Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH:7]=[C:6]1[CH2:18][CH2:19][CH3:20].[N+:25]([O-])([OH:27])=[O:26]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[C:7]([N+:25]([O-:27])=[O:26])=[C:6]1[CH2:18][CH2:19][CH3:20]
Reactant: O=[N+]([O-])O
Reactant: CCCc1cc2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1c([N+](=O)[O-])c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 1-(2-chlorobenzyl)-2-propylindole-6-carboxylate (200 mg) in trifluoroacetic acid (2 ml) was added concentrated nitric acid (0.3 ml) at 0° C. After stirred at 0° C. for 30 minutes, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with a mixture of ethyl acetate and hexane (1:3) to give methyl 1-(2-chlorobenzyl)-3-nitro-2-propylindole-6-carboxylate (73 mg) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]=[C:10]=[O:11])=[CH:4][CH:3]=1.[Br:12][C:13]1[C:22]2[CH:21]=[N:20][CH:19]=[CH:18][C:17]=2[C:16]([NH2:23])=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:23][C:10]([NH:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:11])=[C:17]2[C:22]=1[CH:21]=[N:20][CH:19]=[CH:18]2
Reactant: Nc1ccc(Br)c2cnccc12
Reactant: O=C=NCc1ccc(F)cc1
Product: O=C(NCc1ccc(F)cc1)Nc1ccc(Br)c2cnccc12

Procedure:
The title compound was prepared using 1-fluoro-4-(isocyanatomethyl)benzene, the product of Example 73A and the procedure described in Example 73B (white solid, 108 mg, 65%). MS (ESI+) m/z 376 (M+H)+; MS (ESI−) m/z 374 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 4.35 (d, 5.8, 2H), 7.12 (m, 1H), 7.18 (m, 2H), 7.40 (m, 1H), 7.91 (d, J 8.5, 1H), 7.99 (d, J 6.1, 1H), 8.24 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 8.88 (s, 1H), 9.44 (s, 1H); Anal. Calcd for C17H13BrFN3O: C, 54.56; H, 3.50; N, 11.23. Found: C, 54.61; H, 3.35; N, 11.14.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[CH2:23]([N:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36])[C:24]#[CH:25]>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:25]#[C:24][CH2:23][N:26]3[CH2:35][CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]3=[O:36])[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Reactant: C#CCn1ccc2ccccc2c1=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1sc(C#CCN3CCc4ccccc4C3=O)cc1C(c1ccccc1Cl)=NC2

Procedure:
The title compound was synthesized by coupling 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with 3,4-dihydro-2.(2-propynyl)1(2H)-isoquinolinone [ref. W. Schneider et al. Arch. pharm., 291, 560 (1958)]under the conditions described in EXAMPLE 37. The product was isolated by chromatography over the 50-fold amount of solica gel using tetrahydrofuran/hexane 4:1 for elution. The clean fractions were combined and evaporated and the residue was crystallized from ethyl acetate to give colorless crystals of 2-{3-[4-(2-chlorophenyl) 9 methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2.yl]-2-propynyl}-3,4-dihydro-1(2H)-isoquinolinone with m.p. 164°-166°.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([CH3:22])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:23]1[S:24][C:25]([C:28](OCC)=[O:29])=[CH:26][N:27]=1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>C(O)C>[OH:29][CH2:28][C:25]1[S:24][C:23]([C:5]2[N:4]([CH2:3][O:2][CH3:1])[C:12]3[C:7]([CH:6]=2)=[CH:8][CH:9]=[CH:10][C:11]=3[N:13]([CH3:22])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])=[N:27][CH:26]=1
Reactant: CCOC(=O)c1cnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3n2COC)s1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCn1c(-c2ncc(CO)s2)cc2cccc(N(C)S(=O)(=O)c3cccs3)c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a mixture of ethyl 2-{1-(methoxymethyl)-7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazole-5-carboxylate (2.13 g) and tetrahydrofuran (30 mL) was added lithium aluminum hydride (0.21 g) at 0° C., and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added ethanol (5 mL) and then saturated aqueous ammonium chloride solution (4 mL). The resulting inorganic salt was filtered off, and the filtrate was concentrated. The obtained crystals were subjected to silica gel column chromatography and eluted with ethyl acetate to give the title compound (1.95 g, quantitative) as pale-yellow crystals. melting point 156-157° C.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1([CH2:13][OH:14])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2S[CH2:5][CH2:4]1.[S:16]([O-:21])(O[O-])(=O)=[O:17].[K+].[K+].[OH-].[Na+]>O>[CH3:15][N:2]([CH3:1])[C:3]1([CH2:13][OH:14])[C:8]2[CH:7]=[CH:12][CH:11]=[CH:10][C:9]=2[S:16](=[O:21])(=[O:17])[CH2:5][CH2:4]1
Reactant: CN(C)C1(CO)CCSc2ccccc21
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)C1(CO)CCS(=O)(=O)c2ccccc21
Yield: 50.1 %

