Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C@H:14]([NH:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]Cl)[CH:21]=1)([CH2:16][CH3:17])[CH3:15].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C.C(OCC)(=O)C.O>[C@H:14]([NH:18][C:19]([C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[CH2:26][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:28])([CH2:16][CH3:17])[CH3:15]
Reactant: CC[C@@H](C)NC(=O)c1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC[C@@H](C)NC(=O)c1cccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 80 °C
Yield: 100.1 %

Procedure:
A suspension of tert-butyl piperazine-1-carboxylate (5.32 mmol, 0.990 g), (R)—N-sec-butyl-3-(chloromethyl)benzamide (5.32 mmol, 1.2 g), potassium carbonate (10.63 mmol, 1.469 g) and sodium iodide (0.532 mmol, 0.080 g) in acetonitrile (50 mL) were heated at 80° C. for 3 hours. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, dried (magnesium sulfate) and concentrated under reduced pressure to give the title compound (2 g). MS (ESI) m/z 376.5 [M+H]+
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)=[CH:26][CH:25]=1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Nc1ccc(Cl)cc1
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccc(Cl)cc2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (4-chlorophenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.06 (s, 3H), 2.33 (s, 3H), 4.60 (d, J=3.0 Hz, 2H), 5.77 (bs, 1H), 6.30 (bs, 1H), 7.13-7.20 (m, 3H), 7.32 (d, J=6.8 Hz, 1H), 7.43 (d, J=7.8 Hz, 2H), 7.61 (t, J=7.6 Hz, 1H), 8.58 (d, J=3.4 Hz, 1H); MS (ESI) m/z 340.6 (M+1)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32]>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:23][CH2:24]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Reactant: CC(C)CCBr
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCN(CCC(C)C)CC3)c2n1

Procedure:
Prepared similarly to Example 82 from 2-(butyloxy)-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purin-6-amine and 1-bromo-3-methylbutane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:30]=[C:31]([NH2:36])[C:32]([NH2:35])=[CH:33][CH:34]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]3[NH:35][C:32]4[CH:33]=[CH:34][C:29]([C:28]([F:27])([F:37])[F:38])=[CH:30][C:31]=4[N:36]=3)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Reactant: Nc1ccc(C(F)(F)F)cc1N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1-c1nc2cc(C(F)(F)F)ccc2[nH]1
Yield: 9.6 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.150 g, 0.30 mmol), 4-(trifluoromethyl)benzene-1,2-diamine (0.081 g, 0.45 mmol), trimethyl aluminium (2M solution in toluene) (2 mL), dry toluene (5.0 mL) to afford 0.015 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 4.09 (s, 3H), 7.52 (s, 1H), 7.73-7.85 (m, 5H), 8.02-8.15 (m, 2H), 8.48 (m, 1H), 12.79 (br s, 1H), 13.33 (br s, 1H); MS (m/z): 520.14 (M+H)+.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([CH2:12][NH:13][CH3:14])[NH:10][CH:11]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O.O>[CH2:27]([N:13]([CH3:14])[CH2:12][C:9]1[NH:10][CH:11]=[C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:2][CH:3]=2)[N:8]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CNCc1nc(-c2ccc(-c3ccccc3)cc2)c[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccccc1)Cc1nc(-c2ccc(-c3ccccc3)cc2)c[nH]1
Reaction time: 48 h
Yield: 16 %

Procedure:
(4-(1,1′-biphenyl)-4-yl-1H-imidazol-2-yl)-N-methylmethanamine (1 g; 0.003 mol; prepared according to experimental conditions analogous to the preceding examples and using the appropriate starting compounds and reaction products) was diluted in 20 ml dimethylformamide. Potassium carbonate (1.23 g; 0.009 mol) was added at about 23° C. and then benzyl bromide (0.34 ml; 0.003 mol) was added quite slowly. The reaction mixture was agitated at this temperature for about 48 hours then poured in icy water. The mixture was extracted with ethyl acetate and the organic phase washed with water. After drying over magnesium sulfate, the solvents were concentrated using a rotative evaporator. After purification over a silica column (eluent: ethyl acetate-heptane/8-2), a white solid was obtained in the form of a glue (yield of 16%). Free base. Melting point: 106-108° C. MH+=354.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C(N(CC)C(C)C)(C)C.[C:35]1([C:41]2[O:45][N:44]=[C:43]([NH:46][C:47](=O)[O:48]C3C=CC=CC=3)[CH:42]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([NH:22][C:47]([NH:46][C:43]2[CH:42]=[C:41]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:45][N:44]=2)=[O:48])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Nc1cc(-c2ccccc2)on1)Oc1ccccc1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(-c5ccccc5)on4)c3)c2cc1OC
Temperature: 50 °C
Yield: 69.5 %

