Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11].[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>C(Cl)Cl>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([N:22]2[CH2:23][CH2:24][CH:25]([NH:28][C:29](=[O:32])[CH:30]=[CH2:31])[CH2:26][CH2:27]2)(=[O:20])=[O:21])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
Diisopropylethylamine (6.8 ml, 41.5 mmol) was added in one portion to a stirred solution of 1-(4-nitro-benzenesulfonyl)-piperidin-4-ylamine (2.36 g, 8.3 mmol) in DCM (10 ml) followed by the drop wise addition of acryloyl chloride (0.78 ml, 9.1 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the resulting precipitate was collected by filtration, washed with water and dried under vacuum to give the title compound (2.80 g, 98% yield) as a white solid. δH (500 MHz, DMSO) 8.39-8.51 (m, 2 H) 7.95-8.10 (m, 3 H) 6.11-6.21 (m, 1 H) 6.01-6.10 (m, 1 H) 5.56 (dd, J=10.09, 2.20 Hz, 1 H) 3.61-3.68 (m, 1 H) 3.52-3.60 (m, 2 H) 2.56-2.66 (m, 2 H) 1.83 (dd, J=13.20, 3.30 Hz, 2 H) 1.36-1.47 (m, 2 H). Tr=1.63 min, m/z (ES+) (M+H)+ 340.
Reaction SMILES: I[CH2:2]I.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH:14]=[CH2:15])[CH:6]=1.Cl>C(Cl)Cl>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH:14]2[CH2:2][CH2:15]2)[CH:6]=1
Reactant: ICI
Reactant: C=COc1cc(Br)ccc1OC
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(Br)cc1OC1CC1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 69.5 %

Procedure:
Into a 25 mL flame-dried flask were added diethylzinc (8.75 mL, 1 N solution in hexanes). The solution was cooled to −20° C. and a solution of trichloroacetic acid (1.43 g, 8.75 mmol, dissolved in 2 mL of CH2Cl2 was added dropwise over 10 min, then the solution was stirred an additional 20 min. A solution of diiodomethane (2.38 g, 8.89 mmol) in 1 mL CH2Cl2 was then added dropwise and the solution was stirred an additional 20 minutes. A solution of 4-bromo-1-methoxy-2-vinyloxy-benzene (1.029 g, 4.365 mmol, dissolved in 900 uL CH2Cl2) was then added and the reaction mixture was stirred for 8 h at room temperature. The reaction mixture was poured onto a 100 mL 1 N aqueous HCl solution containing some ice, then extracted 3× with EtOAc. The combined organic phase was washed with 1 N aqueous NaHCO3, brine, then dried (MgSO4), filtered and concentrated. Purification by flash column on silica gel (0-100% Hexanes/EtOAc gradient) to afford titled compound as a colorless crystalline solid (738 mg, 67%). 1H NMR (DMSO-d6) 7.33 (s, 1H), 7.06 (d, J=8.4, 1H), 6.90 (d, J=8.4, 1H), 3.84 (m, 1H), 3.70 (s, 3H), 0.75 (m, 2H), 0.64 (m, 2H). LC/MS (Method B) 3.64 min, [M+1]+ 243/245.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]=1[O:11][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1cccc(O)c1O
Product: COC(=O)c1cccc(OCc2ccccc2)c1OCc1ccccc1

Procedure:
In one embodiment, the compounds can be prepared as shown in Scheme II. A dihydroxy benzoic acid methyl ester is reacted with benzyl chloride, to produce a Bis-benzyloxy benzoic acid methyl ester (1). The Bis-benzyloxy benzoic acid methyl ester can then be heated with LiOH to give a Bis-benzyloxy benzoic acid (2). The Bis-benzyloxy benzoic acid (2) is then reacted with an aminophenyl to produce a phenyl-benzamide (3). The phenyl-benzamide (3) is then reacted with hydrazine to give a triazol (4). The hydroxy groups can then be unprotected in the presence of palladium on charcoal to give the final product.
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([CH3:20])=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:15][C:9]=2[CH2:8][CH2:7]1)=O)C.CCO.[OH-].[K+]>O>[C:16]([C:14]1[S:15][C:9]2[CH2:8][CH2:7][NH:6][CH2:12][CH2:11][C:10]=2[C:13]=1[CH3:20])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)N1CCc2sc(C(C)(C)C)c(C)c2CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(C)(C)C)sc2c1CCNCC2
Temperature: 100 °C

