Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH2:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc2cccc(Br)c2s1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nc2cccc(Br)c2s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.5 %

Procedure:
7-Bromobenzo[d]thiazol-2-amine (550 mg, 2.40 mmol) and DMAP (330 mg, 2.70 mmol) were suspended in DCM (12 mL) and acetic anhydride (0.25 mL, 2.7 mmol) was added. The reaction was stirred under nitrogen at RT for 6 hours, the suspension was filtered, and the solid was washed with DCM. The solid was collected, and the filtrate was concentrated and treated with MeOH. This batch of solid was also collected by filtration. The filtrate was concentrated, and filtered through silica gel (40:1 DCM/MeOH) to provide additional products. The collected solids were combined to afford N-(7-bromobenzo[d]thiazol-2-yl)acetamide (433 mg, 67% yield) as a white solid. MS (ESI pos. ion) m/z: 271 (MH+, 79Br), 273 (MH+, 81Br). Calculated exact mass for C9H7BrN2S: 270 (79Br), 272 (81Br).
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]1(=[O:19])[N:17]2[C:18]3[C:14]([CH:15]=[CH:16]2)=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][NH:8][CH2:7]1.CN([CH:23]=[O:24])C>>[O:19]=[C:6]1[N:17]2[C:18]3[C:14]([CH:15]=[CH:16]2)=[C:13]([CH:23]=[O:24])[CH:12]=[CH:11][C:10]=3[CH2:9][NH:8][CH2:7]1
Reactant: CN(C)C=O
Reactant: O=C1CNCc2cccc3ccn1c23
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2c3c1ccn3C(=O)CNC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
POCl3 (16.37 g, 106.76 mmol) was slowly added to DMF (225 mL) at 0° C. The mixture was stirred for 15 minutes and then treated with a solution of 3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-one (Example 42, 1.46 g, 7.85 mmol) in DMF (10 mL). The reaction mixture was warmed to rt and stirred for 17 h. After removing all solvent, the residue was taken up in H2O, made basic (pH 12-14) using 50% aqueous NaOH and extracted with EtOAc several times. The organic layer was dried over anhydrous MgSO4, filtered and concentrated to give 1.6 g (95%) of a pale-yellow solid: 1H NMR (DMSO-d6) δ 3.58-3.61 (m, 2H), 4.48 (bs, 2H), 7.37 (t, 1H, J=7.5 Hz), 7.97 (d, 1H, J=7.5 Hz), 8.33-8.35 (m, 2H), 8.43-8.45 (m, 1H), 9.95 (s, 1H). HRMS calcd. for C12H10N2O2 (M+) 214.0742, found 214.0737. Anal. (Cl2H10N2O2.0.1H2O) C, H, N.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]([CH3:22])=[N:11]2)=[CH:6][CH:5]=1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C)C=O>[N:23]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]([CH3:22])=[N:11]2)=[CH:6][CH:5]=1)=[N+:24]=[N-:25]
Reactant: Cc1nn(-c2ccc(CCCl)cc2)c(C)c1-c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ccc(CCN=[N+]=[N-])cc2)c(C)c1-c1ccccc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 80.6 %

Procedure:
To a stirred solution of 1-[4-(2-chloroethyl)phenyl]-3,5-dimethyl-4-phenyl-1H-pyrazole (step 1, 0.34 mmol) and KI (56 mg, 0.34 mmol) in N,N-dimethylformamide (2.7 mL) was added sodium azide (44 mg, 0.68 mmol), and then the resulting mixture was stirred for 6 h at 100° C. The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate/toluene (4:1). The organic layer was washed with water (50 mL) and brine (50 mL), then dried (Na2SO4). After removal of the solvent, the crude product was purified by TLC with hexane/ethyl acetate (1:1) to afford 87 mg (81%) of the title compound as yellow oil: 1H-NMR (CDCl3) δ 7.46-7.29 (9H, m), 3.55 (2H, t, J=7.3 Hz), 2.96 (2H, t, J=7.1 Hz), 2.34 (3H, s), 2.30 (3H, s).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH:22]C(=O)OCC2C=CC=CC=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO.C1COCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([F:21])([F:19])[F:20])=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH2:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1Cc2cc(C(F)(F)F)ccc2N(Cc2ccccc2)C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: NC1Cc2cc(C(F)(F)F)ccc2N(Cc2ccccc2)C1
Yield: 90.2 %

