Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][CH2:9][CH2:10][C:11](Cl)=[O:12]>O1CCCC1>[Cl:8][CH2:9][CH2:10][C:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:12]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Product: O=C(CCCl)Nc1ccccc1
Yield: 69.4 %

Procedure:
A solution of 5.6 g (0.06 mole) of aniline in 50 ml of tetrahydrofuran was added dropwise to a solution of 5.0 g (0.04 mole) of 3-chloropropionyl chloride in 50 ml of tetrahydrofuran. The reaction mixture was mechanically stirred and the temperature maintained between 5° and 15° C. throughout the addition. After the final addition, the solution was filtered to remove solid precipitates, and the filtrate was concentrated under reduced pressure to give a white solid. The solid was recrystallized from benzene and petroleum ether (30°-60° C.) to yield 5.1 g (69%) of white solid, mp 114°-115° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[CH2:16][CH2:17][OH:18].O1CCCC1.C(O)(C)(C)C.[K]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1([C:7]2[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=2)[O:18][CH2:17][CH2:16][O:14]1)=[O:5])[CH3:2]
Reactant: OCCCl
Reactant: CCOC(=O)C(=O)c1ccc(Br)cc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCOC(=O)C1(c2ccc(Br)cc2)OCCO1
Temperature: -60 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
To a solution of ethyl-4-bromobenzoylformate (940 mg) and 2-chloroethanol (0.360 mL) in a 2:1 mixture of dimethylformamide:tetrahydrofuran (2.1 mL) was added dropwise at −60° C. a solution of potassium tert-butanol (0.597 mg) in dimethylformamide (2 mL). The reaction mixture was stirred at −60° C. for 4 h then allowed to warm up to room temperature and stirred at room temperature overnight. The reaction mixture was partitioned between an aqueous solution of ammonium chloride and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layer were washed with brine. The crude mixture was concentrated to dryness and purified by chromatography on silica gel to yield the title compound as a colorless liquid (616 mg; 58%). MS (ESI): m/z=300.8 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:12]=[O:13])[NH:6]2.[C:14](OCC)(=[O:16])[CH3:15]>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:16][CH2:14][CH3:15])=[O:13])[NH:6]2
Reactant: CCOC(C)=O
Reactant: O=Cc1cc2c(F)ccc(F)c2[nH]1
Product: CCOC(=O)c1cc2c(F)ccc(F)c2[nH]1

Procedure:
The cooled mixture was dissolved in ethyl acetate, washed with sodium bicarbonate and brine, dried and evaporated. Chromatography on silica gel (1:1 dichloromethane/petrol) followed by recrystallization (dichloromethane/hexane) gave the indole ester (0.75 g). (f) 4,7-Difluoroindole-2-carboxaldehyde
Reaction SMILES: C[O:2][C:3](=[O:26])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:25])[N:15]([CH3:24])[C:16]([CH3:23])=[CH:17][C:18]=2[C:19]([F:22])([F:21])[F:20])=[CH:9][CH:8]=1)[NH2:5].[CH3:27][O:28][CH2:29][CH2:30][C:31]1([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:27][O:28][CH2:29][CH2:30][C:31]1([C:36]([NH:5][C@H:4]([C:3]([OH:2])=[O:26])[CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[C:14](=[O:25])[N:15]([CH3:24])[C:16]([CH3:23])=[CH:17][C:18]=3[C:19]([F:22])([F:20])[F:21])=[CH:11][CH:12]=2)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COCCC1(C(=O)O)CCCC1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(-c3c(C(F)(F)F)cc(C)n(C)c3=O)cc2)C(=O)O)CCCC1

