Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:12][C:13]1[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1)=[N:18]2>>[Cl:23][C:22]1[C:13]([NH:12][C:9](=[O:11])[CH2:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:29]1)[CH:16]=[CH:15]2
Reactant: CCOC(=O)C1CCN(c2ccc3c(N)c(Cl)ccc3n2)CC1
Reactant: O=C(O)CCC1CCCCC1
Product: CCOC(=O)C1CCN(c2ccc3c(NC(=O)CCC4CCCCC4)c(Cl)ccc3n2)CC1
Yield: 84.9 %

Procedure:
Prepared according to the method of example 62(a), using cyclohexanepropanoic acid (280 mg) and 1-(5-amino-6-chloro-2-quinolinyl)-4-piperidinecarboxylic acid, ethyl ester (Example 77(a)) (200 mg), to afford the sub-titled compound (240 mg).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]1[NH:18][C:19]([CH2:39][C:40]([O:42][CH3:43])=[O:41])=[C:20]([C:35]([O:37][CH3:38])=[O:36])[CH:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:34])[C:22]=1[C:23]([O:25][CH3:26])=[O:24])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:34][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:27]=1[CH:21]1[C:20]([C:35]([O:37][CH3:38])=[O:36])=[C:19]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[NH:18][C:17]([CH2:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])=[C:22]1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2O[Si](C)(C)C(C)(C)C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2O)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of dimethyl 2-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl]-4-(2,6-dichlorophenyl)-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate (example 5, 3.90 g/6.01 mmol) in THF (39 ml) was added a solution of tetrabutylammonium fluoride (6.0 ml/6.0 mmol) at 0° C. and the resulting solution was stirred for 30 min at room temperature. The mixture was poured into water. The whole was extracted with dichloromethane (100 ml×2). The combined organic layer was washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, 200-350 mesh/hexane:ethyl acetate=4:1-2:1) to afford a yellow oil (3.20 g/99%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[F:14])[CH3:5].CS(O[CH:20]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]1)(=O)=O.O>CN(C=O)C>[CH3:5][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:20]2[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23]2)=[CH:9][C:8]=1[F:14])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: CN(C)Cc1ccc(O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)Cc1ccc(OC2CN(C(=O)OC(C)(C)C)C2)cc1F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
A mixture of NaH (55-65% disp. in oil, 0.31 g, 7.7 mmol) in dry DMF (10 mL) under nitrogen was cooled by an ice-bath. A solution of 26A (1.0 g, 5.9 mmol) in DMF (10 mL) was added drop-wise over 10 minutes. The mixture was stirred for 30 minutes and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (1.63 g, 6.5 mmol) in DMF (10 mL) was added. The mixture was heated to 80° C. over night and then cooled to RT. Water (100 mL) was added and the mixture was extracted three times with EtOAc (50 mL). The combined organic phases were filtered through a phase separator and the solvent was removed by evaporation. The residue was purified by preparative chromatography on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 10-50% acetonitrile in water/acetonitrile/formic acid (95/5/0.2), 100 mL/min. Fractions were collected, pooled and concentrated in vacuo. DCM was added and the solution was filtered through a phase separator and concentrated by evaporation. There was obtained 1.2 g (55%) of 26B as a solid. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 2.58 (s, 6H), 3.90 (s, 2H), 3.95-4.05 (m, 2H), 4.25-4.35 (m, 2H), 4.81-4.92 (m, 1H), 6.45-6.65 (m, 2H), 7.35-7.45 (m, 1H), 8.42 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CN1CCCC1=O>[OH:17][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:16])[CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C1CCCCCO1
Reactant: CC(=O)c1ccccc1
Solvent: CN1CCCC1=O
Product: O=C(CCCCCO)CC(=O)c1ccccc1

Procedure:
In accordance with the procedure of Example 8, 61.3 g of acetophenone and 57.7 g of ε-caprolactone are condensed in 117.0 g of N-methylpyrrolidone as solvent with 52.9 g of sodium tert-butylate (97%) as base. Working up is as described in Example 8.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=2)[C:26]([NH:28][CH3:29])=[O:27])[C:19]([Cl:33])=[CH:18][N:17]=1>>[Cl:33][C:19]1[C:20]([NH:22][C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=2)[C:26]([NH:28][CH3:29])=[O:27])=[N:21][C:16]([NH:1][C:2]2[CH:14]=[CH:13][C:5]3[N:6]([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:17][CH:18]=1
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(Nc2nc(Cl)ncc2Cl)c1
Product: CNC(=O)c1cccc(Nc2nc(Nc3ccc4c(c3)CCCC(=O)N4C)ncc2Cl)c1
Yield: 47 %