Procedure:
The product of step b) was treated with 2 mL each of EtOH and 40% aqueous KOH. After heating to 100° C. for 12 hours, the reaction was cooled, diluted with water, and extracted 2× into DCM. The title product was purified by preparative HPLC-MS. MS: ESI (positive): 224 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:28])[C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:26]=2)=[O:19])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)Nc2ccc(O)cc2)CC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(NC(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-N-(4-hydroxyphenyl)-2-oxoacetamide (Example 199, 0.40 g, 1.05 mmol), methyl bromoacetate (0.18 g, 1.15 mmol) and potassium carbonate (0.29 g, 2.1 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 80:20 to 35:65) to give the title compound (0.32 g, 67%) as a colorless amorphous.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[CH3:7][C@@H:8]([C@@H:15]1[C@@:19]2([CH3:37])[CH2:20][CH2:21][CH:22]3[C@@:27]4([CH3:36])[CH2:28][CH2:29][CH:30]([O:32][C:33](Cl)=[O:34])[CH2:31][C:26]4=[CH:25][CH2:24][CH:23]3[CH:18]2[CH2:17][CH2:16]1)[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:33]([O:32][C@H:30]1[CH2:29][CH2:28][C@@:27]2([CH3:36])[C:26](=[CH:25][CH2:24][C@@H:23]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:37])[C@H:18]3[CH2:17][CH2:16][C@@H:15]2[C@H:8]([CH3:7])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:31]1)=[O:34]
Reactant: NCC(O)CO
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCC(O)CO)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
3-Amino-1,2-propanediol (2.0 g, 22.0 mmoles) is coevaporated twice with dry pyridine (50 mL each) then dissolved in dry pyridine (147 mL). The solution is stirred in an ice bath, and a solution of cholesteryl chloroformate (10.4 g, 23.1 mmoles) in toluene (50 mL) is added dropwise over 30 minutes. After addition, the ice bath is removed and the reaction mixture is stirred at ambient temperature for 16 hours. The solution is then evaporated, and the residue is coevaporated twice with toluene (50 mL each). The crude product is purified on silica gel (300 mL bed volume) eluting with hexanes:acetone (90:10 [v/v], 1000 mL; then 85:15 [v/v], 1000 mL; then 70:30 [v/v], 1000 mL; then 65:35 [v/v], 1000 mL). Fractions containing pure product by thin layer chromatography are pooled and evaporated to syrup which is dried well in vacuo. The yield is 5.7 g (51%).
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:10][OH:11].C([O-])([O-])=O.[K+].[K+].O>C(O)C>[OH:11][NH:10][C:1](=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 305.6 %

Procedure:
Benzonitrile (1 ml, 9.79 mmol) was mixed with hydroxylamine hydrochloride (1.36 g, 1.96 mmol) and K2CO3 (2.71 g, 1.96 mmol) in anhydrous ethanol (15 ml). The solution was stirred at 80° C. for 16 hr. Water was added and the aqueous phase was extracted with EtOAc (3×), dried over MgSO4 and the volatiles removed in vacuo to give a viscous oil (816 mg, 5.99 mmol, 62%). The compound 10A was used for next step without any further purification. HPLC (4 minutes gradient) tR 0.62 min; MS m/z 137.06 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:17]=[C:16]1[CH2:28][CH2:29][CH3:30].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:55]>>[NH2:55][C:19]1[C:18]2[N:17]=[C:16]([CH2:28][CH2:29][CH3:30])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([NH:2][CH3:1])=[O:31])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCCCCCCCC(=O)NC
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCCCCC(=O)NC

Procedure:
N-Methyl-12-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)dodecanamide (3.8 g, 9.0 mmol) was treated with mCPBA (4.65 g, 26.9 mmol) followed by ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (2.31 g, 12.1 mmol) according to the method described in Part D of Example 8. The crude product was purified as described in Part D of Example 8 to provide 1.036 g of 12-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-methyldodecanamide as a brown crystalline solid, mp 135-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7](=O)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7](=[S:19])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1Nc2ccc(Cl)cc2Nc2ccccc21
Solvent: c1ccncc1
Product: S=C1Nc2ccc(Cl)cc2Nc2ccccc21
Reaction time: 1 h