Procedure:
A suspension of 149E (740 mg, 1.682 mmol) and 5% Pd/C (Degussa type, 300 mg) in a mixed solvent of MeOH-THF (20 mL, 1:1 ratio) was hydrogenated at RT under hydrogen balloon for 1 h. After filtration to remove the catalyst, the filtrate was concentrated and the residue dried in vacuo to afford compound 149F as a clear oil (465 mg, 90%).
Reaction SMILES: Cl[C:2]1[N:25]=[C:5]2[C:6]([NH:10][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[CH3:12])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:24][N:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:11]([NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:39][C:36]3[CH:35]=[CH:34][C:33]([N:30]4[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]4)=[CH:38][CH:37]=3)[N:25]=2)[CH:9]=[CH:8][CH:7]=1)[CH3:12])[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CC(Nc1cccn2nc(Cl)nc12)c1ccccc1N(C)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(Nc1cccn2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc12)c1ccccc1N(C)S(C)(=O)=O

Procedure:
197 h) N-Methyl-N-[2-(1-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-ethyl)-phenyl]-methanesulfonamide was prepared from N-{2-[1-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-ethyl]-phenyl}-N-methyl-methanesulfonamide (75.0 mg, 0.197 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (42.0 mg, 0.220 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (18.0 mg, 0.0329 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow solid (0.008 g, 8%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.77-7.25 (m, 8H), 7.00-6.93 (m, 2H), 6.65-6.30 (m, 3H), 5.40-5.24 (m, 1H), 5.00-4.91 (m, 1H), 3.35-3.29 (m, 3H), 3.19-3.13 (m, 4H), 3.07-3.01 (m, 3H), 2.63-2.58 (m, 4H), 2.36 (s, 3H), 1.72-1.55 (m, 3H). MS=535 (MH)+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:15][CH2:14][S:13][C:9]=3[C:10](=[O:12])[O:11][C:6]=2[CH:5]=[C:4]([CH:16]([CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])[CH:3]=1.O=[C:26]1CCSCC1C(OCC)=O.Cl>C(O)C>[OH:1][C:2]1[C:7]2[C:8]3[CH2:15][CH2:14][S:13][CH2:26][C:9]=3[C:10](=[O:12])[O:11][C:6]=2[CH:5]=[C:4]([CH:16]([CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])[CH:3]=1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)SCC3
Reactant: CCOC(=O)C1CSCCC1=O
Agent: Cl
Solvent: CCO
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)CSCC3
Reaction time: 120 h
Yield: 68 %

Procedure:
A solution of 6.4 g. (0.027 mole) of 5-(3-methyl-2-octyl-resorcinol of Example 1 and 5.0 g. (0.0266 mole) of ethyl 4-oxo-1,3,5,6-tetrahydro-4H-thiopyran-3-carboxylate [prepared according to the method of Bennett and Scorah, J. Chem. Soc., 194 (1927)] in 35 ml. of absolute ethanol was cooled in an ice bath while it was saturated with hydrogen chloride. The resulting deep red solution was tightly stoppered and allowed to stand at room temperature for 120 hours. After one day yellow crystalline material had collected on the bottom of the flask. The reaction mixture was warmed gently on the steam bath for 15 minutes, cooled and poured onto a water-ice mixture. The gum-like material that precipitated was extracted with several portions of chloroform. The chloroform solution was washed with aqueous potassium bicarbonate and with water and dried over sodium sulfate. Evaporation of the solvent left 7.5 g. of a light-colored solid. This material was triturated several times with boiling petroleum ether to remove unreacted keto ester. The residue was recrystallized from an ethyl acetate-petroleum ether mixture to give 6.5 g. (68%) of the desired compound, m.p. 153°-155°C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[CH2:13](Br)[CH3:14]>CC#N>[CH2:13]([C:8]1[C:7]2[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=2)[NH:10][CH:9]=1)[CH3:14]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CCBr
Solvent: CC#N
Product: CCc1c[nH]c2cc(N)ccc12