Procedure:
In an analogous procedure to Example 651, part c, 7-Amino-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 3-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide were combined to yield 3-[5-Chloro-2-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (53.36 mg, 47% yield) as a white powder. 1H-NMR (DMSO-d6) δ 9.39 (s, 1H), 9.03 (s, 1H), 8.39 (d, J=4.4 Hz, 1H), 8.16 (s, 1H), 7.99 (s, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.1 Hz, 1H), 7.47 (m, 1H), 7.44 (br s, 1H), 7.03 (d, J=8.7 Hz, 1H), 3.15 (s, 3H), 2.75 (d, J=4.3 Hz, 3H), 2.39 (m, 2H), 2.08 (m, 2H), 1.94 (m, 2H). LC/MS (ESI+)=451 (M+H). Mp=215-217° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][Br:11]
Reactant: Cc1cc(C#N)ccc1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(Br)c(CBr)c1
Yield: 14.3 %

Procedure:
To a stirred solution of 4-bromo-3-methyl benzonitrile (5 g, 25.5 mmol) in CCl4 (200 mL), was added N-bromosuccinimide (4.99 g, 28.05 mmol) and 2,2-Azobisisobutyronitrile (335 mg, 2.04 mmol). The mixture was heated to reflux overnight then cooled, diluted with CH2Cl2 and quenched with 10% NaHSO3. The layers were separated and the CH2Cl2 layer was washed with saturated NaHCO3 and brine, dried over MgSO4, filtered and concentrated under vacuum. Column chromatography on silica gel (5-10% ethyl acetate/hexanes) afforded 4.31 g (3.65 mmol, 61%) of a mixture of mono- and di-bromo intermediates. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 4.55 (s, 2H) 7.42 (dd, J=8.31, 2.01 Hz, 1H) 7.67-7.78 (m, 2H). Mass spec.: 275.94 (MH)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][NH:16][C:13]=4[N:14]=[CH:15][C:10]3=[N:9][N:8]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:25]([CH2:27][C:28](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:29])#[N:26]>CN(C=O)C>[C:7]1([CH:4]2[CH2:3][CH2:2][N:1]([C:28](=[O:29])[CH2:27][C:25]#[N:26])[CH2:6][CH2:5]2)[N:11]2[C:12]3[CH:18]=[CH:17][NH:16][C:13]=3[N:14]=[CH:15][C:10]2=[N:9][N:8]=1
Reactant: c1cc2c(ncc3nnc(C4CCNCC4)n32)[nH]1
Reactant: N#CCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N#CCC(=O)N1CCC(c2nnc3cnc4[nH]ccc4n23)CC1
Reaction time: 3 h
Yield: 4.4 %

Procedure:
To a suspension of 1-(piperidin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.090 g, 0.37 mmol, Example #2) and pyridine (0.12 mL, 1.5 mmol) in DMF (5 mL) was added perfluorophenyl 2-cyanoacetate (0.14 g, 0.56 mmol, Preparation #6). After about 3 h at ambient temperature, the reaction mixture was quenched with MeOH (0.5 mL) and then purified by RP-HPLC (Table 2, Method b). The appropriate fractions were concentrated and lyophilized to afford 3-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidin-1-yl)-3-oxopropanenitrile as a white solid (0.005 g, 4%): LC/MS (Table 2, Method a) Rt=1.24 min; MS m/z: 310 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]2[S:34][CH:35]=[C:36]([CH3:38])[CH:37]=2)=[N:25][N:24]=1.CC(O)(C)C>C(OCC)C.C(=O)([O-])[O-].[Na+].[Na+]>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[C:7]([O:6][C:5]3[CH:20]=[CH:21][C:2]([NH:1][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:26]([C:33]5[S:34][CH:35]=[C:36]([CH3:38])[CH:37]=5)=[N:25][N:24]=4)=[CH:3][CH:4]=3)=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Cc1csc(-c2nnc(Cl)c3ccccc23)c1
Reactant: Nc1ccc(Oc2ncccc2-c2ccnc(N)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: Cc1csc(-c2nnc(Nc3ccc(Oc4ncccc4-c4ccnc(N)n4)cc3)c3ccccc23)c1
Temperature: 100 °C