Procedure:
A mixture of 7-chloro-5,10-dihydro-11H-dibenzo[b,e]-[1,4]diazepin-11-one (30.5 g., 0.125 mole), phosphorus pentasulfide (27.8 g., 0.131 mole) and one l. of pyridine is heated at reflux temperature for 4 hours and the pyridine is evaporated in vacuo. The residue is stirred for 1 hour with one l. each of saturated aqueous sodium bicarbonate and methylene chloride and filtered to remove some solid product. The organic layer of the filtrate is washed successively with sodium bicarbonate solution and with saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue is combined with the solid obtained above and triturated with hot chloroform and methanol. In this way, 12.2 g. of 7-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione of melting point 274°-275° C is obtained. Concentration of the chloroform-methanol washings affords an additional 8.4 g. of product having the same melting point. Recrystallization from dimethylformamide-water gives an analytically pure sample in the form of pale yellow needles of melting point 276°-277° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13]2)[C:9](O)=[O:10])=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13]2)[C:9]([Cl:27])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)C(c1ccc(Cl)cc1)C1CCC(F)(F)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C(c1ccc(Cl)cc1)C1CCC(F)(F)C1
Reaction time: 1 h

Procedure:
470 mg (1.71 mmol) of (4-chlorophenyl)(3,3-difluorocyclopentyl)acetic acid were dissolved in 8 ml of dichloromethane, and a drop of DMF was added. At 0° C., 1.7 ml (3.42 mmol) of oxalyl chloride were then slowly added dropwise, and the mixture was stirred at this temperature for 1 h. After the reaction had gone to completion, the reaction solution was evaporated under reduced pressure and the residue obtained was taken up in 50 ml of dichloromethane and then once more evaporated to dryness. This gave 500 mg (99% of theory) of the title compound as a colourlees oil. The product obtained in this manner was used without further purification and without further spectroscopic characterization in subsequent reactions.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:12]2[NH:11][CH2:10][CH2:9]1.ClCCC(NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C(N)=O)=C3NCC2)C=CC=1)=[O:36]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)[C:16]([C:17]([NH2:18])=[O:36])=[C:12]2[NH:11][CH2:10][CH2:9]1
Reactant: N#Cc1c(-c2ccc(OC3CCOCC3)cc2)nn2c1NCCC2c1ccccc1N
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Product: NC(=O)c1c(-c2ccc(OC3CCOCC3)cc2)nn2c1NCCC2c1ccccc1N

Procedure:
The desired product was prepared from 7-(2-aminophenyl)-2-(4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile using the procedure similar to step 2 for compound 2. 1H NMR (400 MHz, DMSO-d6) δ 7.38 (d, J=8.8 Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 6.95 (t, J=7.6 Hz, 1H), 6.75 (s, 1H), 6.67 (d, J=7.8 Hz, 1H), 6.49 (t, J=7.6 Hz, 1H), 6.26 (d, J=7.8 Hz, 1H), 5.56 (s, 1H), 5.16 (s, 2H), 4.64-4.54 (m, 1H), 3.91-3.79 (m, 2H), 3.53-3.42 (m, 2H), 3.29-3.19 (m, 1H), 3.01-2.92 (m, 1H), 2.25-2.05 (m, 2H), 2.02-1.91 (m, 2H) and 1.64-1.52 (m, 2H). MS (ESI) m/e [M+1]+ 433.9.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][C:19](O)=[O:20]>>[C:1]([C:5]1[C:6]([NH:14][C:19](=[O:20])[CH2:18][CH2:17][C:16]([CH3:23])([CH3:22])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Reactant: CC(C)(C)CCC(=O)O
Product: CC(C)(C)CCC(=O)Nc1nn2cccnc2c1C(C)(C)C

