Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][CH:32]=[CH:31][C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[CH:15][N:14]([CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18][C:19]([O:21]CC)=[O:20])[C:13]=2[CH:30]=1)=[O:7])([O-:3])=[O:2].C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[N+:1]([C:4]1[CH:34]=[CH:33][CH:32]=[CH:31][C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[CH:15][N:14]([CH:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:18][C:19]([OH:21])=[O:20])[C:13]=2[CH:30]=1)=[O:7])([O-:3])=[O:2].[NH2:1][C:4]1[CH:34]=[CH:33][CH:32]=[CH:31][C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[CH:15][N:14]([CH:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:18][C:19]([OH:21])=[O:20])[C:13]=2[CH:30]=1)=[O:7]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3ccccc3[N+](=O)[O-])cc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccccc1C(=O)Nc1ccc2ncn(C(CC(=O)O)c3ccccc3)c2c1
Product: O=C(O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3ccccc3[N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of ethyl 3-{6-[(2-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (24 mg, 52 μmol) in a mixture of ethanol and water (5:1, 6 mL), was added palladium on carbon (50 mg, 10% w/w Pd) and ammonium formate (17 mg, 270 μmol). The suspension was heated to reflux for 2 hours, cooled to room temperature, filtered through a pad of Celite® and the filtrate was evaporated in vacuo. The residue was taken up in hydrochloric acid (20 mL of a 5N solution) was stirred at room temperature for 72 hours, evaporated in vacuo, and the residue was purified by RP-HPLC to afford the title compounds 3-{6-[(2-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic acid, [LCMS (Method A, Mobile Phase II) RT=3.65 min, MH+ 401], and 3-{6-[(2-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic acid, [LCMS (Method A, Mobile Phase II) RT=3.58 min, MH+ 431].
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[N:12]=[C:11]([NH:13][CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:10]=[C:9]([C:20]([OH:23])([CH3:22])[CH3:21])[CH:8]=2)=[CH:4][CH:3]=1.Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=1.C(N(CC)CC)C>S1(CCCC1)(=O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:12]=[C:11]([NH:13][CH:14]3[CH2:19][CH2:18][N:17]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=4)[CH2:16][CH2:15]3)[N:10]=[C:9]([C:20]([OH:23])([CH3:22])[CH3:21])[CH:8]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(O)c1cc(Cc2ccc(Cl)cc2)nc(NC2CCNCC2)n1
Reactant: Cc1cc(Cl)ccn1
Solvent: O=S1(=O)CCCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCC(Nc3nc(Cc4ccc(Cl)cc4)cc(C(C)(C)O)n3)CC2)ccn1
Temperature: 150 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
A solution of 2-[6-(4-chloro-benzyl)-2-(piperidin-4-ylamino)-pyrimidin-4-yl]-propan-2-ol (76 mg, 0.19 mmol), 4-chloro-2-picoline (24 mg, 0.19 mmol) and triethylamine (53 μL, 0.38 mmol) in sulfolane (0.76 mL) was stirred in a preheated oil bath at 150° C. for 30 minutes. After further addition of 4-chloro-2-picoline (24 mg, 0.19 mmol) and triethylamine (53 μL, 0.38 mmol) the solution was stirred for further 60 minutes at 150° C. It was diluted with ethyl acetate (15 mL) and was washed with 1 M aqueous sodium carbonate solution (20 mL), water (15 mL) and brine (15 mL). The combined aqueous layers were extracted with ethyl acetate (15 mL). The organic layer was dried over sodium sulfate. Concentration and purification by chromatography (SiO2, dichloromethane/methanol/triethylamine=95:4.5:0.5) afforded the title compound (34 mg, 40%) as an off-white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12].[CH3:13][O:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][C:19]([O-])=[O:20]>>[CH3:13][O:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][C:19](=[O:20])[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:11][CH3:12])[C:5]=1[O:9][CH3:10]
Reactant: COC(=O)CCCC(=O)[O-]
Reactant: COc1cccc(OC)c1OC
Product: COC(=O)CCCC(=O)c1ccc(OC)c(OC)c1OC
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 77 %

