Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10](O)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(O)(C1C=CC(C)=CC=1)(=O)=O.O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)CC(O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2c(c1)C=CCC2
Yield: 98.9 %

Procedure:
7-nitro-1,2,3,4-tetrahydo-2-naphthalenol (10.13 g, 0.053 mol) (from Preparation 1) was heated in the presence of TsOH—H2O (1.72 g, 0.009 mol, 0.2 equiv.) in toluene (150 ml) for 2 h at 100° C. The solvent was removed under reduced pressure and the residue was treated with EtOAc (150 ml) and saturated aqueous NaHCO3 (150 ml). The aqueous layer was separated and extracted with additional EtOAc (2×100 ml). The combined organic layers were washed with saturated aqueous NaCl (200 ml), dried (Na2SO4), filtered, and concentrated under reduced pressure to give 7-nitro-3,4-dihydronaphthalene as a brown oil (9.18 g, 100%) which was used in the next step without additional purification. Rf (silica gel): 0.79 (70% hexane: 30% EtOAc); 1H NMR (300 MHZ, CDCl3) 7.95 (dd, J=2.4 and 8.1 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 6.50 (d, J=6.50 Hz, 1H), 6.18 (dt, J=4.5 and 9.6 Hz, 2H), 2.88 (t, J=8.4 Hz, 2H), 2.40-2.34 (m, 2H); 13C NMR (75 MHZ, CDCl3) 147.1, 143.1, 135.3, 131.4, 128.2, 126.5, 121.8, 120.3, 27.4, 22.5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[N:17]=2)=[O:11])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:39]([C:41]1(C)OCC[O:42]1)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]2([C:12]3[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[N:17]=3)[O:42][CH2:41][CH2:39][O:11]2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)n1)c1ccc(Br)cc1
Reactant: CCC1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1ccccc1[C@H](CC1(c2ccc(=O)n(C)n2)OCCO1)c1ccc(Br)cc1
Yield: 16.2 %

Procedure:
A solution of (R)-6-(3-(4-bromophenyl)-3-o-tolylpropanoyl)-2-methylpyridazin-3(2H)-one (example 8, step 3; 235 mg, 571 μmol), and p-toluenesulfonic acid monohydrate (10.9 mg, 57.1 μmol) in 2-ethyl-2-methyl-1,3-dioxolane (2.33 g, 20.0 mmol) was heated for 45 min at 110° C., then partitioned between sat. aq. sodium hydrogencarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; gradient heptane-ethyl acetate) produced the title compound (42 mg, 16%). White semisolid, MS: 455.1 [M+H]+.
Reaction SMILES: N1C=CN=C1.[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O.O1CCCC1>[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][Si:20]([CH3:22])([CH3:21])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: OCCCCCCCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCBr
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
1.55 g of imidazole were added to a solution fo 3.97 g of 8-bromo octanol in 19 ml of dimethylformamide, and over 10 minutes, 3.32 g of terbutyl chloro dimethyl silane in solution in 4.7 ml of tetrahydrofuran were added. The mixture was stirred for one hour at ambient temperature and the insoluble part was filtered off. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed on silica (eluant:cyclohexane-toluene 8-2) to obtain 5.4 g of the expected product.
Reaction SMILES: C1(S(O[CH2:11][CH2:12][N:13]2[CH2:17][C@H:16]([CH:18]([CH3:20])[CH3:19])[N:15]([C:21]3[CH:26]=[CH:25][N:24]4[N:27]=[CH:28][C:29]([C:30]5[CH:35]=[CH:34][C:33]([C:36]6[N:40]=[CH:39][N:38]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:37]=6)=[CH:32][CH:31]=5)=[C:23]4[N:22]=3)[C:14]2=[O:49])(=O)=O)C=CC=CC=1.[NH:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1>>[CH:18]([C@H:16]1[CH2:17][N:13]([CH2:12][CH2:11][N:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:14](=[O:49])[N:15]1[C:21]1[CH:26]=[CH:25][N:24]2[N:27]=[CH:28][C:29]([C:30]3[CH:31]=[CH:32][C:33]([C:36]4[N:40]=[CH:39][N:38]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:37]=4)=[CH:34][CH:35]=3)=[C:23]2[N:22]=1)([CH3:19])[CH3:20]
Reactant: CC(C)[C@H]1CN(CCOS(=O)(=O)c2ccccc2)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Reactant: C1CCNC1
Product: CC(C)[C@H]1CN(CCN2CCCC2)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To the crude (S)-2-(4-isopropyl-2-oxo-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-1-yl)ethyl benzenesulfonate from step 1 (5 mL, 0.051 g, 0.071 mmol) was added pyrrolidine (2 mL) and the reaction stirred overnight at ambient temperature. The reaction was concentrated in vacuo and the material taken up in dichloromethane and washed with 1N NaOH. The combined organic layers were concentrated in vacuo and the residue chromatographed using 2% MeOH/dichloromethane to 5% MeOH/dichloromethane to yield (S)-4-isopropyl-1-(2-(pyrrolidin-1-yl)ethyl)-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (0.041 g, 95%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH2:3]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C1C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([O:1][CH:2]2[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][CH:10]=3)[CH2:3]2)=[O:28])=[CH:22][CH:21]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: OC1CCN(CCc2c[nH]c3ccccc23)C1
Solvent: c1ccccc1
Product: COc1ccc(NC(=O)OC2CCN(CCc3c[nH]c4ccccc34)C2)cc1