Procedure:
3-Ethyl-1H-indol-6-ylamine (B-12) was synthesized following the general scheme above starting from 6-nitroindole and ethyl bromide. Overall yield (42%). HPLC ret. time 1.95 min, 10-99% CH3CN, 5 min run; ESI-MS 161.3 m/z (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][S:18]C(=O)C)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C[O-].[Na+]>O1CCCC1.CO>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][SH:18])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CC(=O)SCc1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(-c2ccc(CS)cc2)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 1.35-A of Step 1 (160 mg, 0.49 mmol) in tetrahydrofuran (1.5 mL) and methanol (1.5 mL) was cooled to 0° C. and degassed. The reaction mixture was treated with sodium methoxide (0.30 mL, 3.3 mmol, 25 wt % solution in methanol) dropwise and stirred at 0° C. for 5 min. The reaction mixture was quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (30 mL). The organic layer was separated and washed with brine (10 mL), dried with sodium sulfate, filtered, and concentrated to give a white solid which was used in the next step without further purification. LCMS found for C14H15O2S2 (M+H)+: m/z=279.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](Cl)[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:17][NH2:18]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([NH:18][CH3:17])[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 67 %

Procedure:
A solution of 4,4′-dichlorobenzhydryl chloride (3.22 g, 11.85 mmol) in a 1.85 M solution of methylamine in tetrahydrofuran (40 ml) was heated at 125° C. in a pressure vessel for 24 h. The cooled reaction mixture was diluted with ethyl acetate, washed with sodium carbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate 8:2) gave 2.12 g (67%) of the title amine as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.57 (3H, s, NCH3), 4.85 (1H, s, CH benzhydryl), 7.0-7.53 (8H, m, aromatics). MS (ESI+) (m/z): 266 (M+H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:11]=1.N1C=CN=C1>CN(C=O)C.CCOCC>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([O:22][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCC(O)c1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Reaction time: 16 h
Yield: 99.6 %

Procedure:
t-Butyidimethylsilylchloride (2.49 g, 16.5 mmol) was added to a solution of the alcohol 6 (3.6 g, 14.0 mmol) and imidazole (1.91 g, 28.0 mmol) in DMF (22 mL) at 23° C. The reaction was stirred for 16 h, diluted with Et2O and washed with 1 N HCl, saturated aqueous NaHCO3 and brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. FCC (silica gel, 100% hex) afforded 5.18 g (63%) of the silyl ether 7 as a clear, colorless oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C@H:3]1[CH2:8][CH2:7][C@H:6]([CH:9]=[O:10])[CH2:5][CH2:4]1.[CH2:13]([CH:16]([CH3:20])[CH:17](O)[OH:18])[CH2:14][CH3:15].C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>O>[F:1][C:2]([F:11])([F:12])[C@H:3]1[CH2:4][CH2:5][C@H:6]([CH:9]2[O:18][CH2:17][CH:16]([CH2:13][CH2:14][CH3:15])[CH2:20][O:10]2)[CH2:7][CH2:8]1
Reactant: O=C[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: CCCC(C)C(O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC1COC([C@H]2CC[C@H](C(F)(F)F)CC2)OC1

