Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)=S.CI>C(O)CCCC>[CH:15]1([C:12]2[CH:13]=[CH:14][C:9]([N:8]=[C:6]3[NH:5][CH2:4][CH2:3][CH2:2][NH:1]3)=[CH:10][CH:11]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NCCCNC(=S)Nc1ccc(C2CCCCC2)cc1
Solvent: CI
Solvent: CCCCCO
Product: c1cc(C2CCCCC2)ccc1N=C1NCCCN1

Procedure:
A solution of 2.9 g of N-(3-aminopropyl)-N'-(4-cyclohexylphenyl)thiourea and 0.65 ml of methyliodide in 20 ml of amyl alcohol is slowly heated to the boiling point and then refluxed for 1 hour. After distilling off the solvent, the residue is taken up in methylene chloride and washed with dilute alkaline solution and water. The methylene chloride is distilled off and the crude 2-(4-cyclohexylphenyl)imino-hexahydropyrimidine is recrystallised from acetonitrile. The purified product has a melting point of 179°-181° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:12][CH:11]=1.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: Oc1ccc(Cl)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-chlorophenol and N-(3-{1-[5-(4-chlorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 7.86 (s, br, 1H), 7.62-6.72 (m, 12H), 5.12-5.02 (m, 1H), 3.68-3.52 (m, br, 2H), 3.02-2.82 (br, 2H), 2.82-2.56 (m, br, 4H), 2.56-2.40 (m, br, 2H), 2.06-1.80 (m, br, 6H), 1.64-1.40 (m, br, 2H), 1.25 (d, 6H, J=6.8 Hz). Anal. Calc. for C32H39Cl3N2O2.1.3MeOH: C, 63.25; H, 7.07; N, 4.42; Found: C, 63.41; H, 6.99; N, 4.17. ESMS m/e: 553.0 (M+H)+.
Reaction SMILES: Br[C:2]1[C:28]([O:29][CH3:30])=[CH:27][C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:30][O:29][C:28]1[C:2]([C:35]2[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=2)=[CH:3][C:4]2[N:8]=[CH:7][N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[C:5]=2[CH:27]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cc2c(cc1Br)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1cc2c(cc1-c1cnn(C)c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
A suspension of (1R,2R)-2-((6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (30 mg, 0.06 mmol) from Step 1 of this Example and 1-methylpyrazole-4-boronic acid pinacol ester (26 mg, 0.1 mmol) in DME (300 μL) was added aq 2M K2CO3 (150 μL, 0.2 mmol). Argon was bubbled into the mixture for 5 min followed by the addition of dichlorobis(triphenylphosphine)palladium II (4 mg, 0.006 mmol). Argon was bubbled into the mixture for an additional 5 min and then the mixture was heated in a sealed tube for 15 h. The mixture was cooled to rt and then partitioned between EtOAc (100 mL) and water (50 mL). The EtOAc layer was separated and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC, using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)-2-((6-((6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (16 mg, 53%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.97-8.06 (m, 2H), 7.87 (s, 1H), 7.80 (s, 1H), 7.66 (d, J=1.1 Hz, 1H), 7.27-7.33 (m, 1H), 7.19-7.25 (m, 2H), 5.44 (s, 2H), 4.78 (d, J=4.3 Hz, 1H), 3.85 (s, 6H), 3.51 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.56-1.66 (m, 2H), 1.12-1.32 (m, 4H). LCMS (ESI) m/z 489 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:26])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][CH:15]=1)=[C:7]2[CH3:25].[CH3:27][O:28][C:29](=[O:32])[CH2:30]Br>>[CH3:27][O:28][C:29](=[O:32])[CH2:30][O:26][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:11]2[C:6]=1[C:7]([CH3:25])=[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][CH:15]=1)[C:9](=[O:12])[NH:10]2
Reactant: Cc1c(Cc2ccc(-n3cccn3)cc2)c(=O)[nH]c2c(F)ccc(O)c12
Reactant: COC(=O)CBr
Product: COC(=O)COc1ccc(F)c2[nH]c(=O)c(Cc3ccc(-n4cccn4)cc3)c(C)c12

