Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[O:16][N:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:13]=2)=[CH:7][CH:6]=1)C.[CH2:28]([O:30][C:31](=[O:42])C1C=CC=C(CC(O)=O)C=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:42])[C:6]1[CH:5]=[CH:10][CH:9]=[C:8]([CH2:11][C:12]2[O:16][N:15]=[C:14]([CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:13]=2)[CH:7]=1)[CH3:29]
Reactant: CCOC(=O)c1cccc(CC(=O)O)c1
Reactant: CCOC(=O)c1ccc(Cc2nc(COc3ccc(OC)cc3)no2)cc1
Product: CCOC(=O)c1cccc(Cc2nc(COc3ccc(OC)cc3)no2)c1

Procedure:
The title compound is prepared essentially as described for 4-[3-(4-methoxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acid ethyl ester, employing 3-carboxymethyl-benzoic acid ethyl ester (45%). LC-MS (m/e): 369 (M+1).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:2]=1.N1C2C(=NC=CC=2)N(CC2C=CC3N=C(S(C)(=O)=O)SC=3C=2)C=1.[NH2:46][CH2:47][C:48]1([OH:54])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:46][CH2:47][C:48]4([OH:54])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]4)[S:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Reactant: NCC1(O)CCCCC1
Agent: CS(=O)(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: OC1(CNc2nc3ccc(Cn4cnc5cccnc54)cc3s2)CCCCC1
Temperature: 125 °C
Reaction time: 15 h

Procedure:
A 4:1 mixture of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole and 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfonyl)benzo[d]thiazole (50 mg) from Step 2 of Example 63 was dissolved in anhydrous DMA (1.5 mL), and then 1-(aminomethyl)cyclohexanol (79 mg, 0.608 mmol) from Step 1 of this Example and DIEA (98 mg, 0.760 mmol) were added. The reaction vessel was sealed and the mixture was heated with stirring at 125° C. for 15 h. LCMS analysis indicated that the reaction was not complete. Further amounts of 1-(aminomethyl)cyclohexanol (79 mg, 0.608 mmol) from Step 1 of this Example and DIEA (98 mg, 0.760 mmol) were added and the mixture stirred at 125° C. for further 5 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford 1-(((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)methyl)cyclohexanol (10 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.38 (dd, J=1.1, 4.7 Hz, 1H), 8.09 (dd, J=1.2, 8.0 Hz, 1H), 7.96 (t, J=5.6 Hz, 1H), 7.67 (s, 1H), 7.19-7.33 (m, 3H), 5.48 (s, 2H), 4.42 (br s, 1H), 1.12-1.62 (m, 12H). LCMS (ESI) m/z 394 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([N:11]([CH2:16][CH2:17][CH3:18])[C:12](=O)[CH2:13][CH3:14])[CH2:6]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH2:16]([N:11]([CH2:12][CH2:13][CH3:14])[CH:5]1[CH2:4][C:3]2[C:2]([NH2:1])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6]1)[CH2:17][CH3:18]
Reactant: CCCN(C(=O)CC)C1Cc2cccc(N)c2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCCN(CCC)C1Cc2cccc(N)c2C1
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
A solution of N-(4-amino-indan-2-yl)-N-propylpropionamide (0.5 g, 2.0 mmol) in dry diethyl ether (10 mL) was added to a slurry of lithium aluminum hydride (0.2 g, 5.4 mmol) in diethyl ether (50 mL) at ambient temperature. After stirring for 1.5 hours water (0.2 mL) followed by 15% sodium hydroxide (0.2 mL) and water (0.6 mL). After stirring for 10 minutes, the inorganic material was filtered off and the resulting solution was evaporated to yield 0.42 g (90%) of the desired product as an oil.:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.F[C:9]1[CH:10]=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([CH3:15])[CH:14]=1>CN(C=O)C.[Cl-].[Na+].O>[CH3:15][C:13]1[CH:14]=[C:9]([CH:10]=[CH:11][C:12]=1[N+:16]([O-:18])=[O:17])[O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccnc1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cccnc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Rinse 35% oil dispersion of KH (12 g, 11 mmol) with 100 mL hexanes twice and dry under vacuum before cooling in an ice bath. Add 100 mL dry DMF then a solution of 3-hydroxypyridine (10 g, 105 mmol) in 100 mL DMF dropwise. Treat with a solution of 5-fluoro-2-nitrotoluene (16.3 g, 105 mmol) in 50 mL DMF to obtain a dark solution. Stir at ambient temperature for 1 hour, pour the mixture into 1 liter of brine and extract twice with 200 mL of EtOAc. Combine the extracts and wash twice with 500 mL brine, dry over MgSO4 and concentrate to 24 g of a dark oil. Purification by chromatography 20% EtOAc in hexanes give the title compound as an oil: ISMS 231 (M+1); C12H10N2O3: calcd: C, 62.61; H, 4.38; N, 12.17. found: C, 62.63; H, 4.58; N, 12.06.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:20](=[O:44])[CH:21]([NH:25][CH2:26][CH:27]([NH:36]C(OC(C)(C)C)=O)[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:22]([CH3:24])[CH3:23])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:20](=[O:44])[CH:21]([NH:25][CH2:26][CH:27]([NH2:36])[CH2:28][C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH:22]([CH3:24])[CH3:23])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C(NCC(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C)C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nccs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(NCC(N)Cc1ccc(F)cc1)C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a solution of 2-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)propyl]amino-3-methylbutyric acid 2-(3-tert-butyl-4-hydroxyphenyl)-1-(thiazol-2-yl)ethylamide (A) (300 mg) in methylene chloride (5 ml), TFA (1 ml) was added under cooling with ice. The mixture was stirred at room temperature for 1 hour and evaporated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:methanol=15:1), giving the titled compound (180 mg, 71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].CC([O-])(C)C.[Na+].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.[NH4+].[Cl-]>C1COCC1>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:6]2[CH3:11])=[O:30])=[CH:27][CH:26]=1
Reactant: COC(=O)CCc1c(C)[nH]c2ccc(F)cc12
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)CCc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(F)cc12
Reaction time: 0.33 h
Yield: 49 %

Procedure:
To a cooled solution (ice bath, 0-5° C.) of methyl 3-(5-fluoro-2-methyl-1H-indol-3-yl)propanoate (80 mg, 0.34 mmol) in THF (2.5 mL) was added tBuONa (2 M in THF, 204 μL, 0.41 mmol), and the mixture was stirred for 20 min at the low temperature. 4-chlorobenzoyl chloride (71.4 mg, 0.41 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was combined with saturated aqueous NH4Cl (1 mL; provided in a 10 mL glass vial) and the organic compound was extracted with ethyl acetate (3×3 mL), washed with brine and water, dried over Na2SO4 and concentrated in vacuo. The crude residue was subjected to flash chromatography (SiO2, ethyl acetate/hexane gradient) to afford the pure title compound as yellow oil in 49% yield (62 mg). C20H17ClFNO3, Mr=373.81; 1H NMR (400 MHz, DMSO-d6) d: 2.19 (s, 3H), 2.59 (t, J=7.4 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H), 3.56 (s, 3H), 6.94 (td, J=2.4/9.2 Hz, 1H), 7.08 (dd, J=4.6/9.0 Hz, 1H), 7.39 (dd, J=2.4/9.2 Hz, 1H), 7.63-7.68 (m, 4H); LCMS (ESI) tR: 3.21 min (>95%, ELSD), m/z: 374.3 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:21])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18](C)=O)=[CH:14][CH:13]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3].FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[C:1]([C:5]1[C:6](=[O:21])[CH2:7][CH:8]([C:12]2[CH:13]=[CH:14][C:15]([SH:18])=[CH:16][CH:17]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(S(C)=O)cc2)CC1=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCC(=O)C1=C(O)CC(c2ccc(S)cc2)CC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 5 g (0.0163 mol) of 2-propionyl-3-hydroxy-5-(4-(methylsulfinyl)phenyl)cyclohex-2-en-1-one in a flask cooled in an ice-water bath was added 25 mL (0.177 mol) of trifluoroacetic anhydride dropwise over 5 minutes. The ice-water bath was removed and the solution stirred at ambient temperature for 3 hours. The solvent was removed in vacuo and the oil remaining was dissolved in 82 mL of 1N NaOH and the solution stirred at ambient temperature overnight. The mixture was diluted with 1200 mL of water, filtered and the filtrate acidified with 5 mL of concentrated HCl with the product precipitating as an oily solid. The product was dissolved in 150 mL of methylene chloride and the solution washed twice with 150 mL portions of water and dried over Na2SO4. Removal of the solvent in vacuo gave the above named product in a yield of 4.0 g (88.7 percent of theoretical).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:26])([CH3:25])[CH3:24])=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([C:30]1[CH:31]=[C:32]([CH2:37][C:38]#[N:39])[CH:33]=[C:34]([CH3:36])[CH:35]=1)#[N:29].[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:10]=[C:11]([CH:37]([C:38]#[N:39])[C:32]2[CH:31]=[C:30]([CH:35]=[C:34]([CH3:36])[CH:33]=2)[C:28]#[N:29])[C:12]([C:23]([CH3:26])([CH3:25])[CH3:24])=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1c(Cl)nc(OCc2ccccc2)nc1OCc1ccccc1
Reactant: Cc1cc(C#N)cc(CC#N)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cc(C(C#N)c2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)(C)C)c1
Reaction time: 1 h
Yield: 29.4 %

Procedure:
To a stirred mixture of 2,4-Bis-benzyloxy-5-tert-butyl-6-chloro-pyrimidine (3.8 g, 10 mmol) and 3-cyano-5-methylphenyl acetonitrile (1.56 g, 10 mmol) in anhydrous DMF (20 ml) at 0° C. (ice bath) under nitrogen atmosphere, was portionwise added 60% sodium hydride (880 mg, 22 mmol). After stirring for 1 hr., the mixture was further stirred at room temperature for overnight. The mixture was then neutralized with aqueous saturated ammonium chloride solution and the crude product was extracted with ether and purified by silica gel column chromatography (eluent, EA:hexanes (1:10)) to afford 1.48 g (30%) of the title compound as a colorless syrup. m.p. 126-128° C.; 1H NMR (200 MHz, CDCl3) δ 1.46 (9H, s), 2.36 (3H, s), 5.29 (1H, d, J=12.2 Hz), 5.38 (1H, d, J=12.2 Hz), 5.46 (2H, s), 5.98 (1H, s), 7.22-7.46 (10H, m); m/z (EI) 502 (M+).
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:8][N:7]=1)=[O:5])C.[CH2:26]([CH2:28][NH2:29])[OH:27].N12CCCNC1=NCCC2.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[OH:27][CH2:26][CH2:28][NH:29][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:8][N:7]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)cn1
Agent: C1CN=C2NCCCN2C1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCCO)nc1
Reaction time: 6 h
Yield: 88.3 %

Procedure:
To a stirred solution of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid ethyl ester (140 mg, 0.41 mmol) in toluene (1 mL) was added ethanolamine (30 mg, 0.49 mmol) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (35 mg, 0.25 mmol) and the reaction stirred under argon for 6 h. Seignette salt solution (4 mL) was added and the solution extracted with ethyl acetate (3×20 mL), dried, filtered, and concentrated in vacuo. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) afforded the title compound (128 mg, 88%) as a light yellow gum. MS: m/e=354.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:24][CH:25]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:24][CH:25]=2)=[C:9]([CH3:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(C)c1)OCC
Reactant: ClCc1coc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCc2coc(-c3ccccc3)n2)c(C)c1)OCC

Procedure:
In analogy to the procedure described in example 108 c], [rac]-2-ethoxy-3-(4-hydroxy-3-methyl-phenyl)-propionic acid ethyl ester [PCT Int. Appl. (2001), WO01/40172A1] was treated with 4-chloromethyl-2-phenyl-oxazole [prepared from benzamide and 1,3-dichloroacetone as described in Bioorg. Med. Chem. Lett. (2000), 10(17), 2041-2044] and sodium hydride in N,N-dimethylformamide to yield [rac]-2-ethoxy-3-[3-methyl-4-(2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-[3-methyl-4-(2-phenyl-oxazol-4-ylmethoxy) -phenyl]-propionic acid as colorless gum.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:31][CH3:32])=[C:26]([F:41])[C:25]=1[CH:42]([OH:51])[C:43]1[CH:44]=[N:45][C:46]([S:49][CH3:50])=[N:47][CH:48]=1>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:31][CH3:32])=[C:26]([F:41])[C:25]=1[C:42]([C:43]1[CH:44]=[N:45][C:46]([S:49][CH3:50])=[N:47][CH:48]=1)=[O:51]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(O)c2cnc(SC)nc2)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2cnc(SC)nc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
Step 2 Dess-Martin periodinane (243 mg, 0.572 mmol) was dissolved in dry CH2Cl2 (1 mL) and then added dropwise to a solution of tert-butyl N-[(1R)-1-(4-chloro-2-fluoro-3-{hydroxy[2-(methylsulfanyl)pyrimidin-5-yl]methyl}phenyl)propyl]carbamate (194 mg, 0.439 mmol) in dry CH2Cl2 (1 mL) and the solution was stirred at rt for 8 h. After this time the reaction mixture was diluted with CH2Cl2 (10 mL) and washed with saturated NaHCO3 (10 mL). The aqueous phase was extracted with CH2Cl2 (3×10 mL) and the combined organic extracts were washed with saturated Na2SO3 (10 mL) and brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo to give crude material (˜200 mg). Purified by silica column (25M on Biotage SP4) eluting 20-40% EtOAc in petroleum ether over 15 column volumes to give tert-butyl N-[(1R)-1-(4-chloro-2-fluoro-3-{[2-(methylsulfanyl)pyrimidin-5-yl]carbonyl}phenyl)propyl]-carbamate (100 mg, 0.23 mmol, 0.52%). m/z: 439.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[C:13]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[C:13]([C:21]1[CH:22]=[CH:23][C:24]([O:27][C:2]2[N:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][CH2:11][CH3:12])=[CH:4][CH:3]=2)=[CH:25][CH:26]=1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CCSc1ccc(Cl)nc1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCSc1ccc(Oc2ccc(C(=O)c3ccccc3)cc2)nc1C#N
Yield: 28.7 %

Procedure:
6-Chloro-3-ethylthio-2-pyridinecarbonitrile (23.8 g) was mixed with 25.8 g of 4-benzoylphenol in the presence of 15.7 g of t-BuOK in 150 ml of THF and 30 ml DMSO. After reaction, the mixture was filtered leaving a solid residue from which 12.4 g of the desired 6-(4-benzoylphenoxy)-3-ethylthio-2-pyridinecarbonitrile (m.p. 88°-90° C.) was recovered. An additional 6.5 g of desired product was isolated from the filtrate by separation on a Water's Prep LC 500 instrument (using a 10% acetone in hexane eluant).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].O>CN(C)C=O>[C:37]([O:36][C:34](=[O:35])[CH2:33][O:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:3]([CH2:1][CH3:2])[N:4]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CCc1cc2c(O)cccc2n1Cc1ccccc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc2c(OCC(=O)OC(C)(C)C)cccc2n1Cc1ccccc1-c1ccccc1
Temperature: 25 °C

Procedure:
2-Ethyl-4-hydroxy-1-(2-phenyl-phenylmethyl)-1H-indole (0.8 g, 0.00245 mol) was added to a slurry of cesium carbonate (0.98 g, 0.003 mol) in 15 mL of dimethylformamide, stirred at room temperature for ten minutes and then the t-butyl bromoacetate was added all at once. After stirring at room temperature overnight, the solution was poured into water and extracted in ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated to an oil that crystallized on standing at room temperature. This material was slurried in hexane and filtered to give 0.93 g of subtitled compound as a tan solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH:9]1[CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[C:39]=1[OH:45]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[O:45][C:39]2[C:40]([CH3:44])=[CH:41][CH:42]=[CH:43][C:38]=2[CH3:37])=[O:15])[CH2:10][CH:9]1[CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C)c1O
Reactant: COC(=O)CC1CN(C(=O)c2c(Cl)n(-c3ccccc3)c3cccnc23)CCN1C(=O)OC(C)(C)C
Product: COC(=O)CC1CN(C(=O)c2c(Oc3c(C)cccc3C)n(-c3ccccc3)c3cccnc23)CCN1C(=O)OC(C)(C)C

Procedure:
The compound of step 1 (254 mg, 507 μmol) and 2,6-dimethylphenol were reacted analogously as described in example 1, step 6. 340 mg of crude title compound were obtained.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3].[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[NH:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29]Br.C(N(CC)CC)C>CC(C)=O>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[NH:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1
Reactant: CCCNC1CCc2ncsc2C1
Reactant: O=C(CCCCBr)Nc1ccc2ccccc2c1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCN(CCCCC(=O)Nc1ccc2ccccc2c1)C1CCc2ncsc2C1

Procedure:
9 is prepared from 1C and 9A using the same method as for 6 with acetone as solvent and triethylamine as base. Reaction temperature is 50° C. After evaporation of the solvent the residue is suspended in water, alkalized with sodium hydroxide solution and extracted three times with dichloromethane. After evaporation of the combined organic phases the product is crystallized as salt of maleic acid from acetonitrile/diethylether.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([NH2:16])[CH3:15]>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:16][CH2:14][CH3:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: CCNC(=O)c1ccc(C(C)(C)C)cc1
Yield: 97 %

Procedure:
4-t-Butyl-N-ethylbenzamide (9 g, 0.044 mol) was prepared in 97% yield from 4-t-butylbenzoyl chloride (9 ml, 0.045 mol) and ethyl amine (70 wt % in water) using Method E2.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C=O)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a 200 mL round-bottomed flask was added 4-hydroxy-3-nitrobenzaldehyde (1.671 g, 10.0 mmol), methyl 2-bromoacetate (0.950 mL, 10.00 mmol), and K2CO3 (1.382 g, 10.00 mmol) in DMF (25 mL). The reaction was stirred at 80° C. for 2 hr. The reaction was poured over ice and the resulting solid was isolated by filtration, washed with water and dried in vacuo to give a light yellow solid (2.031 g, 85% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.71 (s, 3H) 5.18 (s, 2H) 7.52 (d, J=8.84 Hz, 1 H) 8.14 (dd, J=8.84, 2.02 Hz, 1H) 8.44 (d, J=2.02 Hz, 1H) 9.95 (s, 1H). ESI-MS: m/z 240.1 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.[CH:31](OCC)=[O:32]>>[CH:31]([NH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1)=[O:32]
Reactant: CCOC=O
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N)c3ccccc32)cc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(NC=O)c3ccccc32)cc1

Procedure:
A mixture of 5-amino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) and ethyl formate (10 ml) is refluxed for 4 hours. The reaction solution is concentrated and the resulting residue is recrystallized from ethanol/petroleum ether to give 5-formylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.38 g) as colorless columnar crystal, m.p. 211°-213° C.