Procedure:
According to the procedure described in Example 113C, 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (102 mg, 0.3 mmol) in THF (1.5 mL) was treated with N,N-diisopropylethylamine (68 μl, 0.39 mmol), 4-(dimethylamino)pyridine (1.8 mg, 0.015 mmol) and phenyl 5-phenylisoxazol-3-ylcarbamate from Example 113B (109 mg, 0.39 mmol). The reaction mixture was heated to 50° C. for 4 h. After cooling to room temperature, the mixture was partitioned between chloroform and a saturated solution of sodium bicarbonate. The water phase was back extracted three times with chloroform and the organics combined and dried (MgSO4). Concentration under reduced pressure gave a residue which was purified by preparative HPLC (phenylhexyl reverse phase column). The obtained solid was triturated with anhydrous diethyl ether to afford 1-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(5-phenylisoxazol-3-yl)urea as a white solid (110 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ 9.74 (s, 1H), 9.06 (s, 1H), 8.57 (s, 1H), 7.86 (d, 2H), 7.62-7.53 (m, 5H), 7.51 (t, 2H), 7.28 (m, 2H), 6.99 (d, 1H), 4.34 (bs, 2H), 4.00 (s, 3H), 3.77 (bs, 2H), 3.35 (s, 3H); LC-MS (ESI) m/z 528 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:13][C:14]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:13][C:14]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17])=[O:7])[CH3:2]
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: COc1cccc(C(N)=O)c1N
Solvent: c1ccncc1
Product: CCOc1ccccc1C(=O)Nc1c(OC)cccc1C(N)=O
Reaction time: 20 h
Yield: 54.3 %

Procedure:
2-Ethoxybenzoyl chloride (8.9 g, 0.048 mol) was added dropwise to a stirred solution of 2-amino-3-methoxybenzamide (4.0 g, 0.024 mol) in pyridine (35 ml) under a nitrogen atmosphere at 0° C. After 20 hours at room temperature, the solvent was removed by evaporation under vacuum, the residue dissolved in dichloromethane (100 ml) and the solution washed successively with 2N hydrochloric acid (2×100 ml) and saturated aqueous sodium hydrogen carbonate solution (2×100 ml). The organic phase was dried (MgSO4) and evaporated under vacuum, then the resulting oil chromatographed on silica gel (40 g), eluting with a mixture of methanol in-dichloromethane (2%), to give the title compound as a colourless solid (4.1 g, 54%), m.p. 177-179° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5]([CH:11]=[O:12])=[CH:4][CH:3]=1.Cl[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>S1(CCCC1)(=O)=O>[CH:11]([C:5]1[C:6]2[CH:10]=[CH:9][S:8][C:7]=2[C:2]([O:1][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=2)=[CH:3][CH:4]=1)=[O:12]
Reactant: O=Cc1ccc(O)c2sccc12
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: N#Cc1ccc(Oc2ccc(C=O)c3ccsc23)nc1
Temperature: 80 °C

Procedure:
A suspension of 7-hydroxybenzo[b]thiophene-4-carbaldehyde (Preparation 69) (100 mg, 0.62 mmol), 6-chloronicotinonitrile (86 mg, 0.62 mmol) and K2CO3 (258 mg, 1.87 mmol) in sulfolane (3 mL) was heated in a microwave reactor at 130 W/80° C. for 4 h. The mixture was cooled, poured onto ice water and the resulting solid filtered and air-dried to give the title compound: RT=3.40 min; m/z (ES+)=265.2 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([O:30][CH2:31][CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)=[N:17][C:16]=2[CH3:28])=[CH:9][C:8]=1[CH3:29])C.[Li+].[OH-]>>[Cl:27][C:22]1[CH:21]=[C:20]([C:18]2[S:19][C:15]([CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:30][CH2:31][CH3:32])[C:4]([OH:33])=[O:3])=[C:8]([CH3:29])[CH:9]=3)=[C:16]([CH3:28])[N:17]=2)[CH:25]=[CH:24][C:23]=1[F:26]
Reactant: CCOC(=O)C(Cc1ccc(OCc2sc(-c3ccc(F)c(Cl)c3)nc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2sc(-c3ccc(F)c(Cl)c3)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-3-{4-[2-(3-chloro-4-fluoro-phenyl)-4-methyl-thiazol-5-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester was treated with LiOH to obtain [rac]-3-{4-[2-(3-chloro-4-fluoro-phenyl)-4-methyl-thiazol-5-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid as light yellow foam.
Reaction SMILES: [CH:1]1([C:9]([OH:11])=[O:10])[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.C(OC(=O)C)(=O)C>>[CH:3]12[C:6](=[O:8])[O:11][C:9](=[O:10])[CH:1]([CH2:5][CH2:4]1)[CH2:2]2
Reactant: O=C(O)C1CCC(C(=O)O)C1
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)C2CCC1C2