Procedure:
10 g of 4-dimethylamino-4-hydroxymethyl-2,3-dihydro-4H-1-benzothiopyran obtained in Example 6 were suspended in 100 ml of water, to which 50 ml of an aqueous solution of 20 g of potassium peroxomonosulfate was added while stirring under ice cooling. After allowing to react for 1 hour, 3N NaOH solution was added thereto for neutralizing the mixture, followed by extraction with ether. After the ether phase was dried with anhydrous magnesium sulfate, the solvent was condensed to obtain 5.73 g of the title compound as colorless crystals. ##STR34## Melting point: 137°-138° C. IR(KBr) cm-1 : 1290, 1130, 760
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C(O)(=O)C.N1CCCCC1.[C:20]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])(=[O:24])[C:21]([CH3:23])=[O:22]>C1C=CC=CC=1.C(OCC)(=O)C.O>[O:22]=[C:21]([CH2:23][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:20]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: CC(=O)C(=O)OC(C)(C)C
Reactant: Cc1ccc(C=O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: Cc1ccc(CCC(=O)C(=O)OC(C)(C)C)cc1

Procedure:
To a solution of 4-methylbenzaldehyde (2.5 mL, 21.2 mmol) in 25 mL of benzene was added 1 mL each of acetic acid and piperidine. The mixture was heated to reflux with azeotropic removal of water via a Dean-Stark trap. A solution of t-butyl pyruvate (3.36 g, 23.32 mmol) in 5 mL of benzene was added over 7 h by syringe pump. The mixture was cooled, diluted with ethyl acetate and washed three times with saturated aqueous sodium bicarbonate and three times with 1N hydrochloric acid. The organics were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by MPLC on silica-gel eluting with 2.5% ethyl acetate in hexane to give the desired product as a yellow oil: 1H NMR (200 MHz, CDCl3) δ7.75 (d, 1H, J=16.19 Hz), 7.49 (d, 2H, J=8.25 Hz), 7.24 (m, 3H), 2.37 (s, 3H), 1.58 (s, 9H). The above product was dissolved in ethyl acetate and held under hydrogen in the presence of 100 mg of 10% palladium on carbon for 2 hours. The mixture was filtered and concentrated in vacuo to give 1.196 g of the title compound as a pale-yellow oil: 1H NMR (200 MHz, CDCl3) δ7.1-6.9 (m, 4H), 3.12 (t, 2H, J=6.8 Hz), 2.90 (t, 2H, J=7.3 Hz), 1.56 (s, 9H). ##STR29## N-[1(R)-Benzyloxycarbonyl-5-(1,3-dioxo-isoindolin-2-yl)pentyl]-α-(S)-(2-phenyl-ethyl)!glycine-(L)-leucine, N-phenylamide (5d')
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([C:15]([N:17]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18]2)=[O:16])[CH:12]=[CH:11][N:10]=1.[CH:31](=O)/[CH:32]=[CH:33]/[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1.C(O)C>[Cl:8][C:9]1[CH:14]=[C:13]([C:15]([N:17]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:19]3([CH2:20][CH2:21][N:22]([CH2:31]/[CH:32]=[CH:33]/[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:23][CH2:24]3)[CH2:18]2)=[O:16])[CH:12]=[CH:11][N:10]=1
Reactant: O=C(c1ccnc(Cl)c1)N1CC2(CCNCC2)c2ccccc21
Reactant: O=C/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(c1ccnc(Cl)c1)N1CC2(CCN(C/C=C/c3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
1-(2-Chloropyridin-4-yl)carbonylspiro[indoline-3,4′-piperidine]trifluoroacetic acid salt (0.44 g) and trans-cinnamaldehyde (0.29 g) were suspended in tetrahydrofuran (8 ml) and ethanol (6 ml). Borane-pyridine complex (0.26 ml) was added and the reaction stirred vigorously overnight at room temperature. The mixture was evaporated and partitioned between dichloromethane and water. The organics were dried over anhydrous magnesium sulfate and evaporated in vacuo. Flash chromatography [SiO2; ethyl acetate-hexane-triethylamine (25:75:1), increasing polarity to (50:50:1)] yielded 0.42 g (94%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:15]([NH:16][C:17]2[NH:18][C:19]3[C:20]([N:33]=2)=[N:21][C:22]([O:28][CH2:29][CH:30]([F:32])[F:31])=[C:23]([C:25]([OH:27])=O)[CH:24]=3)=[C:14]([Cl:34])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[CH:35]1([CH2:38][NH2:39])[CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[C:15]([NH:16][C:17]2[NH:18][C:19]3[C:20]([N:33]=2)=[N:21][C:22]([O:28][CH2:29][CH:30]([F:32])[F:31])=[C:23]([C:25](=[O:27])[NH:39][CH2:38][CH:35]2[CH2:37][CH2:36]2)[CH:24]=3)=[C:14]([Cl:34])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3nc(OCC(F)F)c(C(=O)O)cc3[nH]2)c1Cl
Reactant: NCC1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3nc(OCC(F)F)c(C(=O)NCC4CC4)cc3[nH]2)c1Cl