Procedure:
N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine (mp 181-183° C.) was prepared from 4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester and 1-(2-methoxyethyl)cyclopentane carboxylic acid (obtained as described in WO 9910313) using the general procedures described in example 36. ES-HRMS m/e calcd for C26H31F3N2O5 (M+Na) 531.2077, found 531.2084.
Reaction SMILES: [H-].[Na+].[N:3]1([C:13]([C:15]2[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=2)[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.I[CH3:31].S([O-])(O)(=O)=O.[K+]>CN(C=O)C>[CH3:31][N:19]([CH2:18][C:17]1[CH:27]=[CH:28][CH:29]=[C:15]([C:13]([N:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][CH2:5][CH2:4]2)=[O:14])[CH:16]=1)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)N2CCCc3ccccc32)c1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1cccc(C(=O)N2CCCc3ccccc32)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
Sodium hydride (0.91 g, 60% dispersion in oil, 23 mmol) was added to a solution of tert-butyl N-(3-(1,2,3,4-tetrahydroquinoline-1-carbonyl)benzyl)carbamate (8.0 g, 22 mmol) in DMF under nitrogen, while cooling in an ice/water bath. Allowed to warm to room temperature over 45 min. The mixture was cooled in an ice/water bath and iodomethane (9.8 g, 68 mmol) was added dropwise. Allowed to warm to room temperatue and stirred for 5 h. 0.3N Potassium hydrogen sulphate was added and the mixture was extracted with EtOAc. The organic phase was washed with water, dried over sodium sulphate and evaporated. Chromatography (30% EtOAc, 70% 60-80 petroleum ether) afforded tert-butyl N-methyl-N-(3-(1,2,3,4-tetrahydroquinoline-1-carbonyl)benzyl)carbamate (7.7 g, 93%) as a yellow gum.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[CH:13])[CH:7]=1)([CH3:3])[CH3:2].[CH2:15]([O:17][C:18](=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][C:21]=1[F:27])[CH3:16].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[C:13][C:23]2[CH:24]=[CH:25][C:20]([CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:28])=[C:21]([F:27])[CH:22]=2)[CH:7]=1)([CH3:3])[CH3:2]
Reactant: C#Cc1cccc(C(=O)OC(C)C)c1
Reactant: CCOC(=O)Cc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(C#Cc2cccc(C(=O)OC(C)C)c2)cc1F

Procedure:
Following General Procedure B and using 3-ethynyl-benzoic acid isopropyl ester (Intermediate 137, 0.099 g, 0.53 mmol), 2-fluoro-4-iodo phenyl acetic acid ethyl ester (0.164 g, 0.53 mmol), triethyl amine (3 mL), copper(I)iodide (0.01 g, 0.05 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.035 g, 0.5 mmol) followed by flash column chromatography over silica gel (230-400 -mesh) using 7-10% ethyl acetate in hexane as the eluent, the title compound was obtained as a light orange oil (0.08 g, 92%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[Br:10]Br>Br>[BrH:10].[Br:10][CH2:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1cccnc1
Agent: Br
Product: O=C(CBr)c1cccnc1
Temperature: 70 °C

Procedure:
To 10 g (82.5 mmol) of 3-acetylpyridine was added 30 ml of 48% hydrobromic acid. The reaction mixture was heated to 70° C., and 4.2 ml of bromine was added dropwise with stirring. After completed addition of bromine, the reaction mixture was stirred further for 15 minutes at the same temperature and cooled on ice. A crystalline compound formed was filtered off and thoroughly washed with acetone. This yields 21 g (90%) of 3-bromoacetylpyridine hydrobromide, melting point 195-200° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[C:12](Cl)(=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:8][C:12](=[O:14])[CH3:13])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1cc(Br)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)Nc1cc(Br)ccc1[N+](=O)[O-]
Yield: 67.1 %

