Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:38][O:39][C:40]([C:43]([O:45]C(C)(C)C)=[O:44])([CH3:42])[CH3:41])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:38][O:39][C:40]([C:43]([OH:45])=[O:44])([CH3:41])[CH3:42])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC(C)(C)C(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC(C)(C)C(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 40.9 %

Procedure:
To a mixture of benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (3.9 g) and anisole (3.9 ml) was added trifluoroacetic acid (15.6 ml) under ice-cooling, and the mixture was stirred at ambient temperature for an hour. To the reaction mixture was added diisopropyl ether and the precipitated crystals were collected by filtration and then washed with diisopropyl ether. To the crystals were added ethyl acetate and water, followed by adjusting to pH 7.5 with sodium bicarbonate. The separated solution was washed with ethyl acetate and then adjusted to pH 2.5 with 10% hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and then dried to obtain 7-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.09 g), mp 173°-177° C. (dec.). The filtrate and the washings were combined with saturated with sodium chloride, followed by extraction with tetrahydrofuran. The extract was washed with a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then evaporated to dryness to give a residue, which was pulverized with diisopropyl ether and collected by filtration to recover the same object compound (0.59 g). Total yield: 1.68 g.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([CH2:41][CH2:42][O:43]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1.CN(C=[O:58])C>>[CH:42]([OH:43])=[O:58].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([CH2:41][CH2:42][N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCOS(C)(=O)=O)c4ccccc43)cn12
Reactant: C1CCNCC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCN4CCCCC4)c4ccccc43)cn12
Product: O=CO
Yield: 52 %

Procedure:
A yellow solution of Intermediate 127a (0.100 mmol) and piperidine (0.049 mL, 0.50 mmol) in dry DMF (2 mL) was stirred at 75° C. for 2.5 h. The cooled solution was concentrated in vacuo, redissolved in MeOH (2 mL), applied to an SCX-2 cartridge (2 g) and washed with MeOH (20 mL). The product was eluted with 2M NH3 in MeOH (15 mL); concentration in vacuo left a yellow solid. MDAP (Method 7) gave the title compound as an off-white solid (37 mg, 52%). LCMS (Method 5): Rt 3.68 min, m/z 654.5 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.3 Hz), 1.20 (9H, s), 1.33-1.38 (2H, m), 1.45-1.55 (6H, m), 1.63-1.72 (2H, m), 1.75-1.86 (2H, m), 1.89-2.02 (2H, m), 2.04-2.12 (1H, m), 2.14-2.21 (1H, m), 2.40 (4H, t, J=4.7 Hz), 2.61 (2H, t, J=7.1 Hz), 2.91 (1H, ddd, J=12.2, 9.2, 4.2 Hz), 3.16 (1H, dt, J=12.0, 4.3 Hz), 3.32 (1H, m), 3.99 (2H, t, J=7.1 Hz), 4.87 (1H, td, J=8.5, 5.7 Hz), 5.54 (1H, t, J=4.3 Hz), 6.04 (1H, s), 6.95 (1H, d, J=8.6 Hz), 7.22 (1H, dd, J=9.8, 2.2 Hz), 7.29 (1H, td, J=7.2, 1.8 Hz), 7.34-7.41 (3H, m), 7.65 (1H, dd, J=9.8, 0.8 Hz), 7.71 (1H, d, J=2.1 Hz), 8.16 (1.4H, s), 8.29 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:18][CH2:17][CH2:16][CH:10]2[CH2:11][NH:12][CH2:13][CH2:14][CH2:15]3)[CH:6]=[CH:7][CH:8]=1.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1.CN(C)C=O>C(N(CC)CC)C>[CH:19]1([C:22]([N:12]2[CH2:13][CH2:14][CH2:15][C:9]3([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:18][CH2:17][CH2:16][CH:10]3[CH2:11]2)=[O:23])[CH2:21][CH2:20]1
Reactant: COc1cccc(C23CCCNCC2CCC3)c1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc(C23CCCC2CN(C(=O)C2CC2)CCC3)c1