Procedure:
The title compound is prepared from N-{2,4-dichloro-3-[6-hydroxycarbonyl-5-(2,2-difluoro-ethoxy)-1H-imidazo[4,5-b]pyridin-2-ylamino]-benzyl)-2,2-dimethyl-propionamide (125 mg, 0.242 mmol), cyclopropylmethyl-amine (25 μl, 0.29 mmol), TBTU (80 mg, 0.25 mmol), TEA (150 μl) in DMF in analogy to example 12c.
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:18]([CH2:23][CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)(Cl)Cl>[OH:1][CH:2]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:23]([CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(CC(O)c2cccnc2)cc1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)=Cc1ccc(CC(O)c2cccnc2)cc1
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
4-[2-Hydroxy-2-(3-pyridyl)ethyl]benzaldehyde (1.34 g) and (carboethoxyethylidene)triphenylphosphorane (4.28 g) were dissolved in 50 ml of chloroform, and stirred for 1.5 hours, and the solvent was distilled off under reduced pressure. The residue obtained was subjected to chromatography on a silica gel column, and from a fraction eluted with chloroform-methanol(10:1v/v) was obtained 1.84 g of ethyl 4-[2-hydroxy-2-(3-pyridyl)ethyl]-α-methylcinnamate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:10](=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[C:22](=[O:25])([O-])[O-:23].[Cs+].[Cs+]>CN(C=O)C>[C:5]([O:23][C:22]([N:16]1[CH2:17][CH2:18][CH:19]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:13]([CH3:14])=[N:12][N:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)[C:10](=[O:21])[CH:9]=3)=[CH:4][CH:3]=2)[CH2:20][CH2:15]1)=[O:25])([CH3:8])([CH3:6])[CH3:4]
Reactant: Cc1nn(-c2ccccn2)c(=O)cc1-c1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccn2)c(=O)cc1-c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 103.5 %

Procedure:
A mixture of 5-(4-hydroxyphenyl)-6-methyl-2-pyridin-2-yl-2H-pyridazin-3-one (97.7 g, 28 mmol), t-butyl 4-methanesulfonyloxypiperidine-1-carboxylic acid ester (15 g, 55 mmol) and cesium carbonate (18 g, 55 mmol) in 75 mL of DMF was stirred at 100° C. overnight. The reaction mixture was cooled to rt, filtered through celite, and concentrated. The crude product was diluted with 100 mL of CH2Cl2, washed with 2N NaCO3, water, NaCl solution, then dried over Na2SO4, and concentrated. The product was purified by flash chromatography (5% MeOH in CH2Cl2) and triturated with EtOAc and hexane to give 4-[4-(3-methyl-6-oxo-1-pyridin-2-yl-1,6-dihydropyridazin-4-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (6.7 g, 72%): MS m/z 463 (M+H).
Reaction SMILES: [BH4-].[Na+].[Si:3]([O:10][CH2:11][C:12]([CH3:42])([CH3:41])[CH2:13][N:14]1[CH:23]=[C:22]([CH:24]=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:26]3[CH:27]=[C:28]([CH:35]=[C:36]([F:39])[C:37]=3[CH3:38])[C:29]([NH:31][CH:32]3[CH2:34][CH2:33]3)=[O:30])[CH:20]=2)[C:15]1=[O:40])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].C([O-])(O)=O.[Na+]>C(O)C>[Si:3]([O:10][CH2:11][C:12]([CH3:42])([CH3:41])[CH2:13][N:14]1[CH:23]=[C:22]([CH2:24][OH:25])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:26]3[CH:27]=[C:28]([CH:35]=[C:36]([F:39])[C:37]=3[CH3:38])[C:29]([NH:31][CH:32]3[CH2:33][CH2:34]3)=[O:30])[CH:20]=2)[C:15]1=[O:40])([C:6]([CH3:8])([CH3:9])[CH3:7])([CH3:5])[CH3:4]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(C=O)c2c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(CO)c2c1
Reaction time: 0.08 h
Yield: 71.2 %