Procedure:
A solution of 5-bromo-2-nitrobenzenamine (0.5 g, 2.3 mmol), acetyl chloride (0.18 ml, 2.5 mmol) and potassium carbonate (0.64 g, 4.6 mmol) was stirred at 0° C. for 2 hours. The mixture was washed with water (2×10 ml) and dried over anhydrous sodium sulfate before removing the solvents. Crude N-(5-bromo-2-nitrophenyl)acetamide (0.40 g, 70%) was obtained after removing of the solvents. A solution of N-(5-bromo-2-nitrophenyl)acetamide (0.3 g, 1.1 mmol) and benzoyl piperazine (0.44 g, 2.3 mml) was stirred at 105° C. under argon atmosphere for 16 hours. The reaction was quenched with 500 ml water and extracted with ethyl acetate (2×10 ml). N-(5-(4-benzoylpiperazin-1-yl)-2-nitrophenyl)acetamide (0.4 g, 93%) was obtained after flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.31 (s, 3H), 3.40-3.57 (m, 8H), 6.56 (dd, J=2.8, 9.7 Hz, 1H), 7.48 (m, 5H), 8.21 (d, J=9.7 Hz, 1H), 8.38 (d, J=9.7 Hz, 1H), 11.0 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 26.4, 47.1, 47.3, 61.4, 103.8, 108.5, 127.2, 127.6, 129.0, 129.1, 130.7, 135.5, 138.3, 155.7, 170.1, 171.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:33][O:34][CH2:35][CH:36]([NH:38][C:39](=[O:47])[CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[CH3:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:44]3[CH2:45][CH2:46][N:41]([CH2:40][C:39]([NH:38][CH:36]([CH3:37])[CH2:35][O:34][CH3:33])=[O:47])[CH2:42][CH2:43]3)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: COCC(C)NC(=O)CN1CCNCC1
Agent: Cl
Product: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)COC)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 34) was reacted with N-(2-methoxy-1-methylethyl)-2-piperazin-1-yl-acetamide dihydrochloride to give cis-2-{4-[4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-(2-methoxy-1-methyl-ethyl)-acetamide in an analogous manner as described in example 1. LR-MS: 658.2 [(M+H)+].
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:14][O:15][C:16](=[O:28])[C:17]1[C:22]([F:23])=[C:21]([F:24])[C:20](Br)=[C:19]([F:26])[C:18]=1[F:27].C1(B(O)O)C=CC=CC=1>O>[CH3:14][O:15][C:16]([C:17]1[C:22]([F:23])=[C:21]([F:24])[C:20]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:19]([F:26])[C:18]=1[F:27])=[O:28]
Reactant: COC(=O)c1c(F)c(F)c(Br)c(F)c1F
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1
Agent: [Cs+]
Solvent: O
Product: COC(=O)c1c(F)c(F)c(-c2ccccc2)c(F)c1F
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A mixture of toluene (370 mL) and water (70 mL) was degassed with nitrogen for 30 minutes. A mixture of cesium carbonate (102.6 g, 315 mmol), 4-bromo-2,3,5,6-tetrafluoro-benzoic acid methyl ester (30.0 g, 105 mmol), phenyl boronic acid (19.26 g, 157 mmol) and tetrakis triphenyl phosphene palladium(0) (11.5 g, 9.9 mmol) were added to the above degassed water/toluene mixture. The reaction mixture was refluxed overnight. After the reaction is completed, it was cooled to room temperature and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 5% ethyl acetate in hexane to obtain the title compound (26.5 g, 88.6%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16](Br)[O:17][C:11]=2[N:10]=[C:9]1[CH:19]([NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][O:17][C:11]=2[N:10]=[C:9]1[CH:19]([NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(NCCN(C)C)c1nc2oc(Br)cc2c(=O)n1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCC(NCCN(C)C)c1nc2occc2c(=O)n1Cc1ccccc1
Reaction time: 3 h

Procedure:
A mixture of 3-benzyl-6-bromo-2-(1-{[2-(dimethylamino)-ethyl]amino}propyl)furo[2,3-d]pyrimidin-4(3H)-one (1-5, 1 equiv) and 10% Pd/C in ethanol is hydrogenated at 1 atm. for 3 h. The mixture is filtered and the filtrate is concentrated to provide 3-benzyl-2-(1-{[2-(dimethylamino)ethyl]amino}propyl)-furo[2,3-d]pyrimidin4(3H)-one (1-6)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[Br:9]N1C(=O)CCC1=O>C(#N)C>[Br:9][C:3]1[CH:4]=[CH:5][C:6]([NH2:8])=[N:7][C:2]=1[Cl:1]
Reactant: Nc1cccc(Cl)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ccc(Br)c(Cl)n1
Reaction time: 13 h
Yield: 86.8 %