Procedure:
The title compound was prepared by the method of Preparation 7a using 8-fluoro-5-hydroxy-4-methyl-3-(4-pyrazol-1-ylbenzyl)-1H-quinolin-2-one and bromoacetic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:23][C:24]#[N:25].CC#N>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:23][C:24]#[N:25])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: N#CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#CCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Yield: 999.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperazinyl)-1H-indazole (6.0 g, 2.7 mmol), NaHCO3 (2.5 g, 3.0 m-mol) chloroacetonitrile (2.5 g, 3.3 mmol) and CH3CN (150 mol) was stirred at reflux under N2 for 18 hours. The cooled reaction was poured into H2O and the aqueous solution was extracted with EtOAc. The EtOAc extract was washed with H2O washed with brine, dried with MgSO4 and concentrated to yield 7.0 g of a tan solid. A 1.3 g sample was recrystallized from EtOAc to yield 0.65 g of a beige solid, m.p. 154°-156° C.
Reaction SMILES: [CH2:1]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:20](OC(=O)C)(=[O:22])[CH3:21]>C1(C)C=CC=CC=1>[C:20]([NH:17][C:16]1[CH:15]=[CH:14][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:19][CH:18]=1)(=[O:22])[CH3:21]
Reactant: CCCCCCCCCCCCc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCc1ccc(NC(C)=O)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
In a 1-liter flask fitted with a stirrer and reflux condenser is added 137.5 grams (0.525 mole) of p-n-dodecylaniline, dissolved in 138 ml of toluene. To this is added over a 15-minute period 57.5 ml of acetic anhydride. The temperature rises from 40° to 80° C. After all the acetic anhydride is added, the reaction mixture is stirred at 40° C. for 3 hours. The reaction mixture is then cooled to yield the crude product which is recrystallized from 800 ml of methanol to give 151.1 grams of the above-named material as a solid melting at 100°-102° C.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C@@H:13]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH3:27])[C:20]=3[O:23]C(C)C)[C@H:15]([CH2:28][NH:29]C=O)[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[ClH:32].B(Cl)(Cl)[Cl:34]>>[ClH:34].[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([C@@H:13]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH3:27])[C:20]=3[OH:23])[C@H:15]([CH2:28][NH2:29])[O:14]2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2].[ClH:32]
Reactant: ClB(Cl)Cl
Reactant: Cc1ccc2c(c1OC(C)C)C[C@@H](C1CCN(C(=O)OC(C)C)CC1)O[C@H]2CNC=O
Agent: Cl
Product: Cc1ccc2c(c1O)C[C@@H](C1CCN(C(=O)OC(C)C)CC1)O[C@H]2CN
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Stir a solution of 4-((1R,3S)-1-formylaminomethyl-5-isopropoxy-6-methyl-isochroman-3-yl)-piperidine-1-carboxylic acid isopropyl ester directly from the previous step in of 5% methanolic hydrochloric acid (4 mL) at room temperature for 2 days. Remove the solvent to give yellow oil. Purify the oil on a 2 g SCX column. The resulting residue was redissolved in 4 mL of anhydrous dichloromethane, cooled to −20° C., and 6 equivalents of BCl3 (using 1M BCl3 in dichloromethane) was added slowly into the solution. After the addition, the reaction mixture was stirred at −20° C. for 2 hours and 0° C. for 1 hour. It was then cooled to −20° C. and quenched with 0.5 mL anhydrous CH3OH. The resulting solution was warmed to room temperature and concentrated. The crude product was purified by 2 g SCX column, followed by 1 g silica gel column (eluted by 7N NH3 in methanol:ethyl acetate=1:10) and the hydrochloride was formed with 2M HCl in diethyl ether. CIMS 363.2 (MH+), tR (min)=2.65.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH2:22][C@H:23]4[CH2:25][O:24]4)=[C:16]([CH2:26][CH3:27])[CH:15]=3)[N:10]=2)[CH:6]=[C:5]([CH3:28])[N:4]=1)[CH3:2].[NH3:29]>CO>[NH2:29][CH2:25][C@@H:23]([OH:24])[CH2:22][O:21][C:17]1[C:18]([CH3:20])=[CH:19][C:14]([C:11]2[N:10]=[C:9]([C:7]3[CH:6]=[C:5]([CH3:28])[N:4]=[C:3]([CH2:1][CH3:2])[CH:8]=3)[O:13][N:12]=2)=[CH:15][C:16]=1[CH2:26][CH3:27]
Reactant: N
Reactant: CCc1cc(-c2nc(-c3cc(C)c(OC[C@H]4CO4)c(CC)c3)no2)cc(C)n1
Solvent: CO
Product: CCc1cc(-c2nc(-c3cc(C)c(OC[C@H](O)CN)c(CC)c3)no2)cc(C)n1