Procedure:
A stirred suspension of 3.5 g. (0.015 mole) of 3-[2-(3-hydroxypyrrolidinyl)ethyl]indole in 50 ml. of dry benzene was treated dropwise with 2.3 g. (0.015 mole) of p-methoxyphenylisocyanate in 15 ml. of dry benzene. After addition (0.5 hour) the mixture was refluxed for 12 hours after which time only a small amount of solid remained suspended. The residue was filtered off and the filtrate was evaporated under vacuum to an orange gum. The product was dissolved in benzene and chromatographed on 200 g. of 60-100 mesh magnesium silicate, eluting first with benzene then benzene with increasing amounts of acetone. At 20% acetone-benzene pure product was obtained from the column; yield 3.5 g. (60%). The glassy solid would not crystallize.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[BrH:24]>C(O)(=O)C.O.[Cu]Br>[Br:24][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Br
Reactant: Nc1ccc(N2CCC(c3ccccc3)CC2)cc1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc(N2CCC(c3ccccc3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-aminophenyl)-4-phenylpiperidine (2 g) in 47% hydrobromic acid (20 ml) and acetic acid (23 ml) was added dropwise sodium nitrite (0.55 g) in water (1 ml) under ice-cooling. The solution was then stirred for 30 minutes at 0° C. The reaction mixture was added dropwise copper(I) bromide (2.27 g) in 47% hydrobromic acid (2.3 ml) under ice-cooling. The reaction mixture was then stirred for 1.5 hours at ambient temperature. The reaction mixture was pulverized with water. The precipitate was collected by filtration. The powder was added 1N-sodium hydroxide (21 ml) and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography over silica using dichloromethane/n-hexane (1:1) as the elution to give 1-(4-bromophenyl)-4-phenylpiperidine (1.23 g).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][CH:20]([CH3:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[S:18])=[CH:12][CH:11]=1>ClCCl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[C:2](=[O:8])[C:3](=[O:5])[N:19]([CH:20]([CH3:25])[C:21]([CH3:23])([CH3:22])[CH3:24])[C:17]2=[S:18])=[CH:14][CH:15]=1
Reactant: CC(NC(=S)Nc1ccc(Cl)cc1)C(C)(C)C
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Product: CC(N1C(=O)C(=O)N(c2ccc(Cl)cc2)C1=S)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
Ethyl chlorooxoacetate (0.62 mL, 5.60 mmol) was added to a stirring solution of the above thiourea (1.00 g, 3.72 mmol) in dichloromethane (15 mL) and the resulting mixture was stirred overnight at room temperature. Concentration, trituration of the residue with diethyl ether, and recrystallization from boiling methanol afforded 0.72 g (60%) of 1-(4-chloro-phenyl)-2-thioxo-3-(1,2,2-trimethyl-propyl)-imidazolidine-4,5-dione as a yellow solid: mp 198.8–199.5° C.; 1H NMR (DMSO-d6): δ 7.61 (d, 2H), 7.40 (d, 2H), 4.82 (q, 1H), 1.45 (d, 3H), 0.98 (s, 9H); IR (KBr): 3500, 2920, 1775 cm1; MS (m/z) 324 (M+).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:33])[N:5]([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[O:15][CH3:16].O.[OH-].[Li+]>C1COCC1.O>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]([N:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[O:15][CH3:16])[CH:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:3]([OH:34])=[O:2])=[O:26])=[CH:23][CH:22]=1
Reactant: COC(=O)C(c1ccccc1Cl)N(Cc1ccc(OC)cc1OC)C(=O)c1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N(Cc2ccc(OC)cc2OC)C(C(=O)O)c2ccccc2Cl)cc1
Yield: 94.7 %

