ccc(C(=O)c4cccs4)c(Cl)c3)c2c1
Yield: 77 %

Procedure:
Using an analogous procedure to that described in Example 1, 6-acetoxy-4-chloroquinazoline hydrochloride was reacted with 4-amino-2-chlorophenyl 2-thienyl ketone to give 6-acetoxy-4-[3-chloro-4-(2-thienylcarbonyl)anilino]quinazoline hydrochloride salt in 77% yield, m.p. >250° C.;
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[N:6][C:7]=1[CH3:8].[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=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>[CH3:8][C:7]1[N:6]=[C:5]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:4]=[CH:3][C:2]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH3:23]
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)ccc1Br
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: Cc1ccccc1-c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)nc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A 40 mL vial was purged with and maintained under an inert atmosphere of nitrogen then charged with tert-butyl 4[(5-bromo-6-methylpyridin-2-yl)methyl]piperazine-1-carboxylate (1.00 g, 2.70 mmol, 1.00 equiv), (2-methylphenyl)boronic acid (0.730 g, 5.40 mmol, 2.00 equiv), tetrakis(triphenylphosphine)palladium (0.310 g, 0.270 mmol, 0.10 equiv), potassium carbonate (1.15 g, 8.32 mmol, 3.08 equiv), dioxane (15 mL), water (3 mL). The resulting solution was stirred overnight at 80° C. and diluted with water (20 mL). The resulting solution was extracted with ethyl acetate (2×20 mL) and the organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (60/40) to provide 1.00 g (92% yield) of tert-butyl 4-[[6-methyl-5-(2-methylphenyl)pyridin-2-yl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 382 [M+H]+.