Procedure:
A mixture of 0.02 mol of trans-4-trifluoromethyl-1-formylcyclohexane (prepared as in Example 3), 0.02 mol of 2-propylpropanediol, 30 ml of toluene and 0.5 g of pTsOH (sic) is heated for 4 hours on a water separator. The pure product is obtained after customary work-up and crystallization.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]([Cl:14])([Cl:13])[C:8]([N:10]=[C:11]=[O:12])=[O:9]>O.CC(C)=O>[Cl:6][C:7]([Cl:14])([Cl:13])[C:8]([NH:10][C:11]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:12])=[O:9]
Reactant: NCCCO
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C(NCCCO)NC(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
3.75 g of 3-aminopropanol are dissolved in a mixture of 10 g of water and 10 g of acetone. 9.4 g of trichloroacetyl isocyanate are subsequently added dropwise. After a slightly exothermic reaction, the mixture is stirred for 1 hour at room temperature, then refluxed for 2.5 hours. Concentration in a rotary evaporator gives 7.7 g of an oily phase, which is taken up in acetone and subjected to column chromatography on silica gel using cyclohexane/ethyl acetate (1:1) as eluent.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].Cl[CH2:14][CH2:15][CH2:16][NH2:17]>C(O)C.O>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:14][CH2:15][CH2:16][NH2:17]
Reactant: Sc1nc2ccccc2o1
Reactant: NCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NCCCSc1nc2ccccc2o1
Yield: 71.6 %