Procedure:
A solution of 1.1 g. of 5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine and 1.3 g. of cyclopropylformyl chloride in 20 ml. of N,N-dimethylformamide containing 1.4 g. of triethylamine was stirred at 25° C. for eight hours. The reaction mixture then was added to 200 ml. of water, and the aqueous solution was extracted several times with diethyl ether. The ethereal extracts were combined, and the solvent was removed therefrom by evaporation under reduced pressure to provide 2-cyclopropylformyl-5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine. The product so formed was dissolved in 70 ml. of tetrahydrofuran containing 1 g. of lithium aluminum hydride, and the reaction mixture was heated at reflux and stirred for three hours. The reaction mixture was then cooled to 25° C. and diluted by the dropwise addition of 30 ml. of ethyl acetate. The tetrahydrofuran solution was decanted, diluted with diethyl ether, washed with water, and dried. Removal of the solvent by evaporation under reduced pressure provided 2-cyclopropylmethyl-5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine as an oil. The oil so formed was dissolved in 50 ml. of diethyl ether through which was bubbled hydrogen chloride gas, thus forming the hydrochloride salt of the above-named compound, which precipitated out of solution. The precipitate was collected by filtration and recrystallized from 25 ml. of diisopropyl ether and 100 ml. of ethyl acetate to afford 0.75 g. of ethyl acetate to afford 0.75 g. of 2-cyclopropylmethyl-5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine hydrochloride. M.P. 154°-156° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29]>C[O-].[Na+].CO>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCCC(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 23.7 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (88 mg, 0.27 mmol) and beta-alanine (122 mg, 1.38 mmol) in 2.2 ml of 0.5 M NaOMe/MeOH solution was microwaved at 120° C. for 10 min. Reaction mixture was concentrated. The residue was dissolved in water (80 ml) and extracted with EtOAc, which was discarded. The aqueous layer was acidified by 1 N HCl to pH=3-4 and extracted with EtOAc. Organic layer was dried over MgSO4, filtered and concentrated. The crude product was triturated with hot MeOH and then CH2Cl2. Solid was collected and dried to provide the title compound 24 mg (0.064 mmol) in 24% yield.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)[CH3:12]>O1CCCC1.Cl>[C:1]([NH:9][N:10]=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccccc1
Reactant: NNC(=O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=NNC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of benzoic acid hydrazide (5.70 g, 0.042 mol) in tetrahydrofuran (75 mL) was added acetophenone (5.5 g, 0.046 mol) followed by concentrated HCl (3 drops). The reaction was allowed to stir for 12 h at 25° C. during which time the product precipitated as a colorless crystalline solid. The product was filtered, washed with tetrahydrofuran (1×30 mL), diethyl ether (3×60 mL) and pentane (2×60 mL), and the crystalline solids were dried in vacuo (6.65 g, 64%). 1H NMR (CD2Cl2): δ2.35 (s, 3H, CH3), 7.30-8.0 (m, 10H, Ph), 9.0 (br, 1H, NH). All other substrates were prepared in a similar fashion.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[N:16]([CH3:21])[CH2:17][CH2:18][C:19]#[N:20])[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:37]=[CH:36][C:27]2[NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])([CH3:33])[C:26]=2[CH:25]=1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[N:16]([CH3:21])[CH2:17][CH2:18][C:19]#[N:20])=[N:7][C:2]([NH:23][C:24]2[CH:37]=[CH:36][C:27]3[NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:33])([CH3:34])[C:26]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: CN(CCC#N)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CN(CCC#N)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl

Procedure:
Title compound was prepared from 3-{[2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-phenyl]-methyl-amino}-propionitrile and 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one in an analogous manner to Example 1221d. Title compound isolated as a white lyophilate (40 mg, 33%). 99% purity, LCMS (510.19 M+H), 1H-NMR (CDCl3, 400 MHz) δ 12.00 (s, 1H), 7.92 (s, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.42-7.37 (m, 3H), 7.02-6.97 (m, 2H), 6.66 (d, J=9.0 Hz, 1H), 3.28 (t, J=6.4 Hz, 2H), 2.73 (s, 3H), 2.53 (t, J=6.6 Hz, 2H), 2.36 (t, J=6.8 Hz, 2H), 2.06 (t, J=6.9 Hz, 2H), 1.27 (s, 6H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:21]=[CH:20][C:15]([CH:16]=[CH:17][CH2:18][OH:19])=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH:16]=[CH:17][CH:18]=[O:19])=[CH:20][CH:21]=1
Reactant: OCC=Cc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=CC=Cc1ccc(Cl)cc1
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
A solution of oxalyl chloride (2.6 mL, 30 mmol) in methylene chloride was cooled to −70° C. in a dry ice/acetone bath and DMSO (4.2 mL, 60 mmol) was added slowly. After 10 minutes, a solution of 4-chlorocinnamyl alcohol (2.0 g, 12 mmol) from Step A in methylene chloride (12 mL) was added. The reaction was stirred at −70° C. for 80 min and then DIPEA (20 mL, 120 mmol) was added. After 5 min, the reaction was allowed to warm to rt over 2 h. The mixture was diluted with methylene chloride and washed with cold 2N hydrochloric acid (80 mL). The organic layer was washed with brine containing some aq. sodium bicarbonate, dried over sodium sulfate, and evaporated. The residue was purified by FC (0 to 10% ethyl acetate in hexanes) to give the title compound as a white solid. 1HNMR (CDCl3): δ 6.71 (dd, J=7.7 and 16.0 Hz, 1H), 7.450 (d, J=16 Hz, 1H), 7.43 and 7.52 (Abq, J=8.4 Hz, 4H), 9.72 (d, J=7.6 Hz, 1H).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][C:5]=2[N:6]=1.[Cl:16][C:17]1[C:18]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1>>[Cl:11][C:9]1[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][C:5]2[NH:6][C:2]([N:27]3[CH2:28][CH2:29][N:24]([C:18]4[C:17]([Cl:16])=[CH:22][C:21]([Cl:23])=[CH:20][N:19]=4)[CH2:25][CH2:26]3)=[N:3][C:4]=2[CH:10]=1
Reactant: FC(F)(F)c1cc2nc(Cl)[nH]c2cc1Cl
Reactant: Clc1cnc(N2CCNCC2)c(Cl)c1
Product: FC(F)(F)c1cc2[nH]c(N3CCN(c4ncc(Cl)cc4Cl)CC3)nc2cc1Cl

Procedure:
2,5-Dichloro-6-(trifluoromethyl)benzoimidazole (255 mg, 1.0 mmol, Example 84c) reacted with 1-(3,5-dichloropyridin-2-yl)piperazine (232 mg, 1.0 mmol, Example 9a) under the conditions of Example 3c to give the title compound as a white solid. M.p. 93.5-196.4° C. MS (ESI, pos. ion) m/z: 452.0, 454.1 (M+1).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:14][CH2:15][OH:16])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OCCCl
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OCCOc1ccc(-n2ccnc2)cc1
Yield: 49.9 %

Procedure:
A stirred mixture of 8.0 g (0.050 mole) of 4-(1H-imidazol-1-yl)phenol, 13.5 ml (0.20 mole) of 2-chloroethanol and 28 g (0.2 mole) of potassium carbonate in 200 ml of methyl ethyl ketone was heated at reflux, filtered, and concentrated to obtain 5.1 g of 2-[4-(1H-imidazol-1-yl)phenoxy]ethanol (50%). This alcohol (0.25 mole) and 5.2 g (0.030 mole) of sulfamic acid phenyl ester in 100 ml of dioxane was heated at reflux for 20 minutes, concentrated and the residual solid triturated in acetone. The triturant was acidified with an anhydrous solution of hydrogen chloride in isopropyl alcohol and the solid hydrochloride collected by filtration. The product was recrystallized from isopropyl alcohol-isopropyl ether to yield 4.26 g of solid, mp 156°-157° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]#[N:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:14]([OH:16])[CH3:15].C([Cl:20])(=O)C>>[ClH:20].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12](=[NH:13])[O:16][CH2:14][CH3:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C#N)CC2)cc1
Reactant: CCO
Reactant: CC(=O)Cl
Product: CCOC(=N)C1(c2ccc(OC)cc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 109.5 %

Procedure:
To a cooled solution of 1-(4-methoxyphenyl)cyclopropanecarbonitrile (35 mg, 0.2 mmol) in ethanol (100 μL, 2 mmol) was added acetyl chloride (170 μl, 2.39 mmol). The mixture was shaken at room temperature for 16 h, then was concentrated in vacuo and dried. To the residue was added a freshly prepared saturated solution of hydrogen chloride in ethanol (1 mL). After 16 h, the reaction mixture was concentrated under reduced pressure to afford the title compound (56 mg) as an oil which was used without further purification.
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1.[CH3:32][N:33]([CH3:38])[CH2:34][C:35](O)=[O:36].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[F:31][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH:21]3[CH2:26][CH2:25][N:24]([C:35](=[O:36])[CH2:34][N:33]([CH3:38])[CH3:32])[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1
Reactant: CN(C)CC(=O)O
Reactant: FC(F)c1nc2ccccc2n1-c1cc(N2CCOCC2)nc(NC2CCNCC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCC(Nc2nc(N3CCOCC3)cc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.7 %