Procedure:
75 g of polyphosphoric acid (Acros) was charged in a 250 mL round bottom flask, followed by addition of 1,2,3-trimethoxybenzene (5.0 g, 29.73 mmol), and mono-methylglutarate (6.516 g, 44.60 mmol). The reaction mixture was stirred mechanically for 2.5 h at 45° C. The reaction mixture was then poured into a 1000 mL beaker containing around 250 mL of ice, and stirred well until all the product precipitated out. The tan colored product was then filtered and washed with water and dried under vacuum. No, purification required at this stage. 6.78 g (77%) of product was obtained, which was pure by NMR.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[N:7]([C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)=[CH:10][N:9]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Cn1cc(Br)cc(N(C(=O)OC(C)(C)C)c2ccc(C=O)cn2)c1=O
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCN(Cc2ccc(N(C(=O)OC(C)(C)C)c3cc(Br)cn(C)c3=O)nc2)CC1
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a solution of (5-bromo-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (1.0 g, 2.45 mmol) in DCM (49 ml) was added 1-methylpiperazine (491 mg, 4.9 mmol), sodium triacetoxyborohydride (1.3 g, 6.12 mmol) and acetic acid (294 mg, 4.9 mmol). The reaction mixture was heated to 40 degrees centigrade and stirred overnight. The reaction was diluted with DCM, washed with saturated aqueous sodium bicarbonate, dried and concentrated. The crude product was purified by flash chromatography using a gradient of 0% to 20% methanol in DCM to give 1.08 g (89.5%) of (5-bromo-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[CH:15]=1)[C:10]([OH:12])=O)[OH:6])[CH3:2].Cl.Cl.[CH3:27][C:28]1[N:33]=[CH:32][C:31]([C@H:34]([NH2:36])[CH3:35])=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[CH:15]=1)[C:10]([NH:36][C@@H:34]([C:31]1[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=1)[CH3:35])=[O:12])[OH:6])[CH3:2]
Reactant: CCN(CC)CC(O)c1cc(C(=O)O)cc(-c2ccc(C)cn2)c1
Reactant: Cc1ccc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)CC(O)c1cc(C(=O)N[C@H](C)c2ccc(C)nc2)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(2-(diethylamino)-1-hydroxyethyl)-5-(5-methylpyridin-2-yl)benzoic acid (30 mg, 0.075 mmol) in N,N-dimethylformamide (5 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (100 mg, 0.48 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (160 mg, 0.42 mmol) and N,N-diisopropylethylamine (300 μL, 1.7 mmol). The reaction mixture was stirred for 16 hours at 25° C. and purified by preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2NH]) to afford the title product.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[C:7]([CH3:14])=[N:8][C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[CH3:14][C:7]1[C:6]([C:4]2[N:15]=[C:16]([NH2:18])[S:17][CH:3]=2)=[C:11]([CH3:12])[CH:10]=[C:9]([CH3:13])[N:8]=1
Reactant: Cc1cc(C)c(C(=O)CBr)c(C)n1
Reactant: NC(N)=S
Agent: Br
Solvent: CCO
Product: Cc1cc(C)c(-c2csc(N)n2)c(C)n1
Yield: 62.1 %

Procedure:
A mixture of 2-bromo-1-(2,4,6-trimethylpyridin-3-yl)ethanone hydrobromide (9.00 g, 27.9 mmol) and thiourea (2.12 g, 27.9 mmol) in 95% EtOH (39.8 mL) was heated at reflux for 120 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(2,4,6-trimethylpyridin-3-yl)thiazol-2-amine (3.80 g) as yellow solids in 62% yield: 1H NMR (500 MHz, CDCl3) δ 6.87 (s, 1 H), 6.31 (s, 1 H), 5.07 (bs, 2 H), 2.49 (s, 3 H), 2.38 (s, 3 H), 2.14 (s, 3 H).
Reaction SMILES: [CH2:1]([C@H:8]([NH2:25])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[S:42][C:41]([S:43](Cl)(=[O:45])=[O:44])=[CH:40][CH:39]=1.O>CC(C)=O>[CH2:1]([C@H:8]([NH:25][S:43]([C:41]1[S:42][C:38]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=2)=[CH:39][CH:40]=1)(=[O:44])=[O:45])[CH2:9][N:10]1[CH2:11][CH2:12][CH:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[CH2:14][CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H](Cc1ccccc1)CN1CCC(Oc2ccc(F)c(F)c2)CC1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=S(=O)(N[C@@H](Cc1ccccc1)CN1CCC(Oc2ccc(F)c(F)c2)CC1)c1ccc(-c2ccccn2)s1
Reaction time: 0.17 h
Yield: 38.8 %