Procedure:
2-Mercaptobenzoxazole (15.2 g; 0.1 mol) was dissolved in ethanol (200 ml); NaOH (4.0 g; 0.1 mol) dissolved in water was added thereto. The reaction mixture was refluxed for 30 minutes, then 3-chloropropylamine (9.3 g; 0.1 mol) dissolved in ethanol (50 ml) was added. The mixture was refluxed for 90 minutes, cooled, filtered from the salt and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol/ether (1:3), (15.0 g; 71.6% yield).
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH:20][C@H:21]3[CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[ClH:34]>O1CCOCC1>[ClH:34].[NH:23]1[CH2:24][CH2:25][CH2:26][C@H:21]([NH:20][C:19]2[C:14]3[CH:13]=[CH:12][N:11]([S:1]([C:4]4[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=4)(=[O:3])=[O:2])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:22]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@H]4CCCN(C(=O)OC(C)(C)C)C4)ncnc32)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@H]4CCCNC4)ncnc32)cc1
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of compound (S)-tert-butyl 3-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (3.4 g, 7.2 mmol) in dioxane (20 mL) at 0° C., a solution of HCl in dioxane (50 mL) was added until the pH was acidic at 0° C. and stirred for 30 min. at the same temperature. The reaction mixture was concentrated in vacuo to give a residue that was triturated with ether to give (S)—N-(piperidin-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride (2 g, 74%) as a free flowing solid. 1H NMR (400 MHz, DMSO-d6): δ 9.19 (s, 1H), 8.32 (s, 1H), 7.98 (d, J=8.2 Hz, 2H), 7.62 (d, J=2.5 Hz, 1H), 7.42 (d, J=8.2 Hz, 2H), 7.22 (d, J=2.5 Hz, 1H), 5.80 (s, 1H), 4.29-4.25 (m, 2H), 3.38-3.32 (m, 1H), 3.19-3.12 (m, 1H), 3.00-2.97 (m, 1H), 2.35 (s, 3H), 2.01-1.95 (m, 2H), 1.75-1.69 (m, 2H). LC-MS: m/z [M+1]=372.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:45]=2[N:44]([CH3:46])[N:43]=[C:42]3[NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[C:5]([C@@H:8]([NH:18][C:19](=[O:36])[CH2:20][N:21]2[C:25]3[C:26]([F:31])([F:30])[C@@H:27]4[CH2:29][C@@H:28]4[C:24]=3[C:23]([C:32]([F:35])([F:34])[F:33])=[N:22]2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[N:6][CH:7]=1.[C:52](OC(=O)C)(=[O:54])[CH3:53].C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]([C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:45]=2[N:44]([CH3:46])[N:43]=[C:42]3[N:47]([S:48]([CH3:51])(=[O:49])=[O:50])[C:52](=[O:54])[CH3:53])[C:5]([C@@H:8]([NH:18][C:19](=[O:36])[CH2:20][N:21]2[C:25]3[C:26]([F:30])([F:31])[C@@H:27]4[CH2:29][C@@H:28]4[C:24]=3[C:23]([C:32]([F:35])([F:33])[F:34])=[N:22]2)[CH2:9][C:10]2[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=2)=[N:6][CH:7]=1
Reactant: Cn1nc(NS(C)(=O)=O)c2cccc(-c3cc(N)cnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)c21
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(c1nn(C)c2c(-c3cc(N)cnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)cccc12)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Compound 35 (20 mg, 0.027 mmol) in methylene chloride (2 mL) was added acetic anhydride (0.03 mL, 0.27 mmol), triethylamine (0.04 mL, 0.027 mmol), and the reaction mixture was stirred for one hour at room temperature. The solution was partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC eluting with acetonitrile and water (with 0.1% TFA) to afford the title compound 38A: 1H NMR (400 MHz, methanol-d4) δ 8.26 (d, 1H), 7.72 (dd, 1H), 7.18 (m, 1H), 7.09 (d, 1H), 6.76 (tt, 1H), 6.46 (d, 1H), 6.42-6.21 (m, 2H), 4.85-4.52 (m, 3H), 3.50 (m, 6H), 3.12 (m, 1H), 3.00-2.80 (m, 1H), 2.59-2.31 (m, 2H), 1.86 (s, 3H), 1.41 (m, 1H), 1.04 (m, 1H). MS (m/z): 778.95 [M+H]+ and 11 mg of compound 38B. MS (m/z) 820.83 [M+H]+.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH2:11]Br.Cl.[NH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23].C(N(CC)CC)C>CN(C=O)C>[Br:10][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[C:3](=[O:13])[N:15]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23])[CH2:11]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(N2Cc3cc(Br)ccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
A mechanically stirred mixture of 4-bromo-2-bromomethyl-benzoic acid methyl ester (121 g, 390 mmol) and 3-amino-piperidine-2,6-dione hydrochloride (64.2 g, 390 mmol) in DMF (400 mL) was treated dropwise with triethylamine (98.5 g, 980 mmol) over 75 minutes. After the addition was completed, the reaction mixture was stirred at room temperature overnight. The mixture was quenched sequentially with acetic acid (50 mL), water (2500 mL) and a 1:1 mixture of ethyl acetate and hexanes (600 mL). After stirring the mixture for 20 minutes, the solid was filtered, washed with water and air dried overnight. The solid was stirred in acetic acid (200 mL) and refluxed for 2 hours. The mixture was cooled to room temperature and filtered. The solid was washed with additional acetic acid, hexanes and air dried overnight to give 25.4 g of 3-(5-bromo-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione as a grey solid, in 20% yield; 1H NMR (DMSO-d6) δ 1.97-2.04 (m, 1H), 2.32-2.46 (m, 1H), 2.56-2.63 (m, 1H), 2.85-2.97 (m, 1H), 4.34 (d, J=17.7 Hz, 1H), 4.47 (d, J=17.7 Hz, 1H), 5.11 (dd, J=13.2 Hz, J=5.1 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.72 (dd, J=8.1 Hz, J=1.5 Hz, 1H), 7.89 (d, J=0.9 Hz, 1H), 11.00 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[N:12]=1.S(Cl)(Cl)=O.[CH3:26][NH:27][CH3:28]>>[CH3:26][N:27]([CH3:28])[C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[S:9][CH:10]=2)[CH:14]=1
Reactant: CNC
Reactant: Cc1ccncc1-c1nc(-c2cccc(C(=O)O)c2)cs1
Solvent: O=S(Cl)Cl
Product: Cc1ccncc1-c1nc(-c2cccc(C(=O)N(C)C)c2)cs1