Procedure:
To a mixture of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-piperidin-4-ylpyrimidin-2-amine (18 mg) and N,N-dimethylformamide (0.36 mL) were added N,N-dimethylglycine (4.8 mg), 1-hydroxybenzotriazole (6.2 mg), and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (8.8 mg), and the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by amino silica gel column chromatography (ethyl acetate, and subsequently chloroform:methanol=96:4). Desired fractions were combined and concentrated under reduced pressure. The residue was solidified by the addition of a small amount of diisopropyl ether to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-{1-[(dimethylamino)acetyl]piperidin-4-yl}-6-morpholin-4-ylpyrimidin-2-amine (9 mg) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=O)=[CH:5]2.P(Cl)(Cl)(Cl)=O.C(Cl)(Cl)Cl>O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]#[N:13])=[CH:5]2
Reactant: Cc1ccc2[nH]c(C(N)=O)cc2c1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2[nH]c(C#N)cc2c1
Reaction time: 1 h
Yield: 80.4 %

Procedure:
A mixture of 340 mg of 5-methylindole-2-carboxamide (1.95 mmol), 1.5 g of phosphorus oxychloride (9.75) and 8 mL of chloroform was refluxed for 2 hs. Then cooled solution was poured into 20 mL of water and stirred for 1 hr. After separation the organic layer was dried over sodium sulfate and concentrated. The residue was purified on silica gel column using hexane-ethyl acetate 5:1 to afford 245 mg of 5-methyl-1H-indole-2-carbonitrile. 1H NMR (600 MHz, CDCl3): δ 8.61 (br, 1H), 7.44 (s, 1H), 7.30 (d, 1H, J=8.4 Hz), 7.21 (d, 1H, J=8.4 Hz), 7.11 (s, 1H), 2.44 (s, 3H). 13C NMR (150 MHz, CDCl3): δC 135.34, 131.25, 128.28, 126.53, 121.33, 114.41, 113.95, 111.39, 106.11, 21.36.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.CN([CH:17]=[O:18])C>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:17]=[O:18])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Product: O=Cc1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 2,5-dibromopyridine (1.0 eq.) in Tol (O. 1M) at −78° C. was added n-BuLi (1.0Seq.). The mixture was stirred for 2 h at −78° C. then DMF (3.0 eq.) was added. The final mixture was stirred for 12 h at −78° C., quenched using saturated aqueous NH4Cl and extracted with Et2O (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9:1) afforded the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][OH:20])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1.[CH2:21](Br)[C:22]#[CH:23]>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:23][C:22]#[CH:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1
Reactant: C#CCBr
Reactant: COCCc1nc2cnc3ccccc3c2n1CCO
Product: C#CCOCCn1c(CCOC)nc2cnc3ccccc3c21
Yield: 94.2 %

Procedure:
Using the general method of Example 1 Part 2-[2-(methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethanol (2.53 g, 9.33 mmol) was reacted with propargyl bromide (80% in toluene, 3.11 mL, 27.9 mmol) to provide 2.72 g of 2-(methoxyethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline as an oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)=[O:3].[CH2:16]=O.Cl.[CH3:19][NH:20][CH3:21].Cl>C(O)C.O>[CH3:19][N:20]([CH2:16][CH2:1][C:2]([C:4]1[CH:5]=[C:6]([O:14][CH3:15])[C:7]([O:12][CH3:13])=[C:8]([O:10][CH3:11])[CH:9]=1)=[O:3])[CH3:21]
Reactant: C=O
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: CNC
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)CCN(C)C)cc(OC)c1OC
Yield: 90.5 %

