Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([NH:10][C:11](=[O:29])[CH2:12][C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:17][CH:18]=2)=[N:6][CH:7]=[CH:8][CH:9]=1.Cl[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36]>O1CCCC1>[Br:3][C:4]1[C:5]([N:10]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:11](=[O:29])[CH2:12][C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:17][CH:18]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(CC1=CCN(C(=O)OCc2ccccc2)CC1)Nc1ncccc1Br
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN(C(=O)CC1=CCN(C(=O)OCc2ccccc2)CC1)c1ncccc1Br
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.20 g, 5.0 mmol) was slowly added to a solution of benzyl 4-{2-[(3-bromopyridin-2-yl)amino]-2-oxoethyl}-3,6-dihydropyridine-1(2H)-carboxylate (1.91 g, 4.43 mmol) in tetrahydrofuran (15 mL) at 0° C. After 30 min, [2-(chloromethoxy)ethyl](trimethyl)silane (0.86 mL, 4.88 mmol) was added. After 4 h, additional sodium hydride (60% dispersion in oil; 0.10 g, 2.5 mmol) was added, followed by [2-(chloromethoxy)ethyl](trimethyl)silane (0.43 mL, 2.44 mmol). After 18 h, the reaction mixture was quenched with saturated ammonium chloride. The mixture was extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (60% hexanes/ethyl acetate→30% hexanes/ethyl acetate) gave the title compound (1.51 g). MS 560.1 (M).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:21][CH3:22])[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)[CH2:21][CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CCCOc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCN(CCCOc1ccc(N)cc1)C(=O)OC(C)(C)C
Yield: 99.9 %

Procedure:
A solution of ethyl-[3-(4-nitrophenoxy)propyl]carbamic acid tert-butyl ester (2.9 g) (from step A above) in ethanol (70 mL) was treated with 10% Pd/C (442 mg) and stirred for 2 hours under 40 psi of hydrogen. The mixture was filtered through a celite pad. The pad was washed with ethanol and the combined solution was evaporated in vacuo to yield [3-(4-aminophenoxy)propyl]-ethyl-carbamic acid tert-butyl ester (2.63 g, 88%). HRMS, Observed: 317.1839; Calcd for M+Na: 317.1835
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([O:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:15][C:14]=1[C:31](=[O:33])[CH3:32])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:34](OCC)(=[O:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36].Cl>C(O)C.O>[CH2:38]([O:37][C:35](=[O:36])[C:34]([OH:40])=[CH:32][C:31]([C:14]1[CH:15]=[C:16]([C:27]([CH3:29])([CH3:28])[CH3:30])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:18][C:13]=1[O:12][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:33])[CH3:39]
Reactant: CC(=O)c1cc(C(C)(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(O)=CC(=O)c1cc(C(C)(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 93.1 %

Procedure:
Sodium ethoxide (2.8 g, 41 mmol) was added to a suspension of the 1-(2,4-bis-benzyloxy-5-tert-butyl-phenyl)-ethanone (7.8 g, 20 mmol) in ethanol (40 ml). Diethyl oxalate (4 ml, 29.5 mmol) was added and the resulting suspension heated under reflux for ˜2 hrs. to give a pale red solution. The solution was allowed to cool and poured into water (200 ml), the mixture was acidified with hydrochloric acid (50 ml, 1M) and extracted with dichloromethane (150 ml). The extracts were washed with water (2×200 ml) and saturated aqueous sodium chloride solution (100 ml). The solution was dried over anhydrous sodium sulphate and concentrated to a yellow gum. Trituration with hexane gave a yellow solid. Solids were removed by filtration and washed with hexane and dried in vacuo (40° C.), to give 4-(2,4-Bis-benzyloxy-5-tert-butyl-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester as a yellow powder (9.1 g, 93%).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1)[CH3:27].C(N(CC)CC)C.Cl>CN(C)C=O>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:36]([NH:35][C:32]4[CH:33]=[CH:34][C:29]([O:28][CH2:26][CH3:27])=[CH:30][CH:31]=4)=[O:37])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: CCOc1ccc(N=C=O)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Reaction time: 2 h