Procedure:
The product of Example 6, Step (a) (0.091 g) was dissolved in acetone (2 ml). Potassium carbonate [0.066 g dissolved in H2O (0.5 ml)] was then added, followed by 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (0.067 g) and the reaction left to stir for 10 mins. Water was then added and the product extracted with ethyl acetate. The combined organic extracts dried, filtered and concentrated. Purification by flash silica column chromatography with 1% MeOH/98.9% CH2Cl2/0.1% aq NH3 as eluent, and then reverse phase HPLC {with a gradient eluent system [50% MeCN/NH4OAcaq (0.1%) to 70% MeCN//NH4OAcaq (0.1%)]} gave the title compound as a solid (0.057 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:18]([C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:21]=1[CH:22]=O)[CH3:19].CO>[Cl-].[Cl-].[Zn+2].C(N(CC)CC)C>[C:13]([C:9]1[N:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([NH:1][CH2:22][C:21]3[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:20]=3[CH2:18][CH3:19])[C:3]2=[N:11][C:10]=1[CH3:12])([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1c(C)nc2c(N)cc(C)cn12
Reactant: CCc1cccc(C)c1C=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)c1c(C)nc2c(NCc3c(C)cccc3CC)cc(C)cn12
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
A mixture of 8-amino-3-carboethoxy-2,6-dimethylimidazo[1,2-a]pyridine (1.4 g, 6 mmol), 2-ethyl-6-methylbenzaldehyde (0.9 g, 6.5 mmol), ZnCl2 (1.0 g, 7.4 mmol), NaB(CN)H3 (0.41 g, 6.5 mmol) and MeOH (30 ml) was refluxed for 5 h. More ZnCl2 (0.2 g) and NaB(CN)H3 (0.1 g) were added. The reaction mixture was refluxed for additional 2 h. Triethylamin (2 ml) was added and the mixture was stirred at R.T for 10 min. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride as eluent. 1.1 g (50%) of the title compound was obtained.
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:39])[C:5](=O)[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]=1.[NH3:40]>C(O)C>[NH2:40][C:5]1[C:4](=[O:39])[C:3](=[O:2])[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[NH:15][CH2:16][CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:9]=1
Reactant: COc1ccc(C(NCC(c2ccccc2)c2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Reactant: N
Solvent: CCO
Product: COc1ccc(C(NCC(c2ccccc2)c2ccccc2)c2cccc(Nc3c(N)c(=O)c3=O)c2)cc1

Procedure:
In a similar manner to that described in Example (1d), 3-methoxy-4-{3-[(4-methoxyphenyl)-(2,2-diphenylethylamino)methyl]phenylamino}-3-cyclobutene-1,2-dione (1.35 g) [prepared as described in step (c) above] and a solution of ammonia in ethanol (2N, 5.2 ml) were reacted, to give the title compound (1.36 g) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:7]=2)[CH:3]=1.[CH3:43][N:44]([Sn](CCCC)(CCCC)CCCC)[CH3:45]>C1(C)C=CC=CC=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.Cl[Pd]Cl>[CH3:43][N:44]([CH3:45])[C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:7]=2)[CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N(C)C
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc2cn(COCC[Si](C)(C)C)nc12
Agent: Cl[Pd]Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(N(C)C)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 120 °C