Procedure:
A solution of (R)-2-ethyl-4-[3-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridine (201 mg, 0.531 mmol) in 7 N NH3 in MeOH (20 mL) is stirred at 65° C. for 24 h. The solvent is evaporated and the residue is dried under HV to give (R)-1-amino-3-{2-ethyl-4-[5-(2-ethyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-propan-2-ol (183 mg) as a pale yellow oil; LC-MS: tR=0.69 min; [M+1]+=397.18.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:34]=[N:33][CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=O.C(NC(C)C)(C)C.[C:42]1([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH2:55][N:56]2[CH:60]=[CH:59][C:58]([NH2:61])=[N:57]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C)C=O>[CH3:25][C:26]1[CH:34]=[N:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:61][C:58]1[CH:59]=[CH:60][N:56]([CH2:55][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2[O:48][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:57]=1)=[O:30]
Reactant: Cc1cnccc1C(=O)O
Reactant: Nc1ccn(Cc2ccccc2Oc2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: Cc1cnccc1C(=O)Nc1ccn(Cc2ccccc2Oc2ccccc2)n1
Reaction time: 0.17 h

Procedure:
A solution of HATU (38 mg, 0.1 mmol) in N,N-dimethylformamide (0.3 ml) was added to 3-methyl-isonicotinic acid (14 mg, 0.1 mmol, AstaTech Inc) followed by N,N-diisopropylamine (0.050 ml, 0.286 mmol) and left to stand for 10 minutes at ambient temperature. A solution of 1-{[2-(phenyloxy)phenyl]methyl}-1H-pyrazol-3-amine (for a preparation see Intermediate 38)(27 mg, 0.101 mmol) in N,N-dimethylformamide (0.1 ml) was then added and the solution left to stand at room temperature overnight. Purification by MDAP (Method D) gave the title compound (20.2 mg); LCMS: (System 1) MH+=385, tRET=0.93 min.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[Si]([N:18]=[C:19]=[O:20])(C)(C)C.CCN(C(C)C)C(C)C>ClCCl>[NH:1]([C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)[C:19]([NH2:18])=[O:20]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(N)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (180 mg, 1 mmol) in dichloromethane was added TMS-NCO (1 g, 8.7 mmol) and DIPEA (1.2 g, 10 mmol). The mixture was stirred at room temperature overnight, then was concentrated in vacuo. The residue was treated with EtOAc/H2O, the organic layer was combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4].[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25].II>O>[C:24]([CH:23]([S:13][CH2:12][C@@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[NH:10][C:8](=[O:9])[CH2:7][CH2:6][C@@H:2]([C:3]([OH:5])=[O:4])[NH2:1])[CH2:22][C:21]([OH:28])=[O:27])([OH:26])=[O:25]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: O=C(O)/C=C\C(=O)O
Agent: II
Solvent: O
Product: N[C@@H](CCC(=O)N[C@@H](CSC(CC(=O)O)C(=O)O)C(=O)NCC(=O)O)C(=O)O
Reaction time: 12 h
Yield: 71 %

Procedure:
In 150 ml of water are dissolved 9.2 g of glutathione and 5.0 g of maleic acid and the solution is allowed to stand at room temperature for 12 hours. One or 2 drops of the reaction mixture is taken as a test sample and one drop of 0.01 N-iodine test solution (Japanese Pharmacopoeia XII) is added. After confirming that the consumption of iodine has ceased, 6.6 g of copper acetate (monohydrate) is added to the reaction mixture and dissolved and any precipitate is filtered off. The filtrate is concentrated to about 70 ml and diluted with ethanol and the precipitated blue copper salt is recovered by filtration and recrystallized from water-ethanol. This copper salt is dissolved in 200 ml of water and hydrogen sulfide is then bubbled through the solution to precipitate the copper sulfide which is then filtered off. The filtrate is concentrated under reduced pressure and diluted with ethanol and the resulting white crystals are collected by filtration, washed with ethanol and recrystallized from water-ethanol. Thus is obtained about 9 g of the title compound as white amorphous crystals (hygroscopic).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.[OH-].[Na+].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1C=CC=CC=1.O>[OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][N:5]1[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: COc1cc2c(cc1OC)C(C(CO)CO)N(C(=O)c1ccccc1)CC2
Yield: 95 %

Procedure:
0.01 mole (2.7 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline is dissolved in 50 ml of benzene with slight warming, and a solution of 0.015 mole (0.6 g) of sodium hydroxide in 10 ml of water is added to the solution. 0.011 mole (0.5 g) of benzoyl chloride is added dropwise to the reaction mixture, under cooling and stirring. When the addition of acid chloride is complete, the mixture is stirred at room temperature for one hour, whereupon the organic phase is separated, and the aqueous phase is extracted twice with chloroform. The combined organic phases are dried and evaporated to yield the aimed compound.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[O:15][CH3:16].[CH2:17](I)[CH2:18][CH3:19]>>[CH3:16][O:15][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:2]=1[O:1][CH2:17][CH2:18][CH3:19])/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCCI
Reactant: CCOC(=O)/C=C/c1ccc(O)c(OC)c1
Product: CCCOc1ccc(/C=C/C(=O)OCC)cc1OC
Yield: 91.4 %

Procedure:
Following a procedure similar to that described in Preparation 116, but using 11.11 g of ethyl (E)-4-hydroxy-3-methoxycinnamate and 10.20 g of propyl iodide, 12.08 g of the title compound were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1.C([Li])CCC.[O:17]=[C:18]1[CH2:24][CH:23]2[CH2:25][CH:19]1[CH2:20][N:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22]2>C(OCC)C.C1COCC1>[OH:17][C:18]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:7]=2)[CH2:24][CH:23]2[CH2:25][CH:19]1[CH2:20][N:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22]2
Reactant: CCOC(=O)N1CC2CC(=O)C(C2)C1
Reactant: CC(C)Oc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)N1CC2CC(C1)C(O)(c1cncc(OC(C)C)c1)C2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a solution of 3-bromo-5-isopropoxypyridine (0.66 g, 3.1 mmol) in dry diethyl ether (15 mL) at −78° C. was added 2.5 M n-butyllithium (1.2 mL, 3.0 mmol). The reaction was stirred for 30 min under nitrogen at −78° C. and then slowly transferred by cannula into a solution of ethyl 6-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate (0.30 g, 1.5 mmol) in THF (15 mL) at −78° C. The reaction was stirred 4 h at −78° C. and then warmed to ambient temperature overnight, at which time it was quenched with saturated aqueous ammonium chloride (20 mL). The reaction was then extracted with chloroform (2×10 mL), and the combined extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. Excess pyridine was removed by repeated azeotropic rotary evaporation with toluene, and the residue was chromatographed on a silica gel column (with 5% methanol in chloroform) to yield the desired product (0.34 g, 61%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.Br[C:34]1[N:35]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:36]([C:39]2[S:40][CH:41]=[CH:42][N:43]=2)=[CH:37][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8]([C:34]2[N:35]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:36]([C:39]3[S:40][CH:41]=[CH:42][N:43]=3)=[CH:37][CH:38]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)n1c(Br)ccc1-c1nccs1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
2-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.44 g, 13.9 mmol) synthesized in Example (1e) and t-butyl 2-bromo-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (5.21 g, 15.8 mmol) synthesized in Example (1g) were dissolved in a mixed solvent of 1,4-dioxane (200 mL) and water (50 mL), and [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (564 mg, 0.691 mmol) and potassium carbonate (9.67 g, 70.0 mmol) were added, followed by stirring at 50° C. for 3 hours under nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (200 mL) was added, and extraction was carried out with ethyl acetate (400 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-50%) to afford the desired compound (7.12 g, yield 88%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][NH:20][C:19](=[O:23])[CH:18]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].Cl[CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[N:34][CH:35]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][N:20]([CH2:29][C:30]4[CH:31]=[N:32][CH:33]=[N:34][CH:35]=4)[C:19](=[O:23])[CH:18]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:24]([F:27])([F:25])[F:26]
Reactant: O=c1cc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc[nH]1
Reactant: ClCc1cncnc1
Product: O=c1cc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1Cc1cncnc1