Procedure:
To 4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-amine and 1-chloro-4-(4-methyl-2-thienyl)phthalazine was added tBuOH. The resulting mixture was heated at 100° C. in a sealed tube for 16 hours. The reaction was diluted with diethyl ether and saturated sodium carbonate and vigorously shaken. The resulting solids were filtered and washed with water, diethyl ether and air dried to yield N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine as an off-white solid. MS m/z=504 [M+H]+. Calc'd for C28H21N7OS: 503.58.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:11]=2)=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:11]=2)=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[O:26][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: COc1cc(CNc2c(F)ccc(O)c2F)cc(-c2cccc(F)c2)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(OC)cc(-c3cccc(F)c3)c2)c1F
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a solution of 2,4-difluoro-3-[[3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]phenol (500 mg, 1.4 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (634 mg, 1.9 mmol, 1.4 eq). The reaction mixture was stirred for 1 h, then ethyl 2-bromoacetate (279 mg, 1.7 mmol, 1.2 eq) was added. The reaction mixture was stirred for a further 1 h, then poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude residue obtained was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as an oil (500 mg, 80%).
Reaction SMILES: C1(C2CC(=O)NN=2)CC1.ClC1C2C(=CC=C(OC)C=2)[N+]([O-])=CC=1.Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[NH:28]/[C:27](=[C:37]2/[C:38]([CH:43]3[CH2:45][CH2:44]3)=[N:39][NH:40][C:41]/2=[O:42])/[CH:26]=1.[C:46]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([SH:56])=[CH:52][CH:51]=1)(=[O:48])[CH3:47]>C(OC(=O)C)(=O)C.C(O)C>[CH:43]1([C:38]2=[N:39][NH:40][C:41](=[O:42])/[C:37]/2=[C:27]2\[NH:28][C:29]3[C:34]([C:25]([S:56][C:53]4[CH:52]=[CH:51][C:50]([NH:49][C:46](=[O:48])[CH3:47])=[CH:55][CH:54]=4)=[CH:26]\2)=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[CH2:45][CH2:44]1
Reactant: COc1ccc2c(c1)C(Cl)=C/C(=C1/C(=O)NN=C1C1CC1)N2
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: COc1ccc2c(c1)c(Cl)cc[n+]2[O-]
Agent: O=C1CC(C2CC2)=NN1
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: COc1ccc2c(c1)C(Sc1ccc(NC(C)=O)cc1)=C/C(=C1/C(=O)NN=C1C1CC1)N2
Temperature: 180 °C

Procedure:
3-Cyclopropyl-1H-pyrazol-5(4H)-one (0.2 mmol) and 4-chloro-6-methoxyquinoline 1-oxide (0.025 g, 0.2 mmol) were stirred in acetic anhydride (1.5 mL) at ambient temperature for 30-40 minutes. The reaction mixture was concentrated and the resulting solid filtered off and washed with a minimum amount of ether. (Z)-4-(4-chloro-6-methoxyquinolin-2(1H)-ylidene)-3-cyclopropyl-1H-pyrazol-5(4H)-one (0.04 g, 0.11 mmol) was dissolved in ethanol (1.5 mL) and 4-acetamidothiophenol (0.019 g, 0.11 mmol) was added. The reaction mixture was heated to 180° C. using a microwave reactor for 5-10 minutes. The mixture was then concentrated and the resulting solid filtered and washed with ether to give Example 47. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.46 (d, J=6.57 Hz, 2H) 0.65-0.71 (m, 2H) 1.43-1.54 (m, 1H) 2.11 (s, 3H) 3.98 (s, 3H) 7.18 (s, 1H) 7.45 (d, J=2.53 Hz, 1H) 7.63 (dd, J=9.09, 2.27 Hz, 1H) 7.70 (d, J=8.59 Hz, 2H) 7.82 (d, J=8.59 Hz, 2H) 8.07 (d, J=9.09 Hz, 1H) 10.39 (s, 1H); ESI-MS: m/z calc'd for C24H22N4O3S 446.52. found 447.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[CH3:13][N:14]([CH3:18])[C:15](Cl)=[S:16].C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:15](=[S:16])[N:14]([CH3:18])[CH3:13])[CH:6]=1
Reactant: CN(C)C(=S)Cl
Reactant: COC(=O)Cc1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)Cc1cccc(OC(=S)N(C)C)c1