Procedure:
6-Chloropyridin-2-amine (2.0 g) was dissolved in acetonitrile (40 ml). N-Bromosuccinimide (3.1 g) was added and the mixture was stirred under shading at room temperature for 13 hours. The reaction solution was concentrated and the resulting residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (2.8 g).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]4[N:41]=[CH:40][CH:39]=[CH:38][N:37]4[CH:42]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]4[N:41]=[CH:40][CH:39]=[CH:38][N:37]4[CH:42]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn4cccnc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3cn4cccnc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][CH:6]([NH:22][C:23](=[O:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH:6]([NH:22][C:23](=[O:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[CH:9][CH:10]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)CCC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
A mixture of (RS)-5-(4-Benzyloxy-phenyl)-4-(7-phenyl-heptanoylamino)-pentanoic acid methyl ester 78 (0.86 g, 1.7 mmol) and NaOH solution (4 M, 0.85 mL, 3.4 mmol) in MeOH-THF (1:1, 6 mL) was stirred at room temperature overnight. The solvent was removed, and the residue diluted with water. The solution was washed with Et2O, acidified with 5% aqueous HCl, and extracted with EtOAc. The organic phase was then washed with brine, dried (Na2SO4) and the solvent removed under reduced pressure to afford 85 (0.81 g, 98%), m.p. 127.7-129.5° C. 1H NMR (DMSO-d6) δ 1.13-1.23 (m, 6H), 1.35-1.44 (m, 2H), 1.47-1.54 (m, 2H), 1.95-2.00 (m, 2H), 2.14-2.22 (m, 2H), 3.86 (br s, 1H), 5.02 (s, 2H), 6.89 (d, J=8.6 Hz, 2H), 7.08 (d, J=8.5 Hz, 2H), 7.15-7.44 (m, 10H), 7.50 (br d, J=8.6 Hz, 1H), 12.01 (br s, 1H). 13C NM (DMSO-d6) δ 174.3, 171.7, 156.7, 142.3, 137.2, 131.1, 130.1, 128.4, 128.2, 127.8, 127.7, 125.6, 114.3, 49.3, 35.5, 35.2, 31.0, 30.5, 29.3, 28.5, 28.4, 25.3. ESMS 488 (M+H)+.
Reaction SMILES: C1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)C=CC=CC=1.[CH2:14]([CH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)[CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:14]([C@H:19]1[CH2:20][CH2:21][C@H:22]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:11][CH2:12][CH2:7][CH2:8][CH2:9][CH2:10][O:13][C:10](=[O:13])[CH:9]=[CH2:8])=[CH:29][CH:30]=2)[CH2:23][CH2:24]1)[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CCCCCC1CCC(c2ccc(O)cc2)CC1
Product: C=CC(=O)OCCCCCCOc1ccc([C@H]2CC[C@H](CCCCC)CC2)cc1

Procedure:
With the exception of replacing the 4-phenylphenol from the synthesis example 1 with 4-(4-pentylcyclohexyl)phenol, 19.4 g of a monoacrylate containing a group (h): 1-pentyl-4-(4-(6-acryloyloxyhexyloxy)phenyl)trans-cyclohexane was obtained in the same manner as the synthesis example 1. Hereafter this monoacrylate is abbreviated as (A-3).
Reaction SMILES: [CH:1]1([C:7]([OH:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]3OCC[O:28]3)[CH2:14][CH2:13]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C1COCC1.C(OCC)(=O)C>[CH:32]1([C:7]([OH:38])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[O:28])[CH2:16][CH2:17]2)=[O:9])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(OCC1CCN(CCCCCCCCCC2OCCO2)CC1)C(O)(c1ccccc1)C1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=CCCCCCCCCCN1CCC(COC(=O)C(O)(c2ccccc2)C2CCCCC2)CC1
Reaction time: 3 h

Procedure:
(1-(9-(1,3-Dioxolan-2-yl)nonyl)piperidin-4-yl)methyl 2-cyclohexyl-2-hydroxy-2-phenylacetate (200 mg, 0.39 mmol) was dissolved in THF (2 mL) and hydrochloric acid (4 mL, 2 M aqueous solution) with stirring at RT. After 3 hours, the reaction mixture was diluted with ethyl acetate and washed with 10% aqueous potassium carbonate solution. The layers were separated and the organic extracts run through a hydrophobic fit. The solvents were removed in vacuo. The title compound was isolated (190 mg, >100%) and it was used without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:7]([NH:27][C:28](=O)[O:29]C(C)(C)C)[CH2:8][C:9]2[CH:17]=[C:16]([CH3:18])[C:15]3[C:11](=[CH:12][N:13](COCC[Si](C)(C)C)[N:14]=3)[CH:10]=2)[NH:5][CH:6]=1.Cl.C(C1NC=CN=1)(C1NC=CN=1)=O.[NH:48]1[CH2:53][CH2:52][CH:51]([N:54]2[CH2:63][C:62]3[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=3)[NH:56][C:55]2=[O:64])[CH2:50][CH2:49]1>C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[C:4]([CH:7]([NH:27][C:28]([N:48]2[CH2:49][CH2:50][CH:51]([N:54]3[CH2:63][C:62]4[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=4)[NH:56][C:55]3=[O:64])[CH2:52][CH2:53]2)=[O:29])[CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([CH3:18])[CH:17]=2)[NH:14][N:13]=[CH:12]3)[NH:5][CH:6]=1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nc(Br)c[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nc(Br)c[nH]2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 72 h