Procedure:
(±)-tert-Butyl 4-((1-(5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (150 mg, 0.226 mmol), trans-dichlorobis(tri-o-tolylphosphine)palladium (II) (17.79 mg, 0.023 mmol), and dimethylaminotri-n-butyltin (0.28 mL, 0.905 mmol) were combined in toluene (1.5 mL) in a microwave tube and sealed. After flushing the mixture with nitrogen, the mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated, dissolved in ethyl acetate, washed with water and brine, concentrated and purified by flash chromatography on silica gel (15-30% EtOAc/Hex) to afford 115 mg (80.8%) as yellow oil. 1H-NMR (CDCl3, 500 MHz) δ 7.81 (s, 1H), 7.30 (m, 2H), 6.97 (m, 2H), 6.84 (s, 1H), 5.54 (s, 1H), 5.59 (m, 2H), 4.94 (q, J=5 Hz, 1H), 3.6-3.75 (m, 2H), 3.54 (m, 2H), 3.43 (d, J=10 Hz, 1H), 3.31 (d, J=10 Hz, 2H), 3.00-3.10 (m, 2H), 2.81 (s, 6H), 2.03-2.12 (m, 2H), 1.85-1.95 (m, 2H), 1.43 (d, J=10 Hz, 3H), 1.41 (s, 9H), 0.85-0.90 (m, 2H), −0.09 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 171.1, 161.3 (d, J=975 Hz), 155.0, 147.0, 143.4, 139.2, 134.1, 128.9, 123.5, 120.9, 115.4, 115.1, 114.9, 97.2, 81.5, 79.3, 74.4, 67.0, 60.4, 41.9, 41.2, 32.3, 28.5, 27.9, 26.9, 23.1, 21.1, 17.8, 17.6, 14.3, 13.7, −1.36; Mass spec.: 627.60(MH)+.
Reaction SMILES: CI.[Br:3][C:4]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[C:14]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([I:13])[CH:11]=[CH:12][C:4]=1[Br:3]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(I)ccc1Br
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)ccc1Br

Procedure:
Methyl iodide (13 g, 91.5 mmol) is added to slurry of 2-bromo-5-iodobenzoic acid (23 g, 70.4 mmol) and K2CO3 (14.6 g, 106 mmol) in DMF (50 mL) at room temperature. After TLC shows complete consumption of the starting material, the reaction is diluted with Et2O and washed three times with a saturated aqueous solution of NaCl. The combined aqueous layers are extracted once with fresh Et2O and once with EtOAc. The organic layers are combined, dried with Na2SO4, filtered and concentrated to an oil. The oil is diluted with a minimal amount of Et2O and filtered through a plug of silica. The silica is rinsed with a 20% ether/hexanes mixture. The eluents are concentrated in vacuo to give 2-bromo-5-iodobenzoic acid methyl ester as a solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[C:26]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([N:36]4[CH2:35][CH2:34][N:33]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:38][CH2:37]4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Product: CN1CCN(c2cc(N3CCc4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 30 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and 1-Boc-piperazine (Aldrich, Cat. No. 343536). LCMS (M+H)+: m/z=509.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[NH:11][C:10]1=[O:26].[C:27](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:27][N:11]1[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)=[CH:13][C:14](=[O:15])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[F:1])[C:10]1=[O:26]
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(-c2cccc(C(F)(F)F)c2)[nH]c(=O)n1-c1ccc(Cl)cc1F
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(-c2cccc(C(F)(F)F)c2)cc(=O)n(-c2ccc(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.8 %

Procedure:
1.00 g of 3-(2-fluoro-4-chlorophenyl)-6-(3-trifluoromethylphenyl)-2,4(1H,3H)-pyrimidinedione was dissolved in 10 ml of dimethylformamide, followed by addition of 0.48 g of anhydrous potassium carbonate and 0.48 g of methyl iodide, and stirring of the solution at room temperature for 4 hours. The resulting reaction solution was poured into water and the precipitated crystals were filtered out and dried to obtain 0.90 g of the objective compound.
Reaction SMILES: O[CH2:2][C:3]1[S:4][CH:5]=[N:6][N:7]=1.[C:8]([O:12][C:13]([N:15]1[CH2:21][CH2:20][C:19]2[C:22]([S:26]C(=O)N(C)C)=[CH:23][CH:24]=[CH:25][C:18]=2[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[OH-].[K+].S(Cl)([Cl:36])=O>CO>[C:8]([O:12][C:13]([N:15]1[CH2:21][CH2:20][C:19]2[C:22]([S:26][CH2:2][C:3]3[S:4][CH:5]=[N:6][N:7]=3)=[C:23]([Cl:36])[CH:24]=[CH:25][C:18]=2[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: OCc1nncs1
Reactant: CN(C)C(=O)Sc1cccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=S(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3nncs3)c2CC1
Yield: 70 %