Yield: 108 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.50 g, 1.40 mmol) and 4-ethoxyphenylisocyanate (0.20 mL, 1.40 mmol) in N,N-dimethylformamide (10 mL), was added triethylamine (0.38 mL, 2.7 mmol) at room temperature under nitrogen. After 2 h, 1 N aq. HCl (15 mL) was added and the solids were isolated by filtration, washed with water (30 mL). The crude solids were slurried in EtOAc (15 mL) for 4 h then filtered, washed with EtOAc (15 mL) and dried in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(4-ethoxy-phenyl)-urea as an off-white solid (0.66 g, 100% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 7.43 min (99.34%); mp: 277-279° C.; 1H NMR (DMSO-d6) δ 1.29 (t, J=7.0 Hz, 3H, CH3), 1.85-2.14 (m, 1H, CHH), 2.23-2.47 (m, 1H, CHH), 2.59 (d, J=17.6 Hz, 1H, CHH), 2.79-3.07 (m, 1H, CHH), 3.94 (q, J=7.0 Hz, 2H, CH2), 4.23-4.36 (m, 1H, CHH), 4.36-4.55 (m, 3H, CHH, CH2), 5.11 (dd, J=4.9, 13.2 Hz, 1H, CH), 6.62 (t, J=5.9 Hz, 1H, NH), 6.80 (d, J=8.9 Hz, 2H, Ar), 7.29 (d, J=8.9 Hz, 2H, Ar), 7.44 (d, J=7.9 Hz, 1H, Ar), 7.51 (s, 1H, Ar), 7.69 (d, J=7.7 Hz, 1H, Ar), 8.40 (s, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.72, 22.49, 31.20, 42.79, 47.10, 51.56, 63.04, 114.44, 119.52, 121.85, 122.91, 126.88, 130.25, 133.39, 142.36, 145.03, 153.24, 155.44, 167.96, 170.99, 172.86; LCMS: MH=437; Anal Calcd for C23H24N4O5: C, 63.29; H, 5.54; N, 12.84. Found: C, 63.27; H, 5.46; N, 12.73.
Reaction SMILES: [C:1]([N:5]([C:7]1[O:8][C:9]2[C:10](=[C:12]([C:24]#[N:25])[C:13]([CH3:23])=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]=2F)[N:11]=1)[CH3:6])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>CS(C)=O>[C:1]([N:5]([C:7]1[O:8][C:9]2[C:10](=[C:12]([C:24]#[N:25])[C:13]([CH3:23])=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]=2[N:37]2[CH2:38][CH2:39][C@H:35]([N:34]([CH3:40])[CH3:33])[CH2:36]2)[N:11]=1)[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N(C)C(C)(C)C)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N(C)C(C)(C)C)nc2c1C#N
Temperature: 150 °C
Reaction time: 4 h

Procedure:
2-(N-tert-butyl-N-methylamino)-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-137) (0.22 g, 0.65 mmol) was suspended in dimethyl sulfoxide (5 ml), then triethylamine (0.19 ml, 1.37 mmol) and (3S)-3-(dimethylamino)pyrrolidine (0.17 ml, 1.34 mmol) were added, followed by stirring in a sealed tube at an external temperature of about 150° C. for 4 hours.
Reaction SMILES: N([O-])=O.[Na+].N[CH:6]1[CH:12]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[ClH:22]>O.[Cu]Cl>[Cl:22][CH:6]1[CH:12]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: Cl
Reactant: NC1CCCCCC1CC(=O)c1ccccc1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(CC1CCCCCC1Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 5 g of sodium nitrite in 20 ml of water is slowly added dropwise at 0°C, whilst stirring, to a solution of 11 g of crude 3-amino-4-cycloheptyl-acetophenone in 70ml of concentrated hydrochloric acid. After completion of the addition the mixture is stirred for a further 30 minutes at 0°C. The reaction solution is then added dropwise at 0 to 5°C, whilst stirring, to a solution of 7 g of freshly prepared copper-(I) chloride in 30 ml of concentrated hydrochloric acid. After completion of the addition, the mixture is stirred for a further hour at room temperature and a further hour at 40 to 50°C. The reaction mixture is now extracted three times with 200 ml of ether at a time. The organic phases are successively washed with water, 2 N sodium hydroxide solution and again with water, dried over sodium sulphate and evaporated in vacuo. Distillation of the evaporation residue in a high vacuum yields crude 3-chloro-4-cycloheptyl-acetophenone in the fraction boiling at about 130°C/0.05 mm Hg.