Procedure:
A mixture of (3-Hydroxy-phenyl)-acetic acid methyl ester (5.5 g, 33.1 mmol), N,N-dimethyl thiocarbamoyl chloride (5.11 g, 41.38 mmol), triethylamine (9.2 mL, 66.2 mmol), N,N-dimethylamino pyridine (0.4 g, 3.31 mmol) and dioxane (50 mL) is stirred at reflux 18 hr. The mixture is concentrated, partioned between 1M aqueous hydrochloric acid (200 mL) and ethyl acetate (3×75 mL). The combined organic extracts are dried over anhydrous magnesium sulfate, filtered, concentrated, and purified via silica chromatography eluting the product with dichloromethane to afford the title compound as a brown oil, 6.8 g, 81%. MS M++1 254. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:12]=1)[C:6]([O:8]C)=[O:7].O.[OH-].[Li+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(OC)cc(S(C)(=O)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C(=O)O)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 3-methoxy-5-methylsulfonylbenzoate (D14) (2.94 g) was dissolved in dioxan (18 ml) and lithium hydroxide monohydrate (0.762 g) in water (18 ml) was added. The mixture was stirred at room temperature for 2 h and then sufficient Amberlyst-15 H+ resin was added to adjust the pH to ˜4. The resin was removed by filtration and washed well with dioxan and the combined filtrates were evaporated. The residue was triturated with ether to give D15 as a pale buff solid (2 crops, 2.29 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1c(F)cccc1F
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4c(F)cccc4F)nc23)CC1

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.053 mMol) 2,6-difluorobenzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][N:11]([CH:37]=[O:38])[CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29]CC[Si](C)(C)C)=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C>C(#N)C>[CH:37]([N:11]([CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([OH:29])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])[CH2:10][CH2:9][P:4](=[O:3])([OH:5])[OH:8])=[O:38]
Reactant: CCOP(=O)(CCN(C=O)CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Agent: C[Si](C)(C)Br
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: COc1c(C)c2c(c(O)c1CC=C(C)CN(C=O)CCP(=O)(O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a solution of crude [2-(formyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonic acid diethyl ester (78 mg, 0.14 mmol) in acetonitrile (1 mL) was added TMSBr (177 μL, 1.4 mmol) and 2,6-lutidine (163 μL, 1.4 mmol). The solution was stirred at room temperature for 1 hour when it was quenched by addition of methanol and 1N aqueous HCl. The product was extracted with EtOAc and purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 29 mg of the product as a white solid. The NMR data of this compound shows two rotamers with the ratio of approximately 70:30. 1H NMR (300 MHz, CD3OD) δ 1.62 and 1.64 (s, 3H), 1.83-1.98 (m, 2H), 2.16 (s, 3H), 3.38-3.55 (m, 4H), 3.78 (s, 3H), 3.80 and 3.91 (s, 2H), 5.22 (s, 2H), 5.39-5.52 (m, 1H), 8.03 and 8.18 (s, 1H) ppm; MS (m/z) 414.2 [M+H]+, 436.2 [M+Na]+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][NH:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][N:17]([C:24]([CH3:25])=[O:26])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C(C)=O)C[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Yield: 54 %

Procedure:
To a solution of trans-3-(3-cyclopentoxy-4-methoxyphenyl)-4-(methoxycarbonyl)pyrrolidine (605 mg, 1.89 mmol) in 5 mL of CH2Cl2 was added 4-dimethylaminopyridine (347 mg, 2.84 mmol), followed by 1 mL of acetic anhydride After 12 hr the reaction was diluted with CH2Cl2 and washed with 1M H3PO4. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (2:1, hexanes:ethyl acetate) provided trans-3-(3-cyclopentoxy-4-methoxyphenyl)-4-methoxycarbonyl-1-(methylcarbonyl)pyrrolidine as a viscous oil (370 mg, 54%). 1H-NMR (300 MHz) analysis indicates a 1:1 mixture of amide rotamers (δ 2.07 and 2.09 singlets). Anal. Calcd for C20H27NO5 : C, 66.46; H, 7.53; N, 3.88. Found: C, 66.19; H, 7.58; N, 3.82.
Reaction SMILES: [ClH:1].Cl.Cl.[CH:4]1([NH:7][C:8]([C:10]2[C:18]3[CH:17]=[C:16]([C:19]4[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([NH:26][CH2:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[N:20]=4)[S:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:9])CC1.[CH3:37]NC(C1C2C=C(C3C([Cl:56])=CN=C(Cl)N=3)SC=2C=CC=1)=O.C(N1CCN(CCCN)CC1)C>>[ClH:25].[ClH:56].[ClH:1].[CH3:4][NH:7][C:8]([C:10]1[C:18]2[CH:17]=[C:16]([C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([NH:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH2:35]4)[N:20]=3)[S:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reactant: CNC(=O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Agent: CCN1CCN(CCCN)CC1
Agent: Cl
Product: CCN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC)cccc4s3)n2)CC1