Procedure:
The product from Example 105B and 4,4-dimethylpentanoic acid were processed using the method analogous to that described in Example 137 to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.89 (s, 9H), 1.44 (s, 9H), 1.48-1.53 (m, 2H), 2.23-2.27 (m, 2H), 6.99 (dd, J=7.1, 4.0 Hz, 1H), 8.48 (dd, J=4.0, 2.0 Hz, 1H), 8.92 (dd, J=6.9, 1.8 Hz, 1H), 9.69 (s, 1H); MS (DCI) m/z 303 (M+H)+.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:10]([I:11])[C:4]=2[N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:29][OH:30])[CH:20]=[N:21][C:22]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Cl:16][C:17]1[CH:18]=[C:19]([CH2:29][OH:30])[CH:20]=[N:21][C:22]=1[N:23]1[CH2:28][CH2:27][N:26]([C:2]2[NH:3][C:4]3[C:10]([I:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][C:5]=3[N:6]=2)[CH2:25][CH2:24]1
Reactant: FC(F)(F)c1cc(I)c2nc(Cl)[nH]c2c1
Reactant: OCc1cnc(N2CCNCC2)c(Cl)c1
Product: OCc1cnc(N2CCN(c3nc4cc(C(F)(F)F)cc(I)c4[nH]3)CC2)c(Cl)c1

Procedure:
The benzoimidazole from step (c) above (69 mg, 0.2 mmol) reacted with (5-chloro-6-piperazin-1-yl-pyridin-3-yl)methanol (68 mg, 0.3 mmol, Example 60c) under the conditions of Example 3c to give the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 538 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:20][O:21][CH2:22][CH2:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1>>[CH3:20][O:21][CH2:22][CH2:23][N:24]1[CH:28]=[C:27]([C:2]2[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=2)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:26]=[N:25]1
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc(Br)c1
Product: COCCn1cc(-c2cccc(CCOCCC(=O)OC(C)(C)C)c2)cn1

Procedure:
The subtitled compound (834 mg) was prepared from tert-butyl 3-(3-bromophenethoxy)propanoate [Preparation 3, Step i)] and 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole using a similar method to that described in Example 18, Step i). MS M+H-C4H8]+=319 (MultiMode+) 1H NMR (300 MHz, CDCl3) δ 7.78 (s, 1H), 7.72 (s, 1H), 7.37-7.22 (m, 3H), 7.07 (d, J=7.5 Hz, 1H), 4.32 (t, J=5.2 Hz, 2H), 3.78 (t, J=5.3 Hz, 2H), 3.70 (t, J=6.5 Hz, 2H), 3.68 (t, J=7.5 Hz, 2H), 3.35 (s, 3H), 2.89 (t, J=7.2 Hz, 2H), 2.49 (t, J=6.4 Hz, 2H), 1.47 (s, 9H)
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])=[CH:10][CH:9]=2)[C:5]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:4][N:3]=1.Br[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:28]=O>C(O)C>[CH2:22]([C:5]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])=[CH:12][CH:13]=2)[C:2]2[N:3]([C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:28][N:1]=2)[N:4]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCc1nnc(N)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=CC(Br)c1ccccc1
Solvent: CCO
Product: CCCCc1nn2c(-c3ccccc3)cnc2n1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 23.6 %

Procedure:
A mixture of 212 mg (0.640 mmole) of 3-amino-5-butyl-4-[(2'-cyanobiphenyl-4-yl)methyl]-4H-1,2,4-triazole (from Example 1, Step D), 151 mg (0.757 mmol) of α-bromophenylacetaldehyde [T. L. Jacobs and W. R. Scott, Jr., J. Am. Chem. Soc., 75, 5500 (1953)], and 2.0 ml of absolute ethanol was stirred at reflux under N2 for 6 hours. The mixture was cooled and concentrated in vacuo. The residue was chromatographed on a column of silica gel (27×2.5 cm) packed in CH2Cl2 (elution with 1% and then 4% MeOH in CH2Cl2). Concentration of the appropriate pooled product fractions afforded 65.3 mg (24%) of the title compound as a yellow oil; homogeneous by TLC in 19:1 CH2Cl2 -MeOH.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.O.C(N=C=NCCCN(C)C)C.[N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][NH2:50])[CH:44]=1>CN(C=O)C>[Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:50][CH2:49][C:45]3[CH:44]=[N:43][CH:48]=[CH:47][CH:46]=3)=[O:18])=[CH:19][CH:20]=2)=[N:4][CH:3]=1
Reactant: O=C(O)c1ccc(Nc2ncc(Br)n3ncnc23)cc1
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1cccnc1)c1ccc(Nc2ncc(Br)n3ncnc23)cc1
Yield: 82.3 %