Reaction SMILES: [NH2:1][C:2]([CH3:12])=[CH:3][C:4](=[O:11])[CH2:5][S:6]([NH:9][CH3:10])(=[O:8])=[O:7].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]([CH3:12])=[CH:3][C:4](=[O:11])[CH2:5][S:6]([N:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:10])(=[O:7])=[O:8]
Reactant: CNS(=O)(=O)CC(=O)C=C(C)N
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(N)=CC(=O)CS(=O)(=O)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
In accordance with the procedure described in Example 7, a solution of 3.8 g of 4-amino-N-methyl-2-oxo-3-pentenesulfonamide and 3.6 ml of benzyl bromide in 50 ml of dimethylformamide was treated with 6 g of potassium carbonate and the mixture was stirred intensively at room temperature for 9 hours. The product was firstly chromatographed on 300 g of silica gel with ethyl acetate as the elution agent and then recrystallized from isopropanol. There were obtained 3.4 g of 4-amino-N-benzyl-N-methyl-2-oxo-3-pentenesulfonamide in the form of colorless crystals, m.p. 115°-118°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.C1(CN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CCCC1.[NH2:44][CH2:45][C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1>>[CH:2]1([CH2:1][N:8]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][C:15]([C:19]([NH:44][CH2:45][C:46]4[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[C:9]2=[O:22])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(CC3CCCC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CC3CCCC3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 61 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(cyclopentylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 61% yield: mp 142-143° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) 8.54-8.43 (m, 2H), 7.63 (d, J=7.2 Hz, 1H), 7.27-7.18 (m, 1H), 6.45 (br s, 1H), 4.53 (d, J=5.7 Hz, 2H), 4.09-4.00 (m, 2H), 3.58-3.52 (m, 2H), 3.17 (d, J=7.2 Hz, 2H), 2.54 (s, 3H), 2.16-1.98 (m, 1H), 1.68-1.49 (m, 6H), 1.19-1.17 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.7, 157.5, 155.5, 153.6, 149.2, 148.8, 135.5, 134.0, 123.5, 116.6, 48.9, 42.6, 42.0, 41.3, 37.9, 30.3, 25.6, 17.2; MS (ES+) m/z 400.3 (M+1).
Reaction SMILES: Cl.C(OC1C([Cl:16])=CC=CC=1C1(OC)CCN(CCC2(O)CCCCC2)CC1)C1C=CC=CC=1.[CH2:34]([O:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]([C:59]2([OH:65])[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]2)[C:49]([N:51]2[CH2:56][CH2:55][CH:54]([O:57][CH3:58])[CH2:53][CH2:52]2)=O)=[CH:44][C:43]=1[Cl:66])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[ClH:16].[CH2:34]([O:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]([C:59]2([OH:65])[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]2)[CH2:49][N:51]2[CH2:52][CH2:53][CH:54]([O:57][CH3:58])[CH2:55][CH2:56]2)=[CH:44][C:43]=1[Cl:66])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC1(c2cccc(Cl)c2OCc2ccccc2)CCN(CCC2(O)CCCCC2)CC1
Reactant: COC1CCN(C(=O)C(c2ccc(OCc3ccccc3)c(Cl)c2)C2(O)CCCCC2)CC1
Agent: Cl
Product: COC1CCN(CC(c2ccc(OCc3ccccc3)c(Cl)c2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 1, step 2, 1-[1-[4-(benzyloxy-3-chlorophenyl]-2-(4-methoxypiperidin-1-yl)ethyl]cyclohexanol hydrochloride was prepared from 1-[1-[4-(benzyloxy)-3-chlorophenyl]-2-(4-methoxypiperidin-1-yl)-2-oxoethyl]cyclohexanol HRMS: calcd for C27H36ClNO3+H, 458.24620; found (ESI, [M+H]+), 458.2443.