Procedure:
The title compound was prepared by a procedure similar to that described for E21 starting from 4-{[(4-{[4-Chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]oxy}-2 (1H)-pyridinone and 5-(chloromethyl)pyrimidine. LC-MS (ESI): m/z 488 [M+H]+; 3.57 min (ret time).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([O:22][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc([N+](=O)[O-])cc3)c2)CC1
Yield: 67.6 %

Procedure:
Following the procedure of Example 69(b) {4-[3-(4-cyanophenoxy)-5-hydroxy-benzoylamino]cyclohexyl}carbamic acid tert-butyl ester 1.1 g (2.43 mmol) and 1-chloro-4-nitro-benzene (0.765 g, 4.86 mmol) were used to afford 0.94 g of the required product. NMR (DMSO-d6): δ 1.2 (4H, m), 1.40 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 6.7 (1H, d), 7.25 (5H, m), 7.55 (2H, m), 7.8 (2H, d), 8.3 (2H, d), 8.4 (1H, d).
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@H:10]([N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=2)[CH2:9]1)C1C=CC=CC=1.Cl[C:38]([O:40][CH2:41][C:42]([Cl:45])([Cl:44])[Cl:43])=[O:39]>CC#N>[Cl:43][C:42]([Cl:45])([Cl:44])[CH2:41][O:40][C:38]([N:8]1[CH2:9][CH:10]([N:21]([C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=2)[CH3:36])[CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:12]1)=[O:39]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: COc1ccc(C(=O)N(C)[C@@H]2CN(Cc3ccccc3)C[C@H]2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Solvent: CC#N
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)OCC(Cl)(Cl)Cl)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Reaction time: 2 h

Procedure:
To a stirred solution of rac-N-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide (1.10 g, 2.05 mmol) in CH3CN (15 ml) at RT was added 2,2,2-trichloroethyl chloroformate (0.56 ml, 4.10 mmol) in two portions (within 30 min.). The reaction mixture was stirred an additional 2 hours, concentrated under vacuo, and then filtrated on silica gel (CH2Cl2 as solvent) to afford the intermediate rac-(3R,4S)-3-(3,4-dichloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benzoyl)-methyl-amino]-pyrrolidine-1-carboxylic acid 2,2,2-trichloro-ethyl ester. This intermediate was then dissolved in AcOH (10 ml) and zinc powder (300 mg) was added in 4 portions over 3 hours. The reaction mixture was then filtered on celite, concentrated under vacuo, taken up in CH2Cl2, and washed with aq. NaHCO3. The organic phases were dried over Na2SO4, and purification by flash chromatography (SiO2, CH2Cl2/MeOH, 90:10) yielded 0.45 g (50%) of the title product as colorless oil. ES-MS m/e: 447.1 (M+H+).