Procedure:
1,3-Cyclopentanedicarboxylic acid (4.0 g., 25 mmole) was converted to the anhydride by refluxing for 3 hours in 20 ml. of acetic anhydride. After removal of excess acetic anhydride, extraction with hexane and evaporation of the hexane, 3.95 g. of cyclopentane-1,3-dicarboxylic anhydride was obtained. The anhydride was combined with 6.51 g. (27 mmole) of 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine in 50 ml. of dichloromethane and stirred at room temperature overnight. The dichloromethane was removed in vacuo and replaced with 75 ml. of toluene. The mixture was refluxed for 24 hours with water separation via a Dean-Stark trap. The product was concentrated under vacuum and chromatographed on 200 g. of silica gel with 5% ethanol/chloroform. The product-containing fractions were combined and concentrated and the residue crystallized (2 crops) from isopropanol with addition of 4N HCl/isopropanol. A second recrystallization from isopropanol gave 1.1 g. of the title compound as the dihydrochloride, hemihydrate; m.p. 201°-203° C.(d).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:22][PH:23]([O-])([O-:27])[O:24][CH2:25][CH3:26].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][C:12]([CH3:15])([S@:10]([NH:9][C@H:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]1[CH:3]=[C:2]([P:23]([CH3:22])(=[O:27])[O:24][CH2:25][CH3:26])[CH:7]=[CH:6][CH:5]=1)=[O:11])[CH3:14]
Reactant: CC(C)(C)[S@@](=O)N[C@H](c1ccccc1)c1cccc(Br)c1
Reactant: CCO[PH](C)([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(C)(=O)c1cccc([C@H](N[S@](=O)C(C)(C)C)c2ccccc2)c1
Reaction time: 8 h

Procedure:
To (R)—N—((R)-(3-bromophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide, 24-c, (11.8 g, 32.3 mmol), ethyl methylphosphite (6.5 g, 64.6 mmol) and Et3N (9.09 g, 96.9 mmol) in THF (100 ml) was added PdCl2(dppf) (2.1 g, 3.23 mmol). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum to provide the crude product, 24-d, (15 g). The crude product was used to the next step directly.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([NH:31][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)NC3CCCCC3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (76 mg, 0.20 mmol), cyclohexylamine (57 uL, 50 mg, 0.50 mmol) and DMAP (82 mg, 0.67 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 39 mg (44% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.09-1.23 (m, 6 H), 1.49-1.59 (m, 4 H), 1.58-1.66 (m, 4 H), 1.68 (s, 9 H), 2.31-2.46 (m, 1 H), 2.96-3.10 (m, 1 H), 3.31-3.40 (m, 2 H), 3.90-3.99 (m, 2 H), 4.53 (d, J=7.42 Hz, 2 H), 7.99 (dd, J=8.7, 1.7 Hz, 1 H), 8.05 (d, J=8.8 Hz, 1 H), 8.21 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=434.0; Anal. Calcd for C23H35N3O3S+1.10 TFA+0.40 EtOAc+0.3H2O (599.69): C, 53.68; H, 6.71; N, 7.01. Found: C, 53.61; H, 6.74; N, 7.02.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[F:15][C:16]1[CH:43]=[CH:42][C:19]([CH2:20][NH:21][C:22]([C:24]2([CH2:37][CH2:38][CH2:39][CH2:40]Br)[C:36]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][C:22]([C:24]2([CH2:37][CH2:38][CH2:39][CH2:40][N:12]3[CH2:13][CH2:14][N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=4)[CH2:10][CH2:11]3)[C:36]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])=[CH:42][CH:43]=1
Reactant: COc1cccc(N2CCNCC2)n1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: COc1cccc(N2CCN(CCCCC3(C(=O)NCc4ccc(F)cc4)c4ccccc4-c4ccccc43)CC2)n1

Procedure:
Prepared analogously to Example 2 b from 1-(6-methoxy-pyridin-2-yl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluorobenzyl-amide.
Reaction SMILES: C([O:8][C:9](=[O:34])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH3:21])[C:17]([NH2:19])=[O:18])=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[N:28]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:20]([CH:16]([C:17]([NH2:19])=[O:18])[C:13]2[CH:12]=[CH:11][C:10]([C:9]([OH:34])=[O:8])=[CH:15][CH:14]=2)[CH3:21])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: [H][H]
Reactant: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1