Reaction SMILES: FC(F)(F)C(O[C:6](=[O:11])[C:7](F)(F)F)=O.[Br:14][C:15]1C(C)=[N+:17]([O-])[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl.C(OCC)(=O)C>[Br:14][C:15]1[C:7]([CH2:6][OH:11])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1c(Br)ccc[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: OCc1ncccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
Trifluoroacetic anhydride (0.52 mL, 3.6 mmol) was added to a solution of 3-bromo-2-methylpyridine 1-oxide (140 mg, 0.72 mmol) in methylene chloride (2 mL) and the mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-75% ethyl acetate in heptane) to afford the title compound as a yellow oil (110 mg, 75%). 1H NMR (400 MHz, DMSO) δ 8.56 (d, J =4.7 Hz, 1H), 8.10 (dd, J=8.0, 1.1 Hz, 1H), 7.32 (dd, J=8.0, 4.7 Hz, 1H), 4.64 (s, 2H); OH peak not observed.
Reaction SMILES: Cl.C(OC([NH:9][C@H:10]([C:12]1[NH:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]4[N:34]=[C:35]([C@@H:38]([NH:40]C(=O)OC(C)(C)C)[CH3:39])[NH:36][CH:37]=4)=[CH:29][CH:28]=2)[CH:21]=[CH:20]3)[N:16]=1)[CH3:11])=O)(C)(C)C>O1CCOCC1.CO>[NH2:9][C@H:10]([C:12]1[NH:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:27]2[CH:28]=[CH:29][C:30]([C:33]4[N:34]=[C:35]([C@@H:38]([NH2:40])[CH3:39])[NH:36][CH:37]=4)=[CH:31][CH:32]=2)[CH:21]=[CH:20]3)[N:16]=1)[CH3:11]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc(-c2ccc(-c3ccc4cc(-c5c[nH]c([C@H](C)NC(=O)OC(C)(C)C)n5)ccc4c3)cc2)c[nH]1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H](N)c1nc(-c2ccc(-c3ccc4cc(-c5c[nH]c([C@H](C)N)n5)ccc4c3)cc2)c[nH]1
Reaction time: 5 h

Procedure:
A solution of 4N HCl in dioxane (10 mL) was added to tert-butyl ((1S)-1-(4-(4-(6-(2-((1S)-1-((tert-butoxycarbonyl)amino)ethyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)ethyl)carbamate (368 mg. 0.59 mmol) in MeOH (10 mL) and stirred at ambient conditions for 5 hours, concentrated, and dried under vacuum. Tetra HCl salt (assume theoretical: 334 mg). LC-MS retention time 1.33 min; calcd. for C26H27N6: 423.23 m/z Found 423.17 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min and an analysis time of 3 min where Solvent A was 5% methanol/95% water/0.1% TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.C1(P(=[CH:34][C:35]([O:37][CH3:38])=[O:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:34]/[C:35]([O:37][CH3:38])=[O:36])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: CO
Product: COC(=O)/C=C/c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.3 %

Procedure:
Added to a solution of 8.68 g (0.044 mol) of 3,4,5-trimethoxybenzaldehyde in 50 ml of methanol were 15.0 g (0.044 mol) of methyl (triphenylphosphoranylidene)acetate, followed by stirring at room temperature for 18 hours. The solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (silica gel: "MERCK #9385", eluent: 1:1 mixed solvent of ethyl acetate and hexane), whereby 11.24 g of the title compound were obtained as a colorless solid (quantitative yield).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:22]([NH:24][CH2:25][C@@H:26]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:27][C:28]1([C:33]([NH:35][C@H:36]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:40][CH:39]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:23])[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=O)C1C=CC=CC=1>[Pd]>[C:59]([O:58][C:56]([C@H:26]([CH2:25][NH:24][C:22](=[O:23])[C@H:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH2:11])[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:27][C:28]1([C:33]([NH:35][C@H:36]([C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])[CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:42][CH:43]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:57])([CH3:60])([CH3:61])[CH3:62]
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NS(C)(=O)=O)CC1(C(=O)N[C@@H](Cc2ccc(OC(C)(C)C)cc2)C(=O)OC(C)(C)C)CCCC1
Agent: [Pd]
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)[C@H](CCCCN)NS(C)(=O)=O)CC1(C(=O)N[C@@H](Cc2ccc(OC(C)(C)C)cc2)C(=O)OC(C)(C)C)CCCC1
Reaction time: 19 h
Yield: 112.8 %

Procedure:
To a solution of tert-butyl (S,S,S)-N-(1-[3-(N6-benzyloxycarbonyl-N2-mesyllysylamino)-2-(tert-butoxycarbonyl)propyl]-1-cyclopentylcarbonyl)-O4-tert-butyltyrosinate (48.64 g, 54.8 mmmol) in industrial methylated spirits (1.0 L) was added 5% palladium-on-carbon (5 g) (water wet) and the mixture was hydrogenated at 345-414 kPa (50-60 psi) and at room temperature for 19 hours. After removal of the catalyst by filtration, the resulting solution was concentrated under reduced pressure to provide the title compound as a colourless oil (46.56 g) which contained ethanol.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:20]1([CH2:26][CH2:27][NH2:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([CH2:26][CH2:27][NH:28][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCCc1ccccc1
Product: c1ccc(CCNc2nccc(-n3cnc4ccccc43)n2)cc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 2-phenylethylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:28]([CH2:35][C:36](=O)[C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)C.[BH]C#N.[Na]>C(O)C>[C:14]([O:13][C:11]([CH2:10][N:7]1[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH:3]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:2]([NH:1][CH:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:35][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:8]1=[O:9])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)C(c2ccccc2)Sc2ccccc21
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: [BH]C#N
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)NC1C(=O)N(CC(=O)OC(C)(C)C)c2ccccc2SC1c1ccccc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
1.2 g of the compound obtained in Example 20 was mixed with 2.0 g of ethyl benzylpyruvate, 20 ml of ethanol and 1 ml of acetic acid and dissolved therein by warming to 40° C. The resulting reaction mixture was stirred for 3 hours. Thereafter, a solution of 400 mg of sodium boron cyanide hydride in 10 ml of ethanol was slowly added dropwise to the reaction mixture, which was then allowed to stand overnight. After the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate. The resulting solution was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The concentrate was fractionated and purified by silica gel column chromatography using a 9:1 mixture of benzene and ethyl acetate as the eluent. Thus, there was obtained 1.66 g of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:14][CH:15]3[CH2:20][CH2:19][N:18](C(OCC)=O)[CH2:17][CH2:16]3)OCC[O:10]2)[CH:6]=[CH:7][CH:8]=1.[BrH:26].CC(O)C>O>[BrH:26].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:10])[CH2:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)N1CCC(CC2(c3cccc(OC)c3)OCCO2)CC1
Agent: Br
Solvent: O
Solvent: CC(C)O
Product: COc1cccc(C(=O)CC2CCNCC2)c1
Yield: 30 %

Procedure:
A mixture of 30 parts of ethyl 4-[2-(3-methoxyphenyl)-1,3-dioxolan-2-ylmethyl]-1-piperidinecarboxylate, 225 parts of a hydrobromic acid solution 48% in water and a small amount of 2-propanol is stirred and refluxed for 2 hours. The reaction mixture is cooled. The precipitated product is filtered off and dried, yielding 9.5 parts (30%) of 1-(3-methoxyphenyl)-2-(4-piperidinyl)ethanone hydrobromide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[CH:18]=[C:19]([NH:23][C:24]([NH:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[O:33][CH3:34])=[O:25])[CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:10]=[CH:9]2)[CH:3]=1.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>N1C=CC=CC=1>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[NH:26][C:24](=[O:25])[NH:23][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[CH:9][N:8]3[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:1][C:38]([CH:35]4[CH2:37][CH2:36]4)=[O:39])[CH:3]=3)=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccccc1NC(=O)Nc1cccc(-c2ccc3ccn(-c4cc(N)ncn4)c3c2)c1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: COc1ccccc1NC(=O)Nc1cccc(-c2ccc3ccn(-c4cc(NC(=O)C5CC5)ncn4)c3c2)c1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Pyridine was added to 1-(3-(1-(6-aminopyrimidin-4-yl)-1H-indol-6-yl)phenyl)-3-(2-methoxyphenyl)urea (13 mg, 0.029 mmol). At room temperature, cyclopropylcarbonyl chloride (17 μL, 0.29 mmol) was added. The reaction solution was stirred at 50° C. for 1.5 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel; EA:Hx=1:4→DCM:MeOH=20:1) yielded N-(6-(6-(3-(3-(2-methoxyphenyl)ureido)phenyl)-1H-indol-1-yl)pyrimidin-4-yl)cyclopropanecarboxamide as white solid.