Procedure:
Stir 2-hydroxymethyl-[1,3,4]-thiadiazole (241 mg, 2.1 mmol) in thionylchloride (5 mL) for 1 h and concentrate in vacuo. Treat this residue with the thiolate prepared from 3-tert-butoxycarbonyl-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.4 g, 1.04 mmol) and potassium hydroxide (1.37 g, 24.5 mmol) in methanol (3.5 mL) according to General Procedure 7 to give 3-tert-butoxycarbonyl-7-chloro-6-([1,3,4]thiadiazol-2-yl-methylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.3 g, 70%). Treat an aliquot with trifluoroacetic acid to obtain the mass spectrum. MS (ES+) m/z: 312 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:10]=[C:9]([CH2:11][O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6])[CH3:2].[NH2:23][OH:24]>>[CH2:1]([C:3]1[C:4]([C:5](=[N:23][OH:24])[NH2:6])=[CH:7][CH:8]=[C:9]([CH2:11][O:12][Si:13]([CH:14]([CH3:15])[CH3:16])([CH:20]([CH3:21])[CH3:22])[CH:17]([CH3:19])[CH3:18])[N:10]=1)[CH3:2]
Reactant: CCc1nc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1C#N
Reactant: NO
Product: CCc1nc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1C(N)=NO

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1d) using 2-ethyl-6-{[(triisopropylsilyl)oxy]methyl}nicotinonitrile (0.75 g, 2.4 mmol) that was obtained in Example 25 (25a) and a 40% aqueous solution of hydroxylamine (0.5 mL). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:7 to 1:1) as the eluent to afford the title compound (0.80 g) in a yield of 95% as a white crystalline solid.
Reaction SMILES: COC1C=CC(C[N:8]2[C:26](=[O:27])[N:25]3[CH:21]([CH2:22][CH:23]([O:28][C:29]4[CH:34]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:32]=[C:31]([O:41][CH3:42])[N:30]=4)[CH2:24]3)[C:20](=[O:43])[NH:19][C:18]3([C:44]([NH:46][S:47]([CH:50]4[CH2:52][CH2:51]4)(=[O:49])=[O:48])=[O:45])[CH:16]([CH2:17]3)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=CC=1.C(Cl)Cl.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[CH3:42][O:41][C:31]1[N:30]=[C:29]([O:28][CH:23]2[CH2:22][CH:21]3[N:25]([C:26](=[O:27])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH:16]4[C:18]([C:44]([NH:46][S:47]([CH:50]5[CH2:51][CH2:52]5)(=[O:48])=[O:49])=[O:45])([NH:19][C:20]3=[O:43])[CH2:17]4)[CH2:24]2)[CH:34]=[C:33]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:32]=1
Reactant: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)NS(=O)(=O)C3CC3)NC(=O)C3CC(Oc4cc(-c5ccccc5)nc(OC)n4)CN3C2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCCNC(=O)N3C2)cc(-c2ccccc2)n1
Yield: 16 %

Procedure:
Compound 2e was dissolved in a 1:2 mixture of TFA:DCM (12 ml) and stirred at RT for 1 h. NaHCO3 was added and the organic layer was separated, dried, filtered and evaporated. The residue was purified by preparative HPLC which gave the pure title compound (32 mg, 16% over two steps). MS (M+H)+639.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[K+].[K+]>CC#N.O>[CH3:18][O:17][C:15](=[O:16])[CH2:14][N:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CCC1CCCN1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CCC1CCCN1CC(=O)OC

Procedure:
A solution of ethyl 3-(pyrrolidin-2-yl)propanoate (3 g, 17.5 mmol), methyl 2-bromoacetate (3 g, 18 mmol) and K2CO3 (3 g, 21.7 mmol) in CH3CN was stirred at 80° C. overnight. The completion of the reaction was monitored by TLC. After the suspension was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL), the combined organic layers were concentrated to give the crude product, which was directly used for the next step without further purification. MS (ESI): 244 (MH+).