Procedure:
To a solution of N-(4-methoxybenzoyl)-N-(2,4-dimethoxybenzyl)-(2-chlorophenyl)glycine methyl ester (30 g) in THF (350 ml) is added a solution of lithium hydroxide monohydrate (4.2 g) in water (85 ml) and the mixture is refluxed for 2 h before cooling and evaporation of excess THF in vacuo. The aqueous solution is extracted with ether to remove neutral compounds and the aqueous solution adjusted to pH2 with conc. hydrochloric acid. The acidic solution is extracted with dichloromethane (×3), washed with water, dried (MgSO4) and evaporated in vacuo to give the title compound (27.6 g) as a solid foam.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:4][C:3]=1[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.[Li]C(C)(C)C.[CH2:32]([Sn:36](Cl)([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH3:35].C(=O)([O-])O.[Na+]>C1COCC1>[C:15]1([C:5]2[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:2]([Sn:36]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:32][CH2:33][CH2:34][CH3:35])=[C:3]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[N:4]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccccc2)nc(-c2ccncc2)c1Br
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(-c2ccncc2)nc(-c2ccccc2)n1COCC[Si](C)(C)C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of the product of Step 2 (13.4 g, 31.2 mmol) in THF (200 ml) at −78° C. was added dropwise tBuLi (22 ml, 1.7M, 38 mmol). After 25 minutes tributyltin chloride (12.37 g, 10.3 ml, 38 mmol) was added dropwise and the mixture was then allowed to reach room temperature overnight. The reaction was then poured into a saturated solution of sodium hydrogen carbonate and washed several times with diethyl ether. The combined organic layers were dried (magnesium sulphate), concentrated in vacuo and the residue purified by silica gel chromatography, eluting with a 0.5:4.5:45:50 mixture of 0.88 ammonia solution:methanol:hexane:diethyl ether to give the title compound (18.5 g, 93%) as a brown viscous oil; MS(AP+) m/e 641/643/644[M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=3)[C:15]([O:17]C(C)(C)C)=[O:16])[O:9][N:8]=2)[CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=3)[C:15]([OH:17])=[O:16])[O:9][N:8]=2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)c1cccc(-c2nc(-c3cccnc3)no2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cccc(-c2nc(-c3cccnc3)no2)c1
Reaction time: 1 h

Procedure:
A solution of the product of Example 45 (180 mg, 0.56 mmol) in methylene chloride (5 mL) was stirred with trifluoroacetic acid (1 mL) at room temperature for 4 hours. It was then concentrated and the residue was stirred in water (15 mL) for 1 hour. The precipitate was collected by filtration and dried to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 7.66 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.83 (t, J=7.5 Hz, 1H), 8.28 (ddd, J=8.0, 1.5, 1.2 Hz, 1H), 8.42-8.51 (m, 2H), 8.70 (t, J=1.6 Hz, 1H), 8.83 (dd, J=5.0, 1.8 Hz, 1H), 9.28 (dd, J=2.2, 1.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 268 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([CH2:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[C:22]([C@H:24]3[CH2:28][CH2:27][CH2:26][N:25]3[CH:29]([CH2:33][CH2:34]O)[C:30]([OH:32])=[O:31])=[O:23])[N:10]2[CH2:13][CH3:14])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2]>Cl>[CH2:13]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([C:1]([NH2:2])=[NH:3])[CH:12]=2)[CH:8]=[C:9]1[CH2:15][CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([C@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH:29]1[CH2:33][CH2:34][O:32][C:30]1=[O:31])=[O:23])[CH3:14]
Reactant: CCn1c(CC[C@@H]2CCCN2C(=O)[C@H]2CCCN2C(CCO)C(=O)O)cc2ccc(C(=N)N)cc21
Agent: Cl
Product: CCn1c(CC[C@@H]2CCCN2C(=O)[C@H]2CCCN2C2CCOC2=O)cc2ccc(C(=N)N)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.9 %