Procedure:
A quantity of 0.46 gm (1 mmol) of 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid benzyl ester in 20 ml of ethanol was hydrogenated at 0.25 gm of palladium/charcoal at 50° C. and a hydrogen pressure of 5 bar. After five hours the catalyst was filtered off over celite, and the filtrate was evaporated in vacuo. The evaporation residue was recrystallized from ethanol/water (8:2).
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)=[O:14])=O)C1C=CC=CC=1.[CH3:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>[Pd]>[CH2:26]([O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:13](=[O:14])[CH:12]([NH:11][S:43]([C:40]2[CH:41]=[CH:42][C:37]([CH3:36])=[CH:38][CH:39]=2)(=[O:45])=[O:44])[CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:21][CH:20]=1)=[O:24])[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Product: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 51.9 %

Procedure:
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy) propanamide (1.0 g) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 4-methylbenzenesulfonyl chloride (778 mg) to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-methylbenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (540 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]\[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1.N1CCCCC1>CO>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4](/[CH:13]=[CH:14]\[CH2:15][N:16]4[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1/C=C\CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1/C=C\CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
A solution of tert-butyl (Z)-4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)allyl]piperazine-1-carboxylate (0.0603 g, 0.155 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0249 g, 0.171 mmol) and piperidine (0.0106 g, 0.124 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and then the residue was subjected to silica gel column chromatography (chloroform/methanol). The resulting solid was washed with a mixed solvent of 50% methylene chloride in hexane to obtain tert-butyl 4-((Z)-3-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}allyl)piperazine-1-carboxylate (0.0303 g, 38%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:28]([O:35][C:36]([N:38]1[CH2:42][CH2:41][CH2:40][CH:39]1[CH2:43]OS(C)(=O)=O)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([O:25][CH2:43][CH:39]5[CH2:40][CH2:41][CH2:42][N:38]5[C:36]([O:35][CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:37])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)OCC1CCCN1C(=O)OCc1ccccc1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(O)ccc32)n1)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Nc1nccc(-n2cnc3cc(OCC4CCCN4C(=O)OCc4ccccc4)ccc32)n1)c1ccccc1
Temperature: 80 °C
Yield: 48.6 %

Procedure:
2-[(S)-1-Phenylethylamino]-4-[5-hydroxybenzimidazol-1-yl]-pyrimidine (25 mg) was dissolved in DMF (2.0 mL) and NaH (60%, 6.0 mg) was added followed by N-benzyloxycarbonyl-2-(methanesulfonyloxy)methylpyrrolidine (20 mg) and the resulting suspension was heated to 80° C. for 1 hour. After cooling to room temperature, the solution was then diluted with 10 mL of aqueous saturated NaHCO3 and extracted with 2×10 mL of of EtOAc. The combined organic extracts were then dried (MgSO4) and concentrated under reduced pressure. The residue was purified with preparative thin-layer chromatography (SiO2, 5% MeOH in CH2Cl2) to yield 17 mg of 2-[(S)-1-Phenylethylamino]-4-[5-((N-benzyloxycarbonyl-pyrrolidin-2-yl)methoxy)benzimidazol-1-yl]pyrimidine. Mass spectrum (ESI) 549.3 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2.Cl[CH2:45][C:46]1[C:47]([CH3:52])=[N:48][O:49][C:50]=1[CH3:51].BrCC1OC(C(F)(F)F)=CC=1>>[CH3:52][C:47]1[C:46]([CH2:45][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])=[C:50]([CH3:51])[O:49][N:48]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: Cc1noc(C)c1CCl
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Product: Cc1noc(C)c1CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 4-(chloromethyl)-3,5-dimethylisoxazole to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (35%) as a colorless solid: mp 165-167° C.; 1H NMR (300 MHz, CDCl3) δ 7.24 (t, 1H), 7.16 (d, 1H), 7.05 (t, 1H), 6.72 (d, 1H), 6.50 (s, 1H), 6.05 (s, 1H), 5.85 (d, 2H), 4.75 (ABq, 2H), 4.67 (ABq, 2H), 2.46 (s, 3H), 2.22 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.5, 167.1, 159.1, 156.1, 149.1, 142.4, 141.7, 131.8, 129.0, 124.3, 123.8, 118.9, 108.8, 108.6, 102.9, 101.6, 93.8, 80.6, 58.2, 33.3, 11.5, 10.7; MS (ES+) m/z 391.3 (M+1).