Procedure:
tert-Butyl 1-(4-bromo-1H-imidazol-2-yl)-2-(7-methyl-2-((2(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethylcarbamate (19.0 mg, 0.035 mmol) was dissolved in a minimum amount of ethyl acetate, and treated with hydrochloric acid (4 N in dioxane, 1.0 mL) (1.0 mL). The mixture was stirred under nitrogen for 3 days. After removal of the solvents, the crude mixture was treated with diethyl ether to give a precipitate which was filtered. The resulting solid was dissolved in dimethylformamide (1.0 mL), cooled to 0° C., and treated with carbonyl diimidazole (6.2 mg, 0.038 mmol, 1.1 equiv) and N′N-diisopropylethylamine (25.0 μL, 4.0 equiv). The reaction was stirred for 5 min at 0° C., warmed to room temperature, stirred for 10 min, and treated with 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (10.1 mg, 0.038, 1.1 equiv). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to afford 7.3 mg, (36%, 2 steps). 1H-NMR (CD3OD, 500 MHz) δ 1.50-1.71 (m, 4H), 2.55 (s, 3H), 2.74-2.93 (m, 2H), 3.16-3.25 (m, 2H), 4.03-4.20 (m, 4H), 4.78 (m, 1H), 5.12-5.19 (m, 1H), 6.63 (d, J=7.9, 1H), 6.94 (d, J=7.9, 1H), 6.94-7.00 (m, 2H), 7.04 (s, 1H), 7.12 (s, 1H), 7.12 (d, J=7.3, 1H), 7.16 (dd, J=7.6, 7.6, 1H), 7.40 (s, 1H), 7.99 (s, 1H). Mass spec.: 577.67 (MH)+.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(=[O:7])=[O:6].Cl[C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:19]=[C:18]([N:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N:30]=[C:29]2[CH:37]([F:39])[F:38])[N:17]=1.CCN(CC)CC>C1COCC1.O>[F:39][CH:37]([F:38])[C:29]1[N:28]([C:18]2[N:19]=[C:20]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:21]=[C:16]([N:11]3[CH2:12][CH2:13][N:8]([S:5]([CH2:4][CH2:3][N:2]([CH3:14])[CH3:1])(=[O:6])=[O:7])[CH2:9][CH2:10]3)[N:17]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CN(C)CCS(=O)(=O)N1CCNCC1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CCS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 43 %

Procedure:
A mixture of the above amine (1.35 g, 6 mmol) and 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (International Publ. No. WO 2002/088112, the disclosure of which is incorporated herein by reference in its entirety) (1.83 g, 5 mmol) and Et3N (1.4 mL, 10 mmol) in 50 mL THF was stirred at room temperature for 5 hrs and then diluted with water. The white solid was collected and dried. Chromatography on alumina, eluting with CH2Cl2 gave 1.42 g (43% yield) of N-[2-({4-[4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine: 1H NMR (CDCl3) δ 7.86 (br dd, J=7.1, 1.2 Hz, 1H), 7.89 (br dd, J=6.8, 1.2 Hz, 1H), 7.53 (t, JHF=53.5 Hz, 1H), 7.46-7.38 (m, 2H), 4.00 (m, 4H), 3.89 (m, 4H), 3.79 (m, 4H), 3.40 (m, 4H), 3.21 (dd, J=8.1, 6.4 Hz, 2H), 2.78 (dd, J=8.1, 6.4 Hz, 2H), 2.27 (s, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6]([CH:7]=[O:8])[C@:5]1([CH3:21])[C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[C:11]([CH:18]([CH3:20])[CH3:19])[CH:10]=1.CC12C(C)(C)C(C(OC[C@@H]3[C@H](COC)[C@]3(C)C3C=C(C(C)C)C=C(C(C)C)C=3)=O)(CC1)OC2=O>>[CH3:1][O:2][CH2:3][C@H:4]1[C@@H:6]([CH:7]=[O:8])[C@@:5]1([CH3:21])[C:9]1[CH:10]=[C:11]([CH:18]([CH3:19])[CH3:20])[CH:12]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1
Reactant: COC[C@@H]1[C@H](C=O)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Agent: COC[C@H]1[C@@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Product: COC[C@H]1[C@@H](C=O)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Yield: 92 %

Procedure:
Following a procedure similar to that for the preparation of Intermediate 45 but using Intermediate 42 as the starting material afforded the title compound (14 mg, 92% yield) as a colorless oil: