Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[N:39][C:40]([O:42][CH2:43][C:44]([CH3:46])=[CH2:45])=[O:41])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@@H:10]([C:27]2[NH:31][C:30](=[O:32])[N:29]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:28]=2)[C:11]2[C:12]([F:26])=[C:13]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:5][CH:4]=1.[CH2:47]([CH:49]([O:52][C:53](=[O:57])[O:54][CH2:55]Cl)[CH2:50][CH3:51])[CH3:48].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[NH2:1][C:2](=[N:39][C:40]([O:42][CH2:43][C:44]([CH3:46])=[CH2:45])=[O:41])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]([C:27]2[N:31]=[C:30]([O:32][CH2:55][O:54][C:53]([O:52][CH:49]([CH2:50][CH3:51])[CH2:47][CH3:48])=[O:57])[N:29]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:28]=2)[C:11]2[C:12]([F:26])=[C:13]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:7][CH:8]=1
Reactant: CCC(CC)OC(=O)OCCl
Reactant: C=C(C)COC(=O)N=C(N)c1ccc(N[C@@H](c2nn(-c3ncccn3)c(=O)[nH]2)c2cc(OC)cc(OCCOC(C)=O)c2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)COC(=O)N=C(N)c1ccc(N[C@@H](c2nc(OCOC(=O)OC(CC)CC)n(-c3ncccn3)n2)c2cc(OC)cc(OCCOC(C)=O)c2F)cc1
Temperature: 25 °C

Procedure:
Under nitrogen atmosphere, a mixture of acetic acid 2-{3-[(R)-{4-[amino(2-methylallyloxycarbonylimino)methyl]phenylamino}-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxyl}ethyl ester (Example 45, 300 mg), carbonic acid chloromethyl ester 1-ethylpropyl ester [CAS No. 176310-42-2] (177 mg), potassium carbonate (80 mg) and N,N-dimethylformamide (5 mL) was stirred at 85° C. for 60 minutes. After cooling the mixture to room temperature, ethyl acetate and water were added thereto. The organic layer was collected, the aqueous layer was reextracted with ethyl acetate, and all the organic layers were combined. The organic layer was sequentially washed with water and with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate-methanol) to obtain the captioned compound (130 mg) as a solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([C:28]#[N:29])([CH3:27])[C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:17]=2[O:30][CH3:31])[C@@H:9]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O)(C)(C)C.[ClH:38].Cl.COC1C=CC(C(C2SCCS2)(C)C)=CC=1CN[C@H]1CCCN[C@H]1C1C=CC=CC=1>>[ClH:38].[ClH:38].[C:28]([C:22]([C:20]1[CH:19]=[CH:18][C:17]([O:30][CH3:31])=[C:16]([CH:21]=1)[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([CH3:27])[C:23]([F:24])([F:25])[F:26])#[N:29]
Reactant: COc1ccc(C(C)(C#N)C(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: COc1ccc(C(C)(C)C2SCCS2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: Cl
Product: COc1ccc(C(C)(C#N)C(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 94 in the same manner of Compound 83.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:27])[N:6]([CH:24]([CH3:26])[CH3:25])[C:7]1[S:8][C:9]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][C:11]=1[C:12](OCC)=[O:13])(=O)C.[O-]CC.[Na+].IC>>[CH3:1][N:4]1[C:12](=[O:13])[C:11]2[CH:10]=[C:9]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:8][C:7]=2[N:6]([CH:24]([CH3:26])[CH3:25])[C:5]1=[O:27]
Reactant: CCOC(=O)c1cc(Cc2ccccc2)sc1N(C(=O)NC(C)=O)C(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CI
Product: CC(C)n1c(=O)n(C)c(=O)c2cc(Cc3ccccc3)sc21

Procedure:
Prepared from N′-acetyl-N-(1-methylethyl)-N-[3-ethoxycarbonyl-5-(phenylmethyl)-2-thienyl]urea (700 mg), sodium ethoxide (400 mg) and iodomethane (0.45 ml) following the method of Example 12, step d) to give the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH:6]=1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.C(Cl)Cl>CN(C)C1C=CN=CC=1>[C:17]([Si:14]([CH3:16])([CH3:15])[O:13][CH:10]1[CH2:9][CH2:8][CH:7]([N:5]2[CH:6]=[C:2]([I:1])[CH:3]=[N:4]2)[CH2:12][CH2:11]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O[C@H]1CC[C@H](n2cc(I)cn2)CC1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCC(n2cc(I)cn2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of trans-4-(4-Iodo-pyrazol-1-yl)-cyclohexanol (Compound 137 D, 1.00 g, 3.42 mmol), tert-butyldimethylsilyl chloride (1.03 g, 6.85 mmol), 4-dimethylaminopyridine (80 mg, 0.7 mmol), 1H-imidazole (699 mg, 10.3 mmol) and DCM (20 mL, 300 mmol) was stirred room temperature for 20 min. The material was transferred to a separatory funnel, extracting with DCM and sat. NaHCO3. The organic layer was dry-loaded onto silica gel for column chromatography, eluting with 3% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as clear oil. 1H NMR (400 MHz, DMSO-d6): δ=0.05 (s, 6H), 0.86 (s, 9H), 1.33-1.47 (m, 2H), 1.70-1.91 (m, 4H), 1.96 (d, J=11.9 Hz, 2H), 3.58-3.75 (m, 1H), 4.11-4.21 (m, 1H), 7.49 (s, 1H), 7.92 (s, 1H). MS (ES+): m/z=407.05 [MH+]. HPLC: tR=3.22 min (polar—5 min, ZQ3).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=4[NH2:28])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30].C([O-])(O)=O.[Na+].O>ClCCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:20][C:19]=4[NH:28][C:29](=[O:31])[CH3:30])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CC(=O)Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylamine, (Example 163), (0.25 g, 0.65 mmol) in 1,2-dichloroethane (6.5 mL) was added acetic anhydride (0.15 mL, 1.6 mmol). The mixture was stirred at room temperature for 18 h and then treated with satd NaHCO3 and H2O. The mixture was extracted with EtOAc (2×75 mL) and the combined extracts were washed with H2O (75 mL) and brine (75 mL), dried over Na2SO4, filtered, and concentrated onto silica gel. Purification by silica gel chromatography (gradient, 10 to 40% EtOAc/hexanes) afforded the title compound as a yellow solid. Mp: 137–138° C. MS (ESI, pos. ion) m/z: 479.2 (M+1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[N:15]([CH3:51])[C:16](=[O:50])[C:17]([CH3:49])=[C:18]2[C:23]=1[C:22](=[O:24])[N:21](CC1C=CC(OC)=CC=1)[C:20](=[O:34])[N:19]2[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([N:43]2[CH2:47][CH2:46][CH:45]([OH:48])[CH2:44]2)=[O:42])[CH:36]=1>C1(OC)C=CC=CC=1>[F:5][C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[N:15]([CH3:51])[C:16](=[O:50])[C:17]([CH3:49])=[C:18]2[C:23]=1[C:22](=[O:24])[NH:21][C:20](=[O:34])[N:19]2[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([N:43]2[CH2:47][CH2:46][CH:45]([OH:48])[CH2:44]2)=[O:42])[CH:36]=1
Reactant: COc1ccc(Cn2c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c3n(-c3cccc(C(=O)N4CCC(O)C4)c3)c2=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Product: Cc1c(=O)n(C)c(Nc2ccc(I)cc2F)c2c(=O)[nH]c(=O)n(-c3cccc(C(=O)N4CCC(O)C4)c3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
Aluminium chloride (0.887 g, 6.65 mmol) was added in small portions to a solution of crude 5-((2-fluoro-4-iodophenyl)amino)-1-(3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)-3-(4-methoxybenzyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (2d) (0.500 g, 0.665 mmol) in Anisole (5 ml). The resulting reaction mixture was stirred at room temperature for 16 h, which was then quenched by addition of MeOH (15 ml) and 2N HCl (0.5 ml). The resulting mixture was concentrated under vacuum and the residue thus obtained was purified by silica gel column chromatography to yield the titled compound (22) (0.13 g)
Reaction SMILES: [CH3:1][C:2]1[CH2:7][O:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH:3]=1>CO.[Pt]>[CH3:1][CH:2]1[CH2:7][O:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1
Reactant: CC1=CCC(C(=O)O)OC1
Agent: [Pt]
Solvent: CO
Product: CC1CCC(C(=O)O)OC1
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To a solution of 5-methyl-3,6-dihydro-2H-pyran-2-carboxylic acid (40 mg, 0.28 mmol) in MeOH (2.0 mL) was added 5% Pt-C (20 mg), hydrogenated for 16 h at 20 psi. The reaction mixture was filtered off through celite, washed with MeOH and concentration of the filtrate gave 2:1 ratio of geometrical isomers of 5-methyl-tetrahydro-pyran-2-carboxylic acid (37 mg, 91%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1Br)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[CH:42]1([CH:47]=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43]1>C1COCC1>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:47]([CH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)[OH:48])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: O=CC1CCCC1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Br)n1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCCC2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 45.5 %

Procedure:
To a solution of (3,5-bis-trifluoromethyl-benzyl)-(2-bromo-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine (117.4 mg, 0.21 mmol) in THF (0.5 mL) at 0° C. was added iPrMgCl/LiCl in THF (0.35 mL, 0.7 mmol). The mixture was stirred at 0° C. for 3 hours. Cyclopentanecarboxaldehyde (41 mg, 0.42 mmol) was added. The mixture was stirred at 0° C. for 3 hours, quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+S Biotage silica column (eluted with 0-30% ethyl acetate in hexanes) to afford the title compound as a colorless oil (55.5 mg, 46%). 1H NMR (400 MHz, CDCl3) δ ppm 0.97-1.10 (m, 1H) 1.33-1.42 (m, 1H) 1.43-1.70 (m, 5H) 1.76-1.86 (m, 1H) 2.17-2.32 (m, 1H) 2.56 (s, 1H) 4.17-4.20 (m, 3H) 4.69-4.79 (m, 3H) 4.81 (s, 1H) 4.90 (d, J=15.77 Hz, 1H) 7.34 (s, 1H) 7.52 (d, J=8.71 Hz, 1H) 7.58 (d, J=8.30 Hz, 1H) 7.66 (s, 2H) 7.77 (s, 1H). MS (ES+) Calc: 581.2, Found: 582.4 (M+1).
Reaction SMILES: F[C:2]1[C:20]2[C:19](=[O:21])[C:18]([C:22]([OH:24])=[O:23])=[CH:17][N:7]3[C@@H:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:25][CH2:26][CH2:27][NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[C:3]=1[F:35].[CH3:36][O:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH2:43])=[CH:40][CH:39]=1>CS(C)=O>[F:35][C:3]1[C:4]([NH:25][CH2:26][CH2:27][NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[C:5]2[O:10][CH2:9][C@H:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:7]3[CH:17]=[C:18]([C:22]([OH:24])=[O:23])[C:19](=[O:21])[C:20]([C:2]=1[NH:43][CH2:42][C:41]1[CH:44]=[CH:45][C:38]([O:37][CH3:36])=[CH:39][CH:40]=1)=[C:6]23
Reactant: COc1ccc(CN)cc1
Reactant: O=C(O)c1cn2c3c(c(NCCNc4ccccn4)c(F)c(F)c3c1=O)OC[C@@H]2c1ccccc1
Solvent: CS(C)=O
Product: COc1ccc(CNc2c(F)c(NCCNc3ccccn3)c3c4c2c(=O)c(C(=O)O)cn4[C@@H](c2ccccc2)CO3)cc1
Temperature: 0 °C
Yield: 56.9 %

Procedure:
A solution of (S)-8,9-difluoro-2,3-dihydro-7-oxo-3-phenyl-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (560 mg, 1.15 mmol) and 4-methoxybenzylamine (520 μL, 5.86 mmol) in DMSO (5 mL) was stirred at 150° C. for 2 h. The reaction mixture was added portionwise at 0° C. to ice-water and the resulting precipitate was combined by filtration, washed with water. The cake washed with EtOH, collected by filtration and then dried to give (S)-9-fluoro-2,3-dihydro-8-(4-methoxybenzylamino)-7-oxo-3-phenyl-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (390 mg, 57%) as a pale yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:16])=[CH:10]2)C.[C:21]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:32][CH:33]=[C:34]([CH2:36]Cl)[N:35]=2)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([C:31]2[O:32][CH:33]=[C:34]([CH2:36][N:12]3[C:13]4[C:9](=[CH:8][C:7]([CH2:6][CH:5]([O:17][CH2:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:15][CH:14]=4)[CH:10]=[C:11]3[CH3:16])[N:35]=2)=[CH:29][CH:30]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1ccc(-c2nc(CCl)co2)cc1
Reactant: CCOC(=O)C(Cc1ccc2[nH]c(C)cc2c1)OCC
Product: CCOC(Cc1ccc2c(c1)cc(C)n2Cc1coc(-c2ccc(C(C)(C)C)cc2)n1)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-ethoxy-3-(2-methyl-1H-indol-5-yl)-propionic acid ethyl ester (preparation 5) was reacted with 2-(4-tert-butyl-phenyl)-4-chloromethyl-oxazole to give rac-3-{1-[2-(4-tert-butyl-phenyl)-oxazol-4-ylmethyl]-2-methyl-1H-indol-5-yl}-2-ethoxy-propionic acid as light brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][CH2:16][CH2:17][NH2:18]>C(Cl)Cl>[CH3:14][O:15][CH2:16][CH2:17][NH:18][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: COCCN
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: COCCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 91.8 %

Procedure:
A solution of 4-nitrobenzenesulfonyl chloride (Fluka, 1.00 g; 4.51 mmol) in DCM (30 mL) was treated with 2-methoxyethylamine (Fluka, 1.9 ml; 22.6 mmol). After 2 hours, the organic solvents were evaporated in vacuo, the residue was taken up in EtOAc and extracted with a saturated NH4Cl solution. The combined organic layers were dried over MgSO4 and evaporated to dryness to give the title compound as a pale yellow solid (1.077 g, 92%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH:5]=[C:6]([O:8]C)[CH:7]=1.[I-].[Na+].C[Si](Cl)(C)C>C(#N)C.O>[I:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH:3]=1
Reactant: COc1cc(I)cc(-c2ccsc2)c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Oc1cc(I)cc(-c2ccsc2)c1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To a suspension of 3-(3-iodo-5-methoxy-phenyl)-thiophene (2.08 g, 6.7 mmol) and sodium iodide (65.73 mmol, 9.85 g) in acetonitrile (80 mL) was added trimethylsilyl chloride (32.86 mmol, 4.16 mL) at room temperature. Then, the resulting light yellow suspension was heated to reflux for 48 h. Then, it was cooled to room temperature and diluted with water (50 mL). The organic compound was extracted into ethyl acetate (2×75 mL) and the combined ethyl acetate extracts were washed with saturated sodium thiosulfate solution (100 mL) to remove the iodine color and was also washed with brine solution (100 mL). Then, the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by using an ISCO 120 g column, eluting with 0-20% ethyl acetate in hexanes to obtain 3-iodo-5-thiophen-3-yl-phenol (1.92 g, 97%) as a light brown oil: ES(+)-HRMS m/e calculated for C10H7IOS (M−H)+ 300.9189, found 300.9189.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[N:39][CH:38]=[CH:37][N:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[N:39][CH:38]=[CH:37][N:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Product: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cnccn2)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J24) (310 mg, 1.0 mmol) and 3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K14) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow oil (280 mg, 52%).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:11][C:10]=2[F:20])[S:6][C:5]=1[NH:21][C:22]1[N:27]=[C:26]([C@@:28]2([OH:45])[CH2:33][CH2:32][N:31](C(OCC3C=CC=CC=3)=O)[CH2:30][C@@H:29]2[OH:44])[CH:25]=[CH:24][CH:23]=1)=[O:3].[H][H]>CO.[Pd]>[F:15][C:14]1[CH:13]=[C:12]([C:16]([OH:19])([CH3:18])[CH3:17])[CH:11]=[C:10]([F:20])[C:9]=1[C:7]1[S:6][C:5]([NH:21][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([C@@:28]3([OH:45])[CH2:33][CH2:32][NH:31][CH2:30][C@@H:29]3[OH:44])[N:27]=2)=[C:4]([C:2]([NH2:1])=[O:3])[CH:8]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc([C@@]4(O)CCN(C(=O)OCc5ccccc5)C[C@@H]4O)n3)s2)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc([C@@]4(O)CCNC[C@@H]4O)n3)s2)c(F)c1

Procedure:
Benzyl (3S,4S)-4-[6-({3-(aminocarbonyl)-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-thienyl}amino)pyridin-2-yl]-3,4-dihydroxypiperidine-1-carboxylate (100 mg, 0.16 mmol) was dissolved in methanol (4.6 mL) and subjected to the H-cube hydrogenator machine, where the solution passed through a palladium on carbon cartridge at 0.5 mL/min at a temperature of 35° C. and a hydrogen pressure of 40 PSI. Once complete, the solution was concentrated and the crude residue was purified by reverse phase HPLC to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][CH:11]([C:13]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)(O)[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.CCN(S(F)(F)F)CC.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10]2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)C(O)(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of 80 mg (0.163 mmol) of 1-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-2,2-dimethylpropan-1-ol (2) in 1 mL of CH2Cl2, 86 uL (0.653 mmol) of DAST was added and it was stirred for 1 h at −78° C. and overnight at rt. Then another 86 uL (0.653 mmol) of DAST was added again and it was stirred 3 h at 38-45° C. Then to the reaction mixture was added 20 mL of CH2Cl2 and 10 mL of ag NaHCO3. The pH was adjusted to 8-9 with 2N NaOH. The water layer was extracted with CH2Cl2 (3×20 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound as a white solid; 1H-NMR (CDCl3) δ 1.06 (s, 9H), 3.37 (s, 2H), 4.05 (s, 2H), 4.44 (s, 1H), 6.55 (d, J=8 Hz, 2H), 6.67 (m, 1H), 7.25 (d, J=6.6 Hz, 4H), 7.33 (d, J=7 Hz, 4H); Mass Spectrum: m/e 472 (M+1 35Cl, 35Cl) and 474 (M+1 35Cl, 37Cl).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([Cl:20])[CH:14]=2)=[C:7]([Cl:21])[C:6]=1[CH3:22])(=[O:3])[CH3:2].[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>>[C:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])=[C:15]([Cl:20])[CH:14]=2)=[C:7]([Cl:21])[C:6]=1[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(C)C(=O)Cl
Reactant: CC(=O)Oc1cc(Cl)c(Oc2ccc(N)c(Cl)c2)c(Cl)c1C
Product: CC(=O)Oc1cc(Cl)c(Oc2ccc(NC(=O)C(C)C)c(Cl)c2)c(Cl)c1C
Yield: 74.2 %

Procedure:
Methyl[3,5-dichloro-4-(4-amino-3-chlorophenoxy)phenyl] acetate (17 mg) was coupled with isobutyryl chloride (5.0 mg), using the method described in Example 1(h). After purification on column (silica gel, ethyl acetate/petrolium ether, 1:4), 15 mg (74%) of methyl(3,5-dichloro-4-[3-chloro-4-isobutyramidophenoxy]phenyl) acetate was obtained, which was hydrolysed using the method described in Example 1(i). This gave 4 mg (27%) of 3,5-dichloro-4-(4-isobutyramido-3-trifluoromethylphenoxy)phenylacetic acid, m/z 416, 418.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](I)[CH2:24][CH3:25]>>[C:1]1([S:7]([C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([O:20][CH2:23][CH2:24][CH3:25])[CH2:15]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(CCCN1CCCC(O)C1)S(=O)(=O)c1ccccc1
Reactant: CCCI
Product: CCCOC1CCCN(CCCC(C)(C)S(=O)(=O)c2ccccc2)C1

Procedure:
The title compound was prepared from 1-(4-benzenesulfonyl-4-methylpentyl)-3-hydroxypiperidine and n-propyl iodide. NMR of hydrochloride salt:
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[NH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35]>>[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: CN(C)CCN
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Agent: Cl
Product: CN(C)CCNC(=O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 149) and 20.7 mg (0.23 mmol) of N-(2-aminoethyl)-N,N-dimethylamine are reacted together by general method E. 17.4 mg (24.8% of theory) of the title compound are obtained.