Procedure:
130 mg(0.269 mmole) of 2-[(R)-2-[[(S)-2-[2-(6-amidino-1-ethylindol-2-yl)ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]-4-hydroxybutanoic acid was dissolved in 5 ml of 3N—HCl, and the resulting solution was stirred for 18 hours at room temperature and then evaporated under reduced pressure to remove the solvent. The residue was purified with column chromatography [eluent: ethyl acetate/methanol(3:1) on NH-DM1020 silica to obtain 70 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:39])[C@@H:12]([N:24]2[C:28](=[O:29])[CH:27]([C:30]3[CH:35]=[CH:34][C:33]([S:36][CH3:37])=[CH:32][CH:31]=3)[NH:26][C:25]2=[O:38])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[S:8][CH:9]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:48])C=1>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:39])[C@@H:12]([N:24]2[C:28](=[O:29])[CH:27]([C:30]3[CH:31]=[CH:32][C:33]([S:36]([CH3:37])=[O:48])=[CH:34][CH:35]=3)[NH:26][C:25]2=[O:38])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[S:8][CH:9]=1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2C(F)(F)F)N2C(=O)NC(c3ccc(SC)cc3)C2=O)n1
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2C(F)(F)F)N2C(=O)NC(c3ccc(S(C)=O)cc3)C2=O)n1
Reaction time: 0.17 h
Yield: 52.6 %

Procedure:
To a solution of 2-[(S)-2-[4-(4-methylsulfanyl-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-(2-trifluoromethyl-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester (95 mg, 0.16 mmol) in dichloromethane (15 mL) was added 3-chloroperbenzoic acid (75% purity) (45 mg, 0.19 mmol) at 0° C. After stirring for 10 minute the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was dried over sodium sulfate, filtered, concentrated and the residue was purified by chromatography over silica gel eluted with acetone. The isolated material was precipitated from acetone with an excess of hexanes to afford 2-[(S)-2-[4-(4-methanesulfinyl-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-(2-trifluoromethyl-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester as an amorphous white solid (50 mg, 52%).
Reaction SMILES: Cl[C:2]1[C:3]([CH2:26][NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[C:30]([Cl:41])[CH:29]=2)=[C:4]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:19])=[N:16][CH:17]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:42]C1C=CC(C2C=CC(N)=CC=2)=C(C)C=1>>[Cl:42][C:7]1[C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:19])=[N:16][CH:17]=2)=[C:3]([CH2:26][NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[C:30]([Cl:41])[CH:29]=2)[CH:2]=1
Reactant: O=C(O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(Cl)c2CNc2ccc(-c3ccc(Cl)cc3)c(Cl)c2)cn1
Reactant: Cc1cc(Cl)ccc1-c1ccc(N)cc1
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)c(Cl)cc2CNc2ccc(-c3ccc(Cl)cc3)c(Cl)c2)cn1

Procedure:
The title compound was prepared as described in Example 77 substituting 2,4′-dichloro-[1,1′-biphenyl]-4-amine (see Example 74) for 4′-chloro-2′-methyl-[1,1′-biphenyl]-4-amine.
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH2:9][CH2:10]CC)=[O:7])=[CH:4][N:3]=[CH:2]1.[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH:13]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:15][C:14]=1[CH2:19][N:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=[CH:2]1
Reactant: ClCc1ccccc1
Reactant: CCCCOC(=O)c1cnc[nH]1
Product: CCOC(=O)c1cncn1Cc1ccc2ccccc2c1
Yield: 162.3 %

Procedure:
2.4 g (17.1 mmol) of butyl imidazole-5-carboxylate were reacted with 4.1 g (32.1 mmol) of benzyl chloride analogously to procedure 8a. 7.3 g (78%) of the product were obtained.
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][C:12]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([C:15](=[O:26])[NH:16][C@@H:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH3:18])[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>[Pd]>[C:30]([O:29][C:28](=[O:34])[NH:27][C:12]1([C:15](=[O:26])[NH:16][C@@H:17]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH3:18])[CH2:13][CH2:14][CH:9]([NH2:8])[CH2:10][CH2:11]1)([CH3:31])([CH3:32])[CH3:33]
Reactant: [H][H]
Reactant: C[C@@H](NC(=O)C1(NC(=O)OC(C)(C)C)CCC(NCc2ccccc2)CC1)c1ccc(F)cc1
Agent: [Pd]
Product: C[C@@H](NC(=O)C1(NC(=O)OC(C)(C)C)CCC(N)CC1)c1ccc(F)cc1