Procedure:
By the reaction in the same manner as in Example 60 using 3-[2-(4-methylpyridin-3-yl)-1,3-thiazol-4-yl]benzoic acid (248 mg), thionyl chloride (0.09 ml) and aqueous dimethylamine solution (50%, 5 ml), the title compound (200 mg) was obtained as colorless powder crystals.
Reaction SMILES: Br[C:2]1[N:3]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:4]2[N:5]=[C:6]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:7]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:8](=[O:11])[C:9]=2[N:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:41]([NH:43][CH3:44])[CH3:42].C(#N)C>C(Cl)Cl>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([N:7]2[C:8](=[O:11])[C:9]3[N:10]=[C:2]([N:43]([CH2:41][CH3:42])[CH3:44])[N:3]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:4]=3[N:5]=[C:6]2[C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=2)=[CH:17][CH:16]=1
Reactant: CCNC
Reactant: O=c1c2nc(Br)n(-c3ccccc3)c2nc(-c2ccc(C(F)(F)F)cc2)n1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CCN(C)c1nc2c(=O)n(-c3ccc(Cl)cc3)c(-c3ccc(C(F)(F)F)cc3)nc2n1-c1ccccc1
Temperature: 200 °C
Yield: 49.4 %

Procedure:
8-Bromo-1-(4-chloro-phenyl)-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one (19.0 mg, 0.0348 mmol), potassium carbonate (400 mg, 2.89 mmol), and ethyl-methyl-amine (172 mg, 2.91 mmol) are mixed in a microwave tube with 1 mL of dry acetonitrile. The tube is then capped and heated to 200° C. for 40 min in a microwave reactor. Then the reaction mixture is diluted with CH2Cl2 and filtered. The filtrate is evaporated and the crude product is purified by column chromatography, yielding 9 mg (49%) of the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.54 (m, 4H), 7.47 (m, 1H), 7.42 (d, 2H), 7.30 (d, 4H), 7.08 (d, 2H), 3.17 (q, 2H), 2.90 (s, 3H), 1.03 (t, 3H). HPLC-MS calculated for C27H21ClF3N5O (M+H+) 524.1. Found: 524.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[N:15]2)[N:4]=1>CCOC(C)=O.CCO.O=[Pt]=O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([NH2:19])[CH:16]=[N:15]2)[N:6]=1
Reactant: COc1cc(OC)nc(OCCn2cc([N+](=O)[O-])cn2)n1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(OC)nc(OCCn2cc(N)cn2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4,6-dimethoxy-2-(2-(4-nitro-1H-pyrazol-1-yl)ethoxy)pyrimidine (2.05 g, 6.93 mmol), in EtOAc (3.0 mL, degassed) and EtOH (9 mL, degassed), PtO2 (135 mg, 0.70 mmol) was added and the reaction mixture was stirred at rt under a H2-atmosphere for 3 h. The mixture was diluted with EtOH, filtered over celite and the filter cake was rinsed with EtOH. The filtrate was concentrated to obtain the title compound as a red oil. LC-MS conditions A: tR=0.58 min, [M+H]+=266.02.
Reaction SMILES: [F-:1].[K+].C1OCCOCCOCCOCCOCCOC1.Cl[C:22]1[N:31]2[CH:32]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[N:34]=[C:30]2[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[N:23]=1.O>CN(C=O)C>[F:1][C:22]1[N:31]2[CH:32]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[N:34]=[C:30]2[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[N:23]=1
Reactant: [F-]
Reactant: Fc1ccccc1-c1cn2c(Cl)nc3c(c2n1)CCCC3
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccccc1-c1cn2c(F)nc3c(c2n1)CCCC3
Temperature: 25 °C

Procedure:
To a solution of 700 mg of potassium fluoride and 200 mg 18-crown-6 in 10 mL of DMF was added 5-Chloro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (200 mg). This mixture was refluxed for 1.5 h, cooled to room temperature and poured into water. The aqueous solution was extracted with ethyl acetate, the organic layer was separated and dried, and the solvent removed m vacuo to yield 5-Fluoro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (Compound 41), m.p. 154°-155° C.