Procedure:
Sodium borohydride (0.804 g) was added to a stirred solution of 3-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-4-formyl-1-oxo-1,2-dihydroisoquinolin-6-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide (Example 26f, 8 g) in ethanol (80 mL) at room temperature under nitrogen. After 5 min, saturated aqueous NaHCO3 (40 mL) was added and the mixture extracted with ethyl acetate (100 mL). The organic layer was washed with water (40 mL), dried (Na2SO4), filtered and evaporated. The residue was purified (SiO2 chromatography, elution with 5-50% ethyl acetate in isohexane) to give the subtitle compound (5.72 g) as a solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCCCCN1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCCCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring 0° C. suspension of NaH (18.3 g, 763 mmol) in THF (195 mL) was added by addition funnel azepan-2-one (75.0 g, 667 mmol) in THF. An additional 2L of solvent was added as the reaction progressed in order to maintain agitation of the very viscous reaction suspension. Following addition, the reaction was allowed to warm to room temperature, and when the evolution of H2 gas ceased after stirring overnight, benzyl bromide was added dropwise by addition funnel and the reaction was stirred overnight. The crude product was filtered through Celite and concentrated in vacuo. Recrystallization from hexanes and ethyl acetate provided pure 1-benzyl-azepan-2-one as a white fluffy solid. 1H NMR (CDCl3, 300 MHz) 7.38-7.24 (5H, m), 4.61 (2H, s), 3.33-3.29 (2H, m), 2.65-2.61 (2H, m), 1.77-1.66 (4H, m), 1.56-1.46 (2H, m) ppm. 13C NMR (CDCl3, 75 MHz) 176.13, 138.06, 128.67, 128.31, 127.43, 51.20, 49.04, 37.33, 30.12, 28.26, 23.58 ppm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[NH:15][N:14]=[CH:13]3)=[CH:4][CH:3]=1.Cl.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][Cl:26]>>[ClH:26].[OH:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[N:15]([CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])[N:14]=[CH:13]3)=[CH:6][CH:7]=1
Reactant: CN(C)CCCl
Reactant: O=c1[nH]ncc2cc(/C=C/c3ccc(O)cc3)ccc12
Agent: Cl
Product: CN(C)CCn1ncc2cc(/C=C/c3ccc(O)cc3)ccc2c1=O

Procedure:
Following the procedure of Example 15 above trans-6-[2-(4-hydroxyphenyl)ethenyl]-1(2H)phthalazinone (19.8 ) and 2-dimethylaminoethyl chloride hydrochloride (17.3 g) were reacted to give the 2-(2-dimethylaminoethyl)derivative as the hydrochloride (16 g), mp 283°-285° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][C:7]#[N:8].[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH:20]=O)=[CH:15][N:14]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[C:7]([NH2:8])=[N:19][C:17]3[N:18]=[C:13]([NH2:12])[N:14]=[CH:15][C:16]=3[CH:20]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ncc(C=O)c(N)n1
Reactant: COc1cccc(CC#N)c1
Product: COc1cccc(-c2cc3cnc(N)nc3nc2N)c1

Procedure:
The title compound was prepared according to Example 1, starting from 3-methoxybenzyl cyanide and 2,4-diamino-5-pyrimidine-carboxaldehyde; mp 284°-286 ° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17](Br)[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[CH2:21]([Sn](CCCC)(CCCC)CC=C)[CH2:22][CH2:23]C.C(OCC)(=O)C.O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH2:23][CH:22]=[CH2:21])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 120 °C
Yield: 68.8 %