Procedure:
3,4,5-Trimethoxyacetophenone (50 g, 237.8 mmole), paraformaldehyde (9.75 g, 304.7 mmole), dimethylamine hydrochloride (26.42 g, 324.0 mmole) and 5 mL conc. HCl were dissolved in 200 mL absolute ethanol and refluxed for 10 hours. Additional dimethylamine hydrochloride (13.21 g, 162.0 mmole) and paraformaldehyde (9.75 g, 304.7 mmole) were added and the solution returned to reflux. After 54 hours (total reaction time), 80 mL of 10% HCl and 500 mL of water were added and the solution was extracted with ethyl ether. The acidic aqueous layer was adjusted to pH 10 with 10% NaOH. The basic solution was extracted with ethyl acetate, dried over MgSO4, filtered and evaporated in vacuo to provide 57.5 g of a yellow oil (92%). 1H NMR (CDCl3): δ2.30 (s, 6H); 2,74 (t, 2H); 3.11 (t, 3H); 3.91 (s, 9H); 7.23 (s, 1H); 7.32 (s, 1H).
Reaction SMILES: [C:1]([O:6]CCCO)(=[O:5])[C:2](C)=[CH2:3].[C:11]1(=[O:18])[CH:16]=CC(=O)C=C1.CC1C(=CC(=CC=1)N=C=O)[N:22]=[C:23]=[O:24]>C=CC1C=CC=CC=1>[C:1]([OH:6])(=[O:5])[CH:2]=[CH2:3].[NH2:22][C:23]([O:18][CH2:11][CH3:16])=[O:24]
Reactant: C=C(C)C(=O)OCCCO
Reactant: O=C1C=CC(=O)C=C1
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Solvent: C=Cc1ccccc1
Product: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A vinyl terminated, fully reacted urethane acrylate was prepared by charging 422 parts of the oxypropylated novolac prepared in Example 1 (2.65 hydroxyl equivalents), 381 parts of hydroxypropyl methacrylate (2.65 moles), 1283 parts of styrene solvent, and 0.28 parts of p-benzoquinone inhibitor to a reactor and heating to 50° C to effect dissolution of the reactants. To the solution was added 460 parts (2.65 moles) of toluene diisocyanate (a commercially available mixture of approximately 80 percent 2,4-isomer and 20 percent 2,6-isomer) and the solution was heated and maintained at about 70° - 80° C with stirring for about 4 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7](Cl)=[O:8].C(N(C(C)C)C(C)C)C.[CH3:29][O:30][C:31]([CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH2:35][CH2:34]1)=[O:32]>CN(C=O)C>[CH3:29][O:30][C:31]([CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]([C:7]([C:6]2[C:5]([O:4][C:3]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:2]=3[Cl:1])=[N:13][CH:12]=[C:11]([F:14])[CH:10]=2)=[O:8])[CH2:35][CH2:34]1)=[O:32]
Reactant: COC(=O)C1CCNc2ccccc21
Reactant: O=C(Cl)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)c2cc(F)cnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.8 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-5-fluoro-nicotinoyl chloride (48.1 mg, 0.15 mmol, 1.0 equiv; Example 146, Step 1) in anhydrous DMF (1 mL) was added N-ethyldiisopropylamine (97 mg, 128 μL, 0.75 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and 1,2,3,4-tetrahydro-quinoline-4-carboxylic acid methyl ester (31.6 mg, 0.165 mmol, 1.1 equiv; [CAS RN 68066-85-3]) and the reaction mixture stirred at rt for 2 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 9.1 mg (13%) of the title compound as a light yellow solid. MS (ISP): 475.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([O:19]CC)=O)[CH2:11][CH2:10]1.O.[NH2:23][NH2:24]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([NH:23][NH2:24])=[O:19])[CH2:11][CH2:10]1
Reactant: NN
Reactant: CCOC(=O)CCN1CCN(c2ccccc2OC)CC1
Solvent: CCO
Solvent: O
Product: COc1ccccc1N1CCN(CCC(=O)NN)CC1
Yield: 86.1 %

Procedure:
A solution of ethyl 3-[4-(2-methoxyphenyl)piperazino]propanoate D1 (8.30 g, 28.38 mmol) and hydrazine monohydrate (8.52 g, 8.3 mL, 170.03 mmol) in ethanol (80 mL) was refluxed for 18 hrs. The solvent was evaporated under reduced pressure, the resulting solid was slurred in 50% acetone in hexane, filtered and dried to afford 6.80 g (87%) 3-[4-(2-methoxyphenyl)piperazino]propanohydrazide D2 as a white solid.