Procedure:
Using the method of 2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide tri-hydrochloride, the title compound is synthesized from 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methylamide and 3-(4-ethylpiperazin-1-yl)-propylamine and isolated as a yellow solid. ES+(m/z) 473 (35Cl) and 475 (37Cl) [M(free base)+H].
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([CH:16]=[N:17][OH:18])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].BrN1C(=O)[CH2:25][CH2:24][C:23]1=O.ClC(C)=C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:20][C:2]([F:1])([F:19])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([C:16]3[CH:23]=[C:24]([CH3:25])[O:18][N:17]=3)=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(N1CCc2ccc(C=NO)cc2CC1)C(F)(F)F
Agent: C=C(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccc3c(c2)CCN(C(=O)C(F)(F)F)CC3)no1
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 36.4 %

Procedure:
To a solution of 3-Trifluoracetyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-carbaldehyde oxime (17.2 g) in chloroform (700 ml) was added N-bromosuccinimide (11.8 g), portionwise over 5 min., and the mixture stirred for 1.5 h. 2-Chloropropene (30.3 ml) was added and the reaction cooled to −20° C. Triethylamine (25.1 ml) in chloroform was added over 10 min. and the reaction stirred at room temperature for 18 h. The solution was washed with 2M HCl, dried and evaporated and the residue chromatographed on Si gel, gradient eluting with 10-20% EtOAc in hexane to give the title compound (7.1 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH3:17])[CH:12]([CH2:18][NH2:19])[CH2:11]2)=[CH:4][CH:3]=1.C1([O:26][C:27](=O)[NH:28][C:29]2[CH:34]=[C:33]([C:35]3[N:39]([CH3:40])[N:38]=[N:37][N:36]=3)[CH:32]=[C:31]([CH2:41][CH3:42])[CH:30]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH2:41]([C:31]1[CH:30]=[C:29]([NH:28][C:27]([NH:19][CH2:18][CH:12]2[CH:13]([CH2:16][CH3:17])[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:11]2)=[O:26])[CH:34]=[C:33]([C:35]2[N:39]([CH3:40])[N:38]=[N:37][N:36]=2)[CH:32]=1)[CH3:42]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Reactant: CCC1CCN(CCc2ccc(F)cc2)CC1CN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(NC(=O)NCC2CN(CCc3ccc(F)cc3)CCC2CC)cc(-c2nnnn2C)c1
Reaction time: 18 h
Yield: 50.9 %

Procedure:
A solution of 1-[2-(4-fluorophenyl)ethyl]-4-ethyl-piperidin-3-ylmethylamine (52 mg, 199 μmol) and [3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-carbamic acid phenyl ester (50 mg, 199 μmol) in N,N-dimethylformamide (1.0 mL) was treated with triethylamine (55 μL, 398 μmol). After 18 hours, the mixture was concentrated under vacuum. The residue was purified by flash chromatography, eluting with 5% methanol in dichloromethane containing 0.5% aqueous ammonium hydroxide, provided an amorphous solid (50 mg, 51%). 1H NMR (300 MHz, CDCl3) δ8.37 (s, 1H), 7.74 (s, 1H), 7.56 (s, 1H), 7.11 (m, 2H), 7.03 (s, 1H), 6.92 (t, J=9 Hz, 2H), 6.11 (m, 1H), 4.12 (s, 3H), 3.53 (m, 1H), 3.18 (m, 2H), 3.00 (m, 1H), 2.80 (m, 2H), 2.63 (m, 4H), 2.2-2.0 (m, 2H), 1.82 (m, 1H), 1.66 (m, 2H), 1.40 (m, 1H), 1.3-1.1 (m, 2H), 1.20 (t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H). Mass spec (ES+) m/z 494.4 (M+H+, 100%).