Procedure:
A mixture of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.62 g, 1.744 mmol), tributyl(2-propen-1-yl)stannane (0.924 g, 2.79 mmol) and Pd(PPh3)4 (0.201 g, 0.174 mmol) in N,N-Dimethylformamide (DMF) (14 ml) was heated in a microwave reactor at 120° C. for 30 min. The vessel was cooled to RT and ethyl acetate (200 mL) and water (200 mL) were added. The organic layer was separated, washed with brine (200 mL), dried over MgSO4, filtered and concentrated. The crude material was purified on silica gel (hexanes/ethyl acetate) to give 0.38 g of a mixture of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(2-propen-1-yl)benzonitrile and Bu3SnBr. The material was used without further purification. N4011-30-100. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20-7.29 (m, 2H), 7.17 (s, 1H), 7.02 (s, 1H), 6.84 (s, 1H), 5.78-5.96 (m, 1H), 5.01-5.18 (m, 2H), 3.91 (s, 2H), 3.37 (d, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:18]1[N:27]=[C:26]([N:28]([CH3:30])[CH3:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.C(N(CC)CC)C>CC(O)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:9][CH2:10][C@@H:11]([CH2:14][NH:15][C:18]2[N:27]=[C:26]([N:28]([CH3:30])[CH3:29])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CN)CC1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CN(C)c1nc(NC[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)nc2ccccc12
Temperature: 170 °C
Yield: 64.1 %

Procedure:
A mixture of cis-(4-aminomethyl-cyclohexyl)-carbamic acid tert-butyl ester (1.14 g, 5 mmol), (2-chloro-quinazoline-4-yl)-dimethyl-amine obtained in step B of example 1 (1.035 g, 5 mmol), and triethylamine (1.5 mL, 11 mmol) in 2-propanol (2.5 mL) was heated at 170° C. for 35 min using a Smith Microwave Synthesizer. The mixture was concentrated and the residue was purified by column chromatography (silica gel, CH2Cl2 to 10% 2 M NH3/MeOH in CH2Cl2) to give cis-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.28 g, 80%) as a white solid.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[CH3:25][O:26][C:27](=[O:39])[C@@H:28]([NH2:38])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Br:37])[CH:31]=1>>[CH3:25][O:26][C:27](=[O:39])[C@@H:28]([NH:38][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:14]=1[NH:13][S:10]([C:6]1[C:3]2=[N:4][S:5][N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=1)(=[O:12])=[O:11])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Br:37])[CH:31]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)c(Br)c1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Cl)c(Br)c1)NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoic acid was coupled to (S)-2-amino-3-(3-bromo-4-chloro-phenyl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C, to afford the title compound. HPLC: RT=10.85 min. MS (ESI+): mass calcd. for C23H17BrClIN4O5S2, 735.80; m/z found, 735/737 [M+H]+. 1H NMR (500 MHz, CDCl3): 11.31 (s, 1H), 8.36 (d, J=7.1, 1H), 8.22 (d, J=8.7, 1H), 8.08 (d, J=1.4, 1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.36-7.28 (m, 3H), 6.96-6.90 (m, 2H), 6.46 (d, J=7.1, 1H), 4.93 (q, J=5.5, 1H), 3.82(s, 3H), 3.23-3.10 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:10]=[CH:11][C:12]=2[NH:13][C:14]([C:16]2[N:17](COCC[Si](C)(C)C)[CH:18]=[C:19]([C:21]#[N:22])[N:20]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CCOC(C)=O.C(Cl)Cl>[C:1]1([C:7]2[CH:8]=[C:9]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:10]=[CH:11][C:12]=2[NH:13][C:14]([C:16]2[NH:17][CH:18]=[C:19]([C:21]#[N:22])[N:20]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(-c2ccccc2)cc1C1=CCCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(-c3ccccc3)cc2C2=CCCCC2)n1
Yield: 60 %

Procedure:
The title compound was prepared by the procedure of Example 11, step (g) using 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (3-cyclohex-1-enyl-biphenyl-4-yl)-amide (as prepared in the previous step, 16 mg, 0.032 mmol). Silica gel chromatography (2-3% EtOAc/DCM) afforded the title compound (7.1 mg, 60%) as a white solid. 1H-NMR (1:1 CDCl3/CD3OD; 400 MHz): δ 8.36 (d, 1H, J=8.6 Hz), 7.88 (s, 1H), 7.59-7.62 (m, 2H), 7.54 (dd, 1H, J=8.6, 2.3 Hz), 7.42-7.46 (m, 3H), 7.34 (m, 1H), 5.92 (m, 1H), 2.29-2.37 (m, 4H), 1.79-1.94 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C23H20N4O, 369.2 (M+H), found 369.1.