Procedure:
(R)-tert-butyl 4-(benzylamino)-1-(1-(4-fluorophenyl)ethylcarbamoyl)cyclohexylcarbamate (Intermediate 94, the “cis” isomer, 87 mg) was hydrogenated at 1 atm hydrogen gas using 10% Pd/C (26 mg, Degussa type E101 NE/W 50% wet) for 16 hours. The reaction was filtered over celite to yield {4-Amino-1-[(R)-1-(4-fluoro-phenyl)-ethylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester (70 mg). MS MH+ 380.4
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=1[OH:18])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:24]O>>[CH3:24][O:2][C:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=1[OH:18])=[O:3]
Reactant: CO
Reactant: CC(C)(C)c1cc(C(=O)O)c(O)c(S(C)(=O)=O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C(C)(C)C)cc(S(C)(=O)=O)c1O

Procedure:
1.0 g (0.003 mol) of 2-carboxy-4-(1,1-dimethylethyl)-6-methylsulfonylphenol prepared in Example 3 is dissolved in 6 ml of methanol, and heated under reflux with 0.1 ml of concentrated sulfuric acid for 2 days. The mixture is poured onto ice-water, and this is extracted with ethyl acetate, the solvent is removed in vacuo and the residue is subjected to chromatography on silica gel using ethyl acetate/toluene 4:1 as the eluting agent.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:39]=1[O:40][CH2:41][CH2:42][CH3:43]>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.C(O)C>[F:33][C:34]1[CH:35]=[C:36]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:16]=2)[CH:37]=[CH:38][C:39]=1[O:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCOc1ccc(B(O)O)cc1F
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCOc1ccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)cc1F
Yield: 61.9 %

Procedure:
Prepared according to the method described in Example 33a) from toluene (5 ml), aqueous sodium carbonate (2 M, 1 ml), (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.25 g, Example 40a), ethanol (1 ml), 3-fluoro-4-propoxybenzeneboronic acid (0.23 g) and tetrakis(triphenylphosphine)palladium(0) (22 mg) with heating at reflux for 4 hours. The residue obtained after work-up was purified by column chromatography over silica eluting with ethyl acetate to give the title compound as a white solid (0.19 g)
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[OH:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>O1CCOCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:44]4[CH2:45][CH2:46][N:41]([CH2:40][CH2:39][OH:38])[CH2:42][CH2:43]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Reactant: OCCN1CCNCC1
Solvent: C1COCCO1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CCN(CCO)CC3)CC2)n1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (150 mg, 0.280 mmol) and N-(2-hydroxyethyl)piperazine (360 mg, 2.77 mmol) in 1,4-dioxane (15 mL) was refluxed for 3 hrs. The reaction mixture was then cooled to room temperature and the solvent was removed under vacuum. The residue was partitioned between CH2Cl2 and H2O. The phases were separated, the organic phase was dried (Na2SO4), and the solvent was removed under vacuum. Recrystallization from CH2Cl2/hexanes gave 2-{4-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-1-piperazinyl}ethanol (134 mg, 72%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[CH3:12][N:13]=[C:14]=[O:15]>C(#N)C>[CH3:12][NH:13][C:14]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])=[O:15]
Reactant: CN=C=O
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CC#N
Product: CNC(=O)NCCSCc1[nH]cnc1C
Yield: 58.8 %

Procedure:
A mixture of 4 -methyl-5-((2-aminoethyl)thiomethyl)imidazole (5.1 g.) and methyl isocyanate (2.0 g.) in acetonitrile was heated for 18 hours in a pressure vessel at 100°. After cooling, the solid obtained was collected and recrystallised from isopropyl alcohol-acetonitrile to give N-methyl-N'-[2-((4-methyl-5-imidazolyl) methylthio)ethyl]urea (4.0 g.) m.p. 158°-159°.