Procedure:
A solution of 4-(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)-benzoic acid (0.230 g, 0.69 mmol), 3-hydroxybenzotriazole (0.103 g, 0.76 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrate (0.146 g, 0.76 mmol) in DMF (5 mL) and 3-picolylamine (0.077 mL, 0.76 mmol) is stirred at room temperature for 21 hours. The solvent is removed in vacuo and the residue is triturated with diethyl ether, ethyl acetate and dichloromethane. A pale yellow solid is obtained, washed with water and dried to afford the title compound (241 mg, 82%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10].[N+](=[CH2:14])=[N-]>C(OCC)C>[C:7]([C:6]1[N:2]([CH3:1])[C:3]([N+:9]([O-:11])=[O:10])=[N:4][CH:5]=1)(=[O:8])[CH3:14]
Reactant: Cn1c(C=O)cnc1[N+](=O)[O-]
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CC(=O)c1cnc([N+](=O)[O-])n1C
Temperature: 0 °C
Reaction time: 168 h

Procedure:
To a solution of 0.70 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde in 180 ml. of diethyl ether, a solution of 0.43 g. of diazomethane in 86 ml. of diethyl ether is added under cooling at about 0° C. After standing at room temperature for 7 days, the reaction mixture is filtered and then evaporated to dryness. The residue (0.60 g.), dissolved, in 6 ml. of chloroform, is chromatographed on 6 plates of silica gel, eluting with a 9:1 (v/v) chloroform:methanol mixture, and TLC spots are visualized under U.V. light. The silica gel, which corresponds to an Rf value from 0.64 up to 0.76 is collected and extracted with methanol. From this solution, after filtration and concentration, 0.065 g. of 5-acetyl-1-methyl-2-nitroimidazole is obtained, m.p. 81°-83° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=2)=[O:5])C.[Li+].[OH-].Cl>O1CCCC1.C(O)C>[C:16]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:15]2)#[N:17]
Reactant: CCOC(=O)c1cnc2ccc(C#N)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccc2ncc(C(=O)O)cc2c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 107 %

Procedure:
To a solution of 6-cyano-quinoline-3-carboxylic acid ethyl ester (1.28 g) in tetrahydrofuran (6 ml) and ethanol (6 ml) was added a 1M aqueous LiOH solution (6.79 ml) at 0° C. The mixture was stirred at 0° C. for 1.5 h, then the mixture was acidified with 1M aqueous HCl. The precipitate was filtered off, washed with water and a small amount of ether and dried to give the crude title compound (1.2 g) as an off-white solid that was used in the next step without further purification. MS (m/e, ISP neg. ion)=197.2 [M−H+].
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH3:14])[C:10](=[O:15])[C:9]([F:17])([F:16])[CH2:8][N:7]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:6]=2[N:23]=1.[NH2:24][C:25]1[CH:40]=[CH:39][C:28]([C:29]([NH:31][CH:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[O:30])=[CH:27][C:26]=1[O:41][CH3:42].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:18]1([N:7]2[CH2:8][C:9]([F:17])([F:16])[C:10](=[O:15])[N:11]([CH2:12][CH2:13][CH3:14])[C:5]3[CH:4]=[N:3][C:2]([NH:24][C:25]4[CH:40]=[CH:39][C:28]([C:29]([NH:31][CH:32]5[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]5)=[O:30])=[CH:27][C:26]=4[O:41][CH3:42])=[N:23][C:6]2=3)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc21
Yield: 59.5 %

Procedure:
A mixture of 0.05 g (0.15 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-propyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-144), 0.05 g (0.17 mmole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.04 g (0.22 mmole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 160 degrees for 2 hours in a microwave reactor. The cooled reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient, 0:100-25:75) to give 0.051 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-5-propyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-165).