Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][C:3]1=O.[C:15]([O:19][C:20](=[O:32])[CH2:21][CH2:22][N:23]([CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:24]([NH2:26])=[S:25])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20](=[O:32])[CH2:21][CH2:22][N:23]([CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:24]1[S:25][C:2]2[CH2:7][CH:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:5][CH2:4][C:3]=2[N:26]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)CCN(C(N)=S)C1CCCC1
Reactant: O=C1CCC(c2ccccc2)CC1Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCN(c1nc2c(s1)CC(c1ccccc1)CC2)C1CCCC1
Yield: 98.7 %

Procedure:
The 2-bromo-4-phenylcyclohexanone (2.30 mmol) and 3-(1-Cyclopentyl-thioureido)-propionic acid tert-butyl ester (257 mg, 0.945 mmol) were combined as in general procedure B (13 mL THF, 40° C., 15 h). After aqueous workup, the crude product was purified by silica gel chromatography (gradient, hexane→10% EtOAc-hexane) to afford 3-[cyclopentyl-(6-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amino]-propionic acid tert-butyl ester (398 mg). The ester was dissolved in CH2Cl2 (2 mL) and TFA (2 mL) was added. The reaction mixture was stirred at room temperature, until the starting material, was consumed by TLC. The volatiles were removed and the residue was dissolved in MeOH. NaOH solution (0.90 mmol) was added followed by half-saturated NaCl (20 mL). The aqueous layer was extracted with CH2Cl2 (3×15 mL) and dried over MgSO4 to provide 3-[Cyclopentylcyclopentyl-(6-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amino]-propionic acid. The sodium salt was prepared by general procedure J and triturated with hexane to yield 3-[cyclopentyl-(6-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amino]-propionic acid, sodium salt (336 mg) LCMS m/z: 372 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]2[NH:7][C:8]([C:10]([C:18]3[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]4[C:19]=3[CH:20]=[CH:21][NH:22]4)([CH3:17])[CH2:11][CH2:12][C:13]([O:15]C)=[O:14])=[N:9][C:5]=2[CH:4]=1)#[N:2].[OH-].[K+]>CO>[C:1]([C:3]1[CH:31]=[CH:30][C:6]2[NH:7][C:8]([C:10]([C:18]3[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]4[C:19]=3[CH:20]=[CH:21][NH:22]4)([CH3:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)CCC(C)(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C)c2[nH]ccc2c1C(C)(CCC(=O)O)c1nc2cc(C#N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(±)-Methyl 4-(5-cyano-1H-benzo[d]imidazol-2-yl)-4-(5-methoxy-7-methyl-1H-indol-4-yl)pentanoate (Example 155-L) (8.5 mg, 0.020 mmol) was dissolved in MeOH (300 μL) and then treated with 10% aq. KOH (70 μl, 0.125 mmol) and stirred at room temperature for 30 minutes. The reaction was directly purified using preparative HPLC (HC-B) to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.87 (br. s., 1H) 7.92 (br. s.) 7.53 (br. s.) 7.42-7.49 (m) 7.09 (t, J=2.78 Hz, 1H) 6.73 (s, 1H) 5.62 (br. s., 1H) 3.43 (s, 3H) 2.55-2.64 (m, 2H) 2.42 (s, 3H) 1.95-2.05 (m, 2H) 1.88 (s, 3H). MS (ESI+) m/z 403.3 (M+H).
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[F:60][C:61]([F:77])([F:76])[C:62]1[CH:63]=[C:64]([C:68]2[O:72][C:71]([C:73](O)=[O:74])=[CH:70][CH:69]=2)[CH:65]=[CH:66][CH:67]=1>CN(C=O)C.O>[O:20]=[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]1)[CH2:18][NH:17][C:73]([C:71]1[O:72][C:68]([C:64]2[CH:65]=[CH:66][CH:67]=[C:62]([C:61]([F:77])([F:60])[F:76])[CH:63]=2)=[CH:69][CH:70]=1)=[O:74]
Reactant: O=C(O)c1ccc(-c2cccc(C(F)(F)F)c2)o1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2cccc(C(F)(F)F)c2)o1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 36.1 %

Procedure:
DIPEA (75 mg, 0.1 mL, 0.59 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt (100 mg, 0.23 mmol) in DMF (1 mL). HOBT (32 mg, 0.23 mmol) and EDCI (44 mg, 0.23 mmol) were then added at room temperature. After 2 minutes, 5-(3-trifluoromethyl-phenyl)-furan-2-carboxylic acid (50 mg, 0.20 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 40 mg (37% yield) of 5-(3-trifluoromethyl-phenyl)-furan-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 86.88%. 1H NMR (DMSO-d6): δ 8.8-8.7 (t, 1H), 8.3 (s, 1H), 8.2 (t, 1H), 7.9-7.6 (m, 5H), 7.6-7.5 (t, 1H), 7.4-7.3 (d, 1H), 7.3-7.2 (m, 1H), 4.3-4.1 (m, 2H), 3.8-3.4 (m, 6H), 3.2-3.1 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1>CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:23]2[CH:22]=[CH:21][N:20]=[C:19]([Cl:18])[CH:24]=2)=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Clc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cc(Oc2ccc(OCc3ccccc3)cc2)ccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirring RT suspension of NaH (0.739 g of a 60% by weight oil dispersion, 18.48 mmol) in DMF (20 mL) was added 4-benzyloxy phenol (3.70 g, 18.48 mmol). The mix was stirred 10 min before cooling to 0° C. and adding 2,4-dichloropyridine (2.734 g, 18.48 mmol). The reaction was warmed to RT. After stirring for 60 h, the reaction was quenched with saturated aqueous NaHCO3 and then basified with 2N NaOH. The crude was extracted twice with Et2O. The organic layers were washed three times with 2 N NaOH, once with brine, then combined and dried over Na2SO4, filtered and dried in vacuo. The crude residue was eluted on a silica gel column with a hexanes/EtOAc system to yield title compound, isolated as the major regioisomer.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[O:6][CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>ClCCl>[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[O:6][CH2:5][CH2:4]1)=[O:30]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CCO2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
(R)-Methyl 4-aminochromane-6-carboxylate hydrochloride (A-03) (0.6 g, 2.462 mmol, 1.0 eq) was dissolved in dichloromethane and DIPEA (2.5 eq) under nitrogen, and 2-chlorobenzoic acid chloride (0.37 ml, 2.954 mmol, 1.2 eq) was added at 0° C. The reaction mixture was stirred for 3 h at RT. Then the reaction mixture was concentrated, and the residue was taken up in ethyl acetate, washed with 10% ammonium chloride solution, sat. NaHCO3 solution and with sat. NaCl solution, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, cyclohexane:ethyl acetate 2:1) to yield (R)-methyl 4-(2-chlorobenzamido)chromane-6-carboxylate (B-05). Yield: 92%
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:34]([C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41](=[O:46])[CH2:40]2)([OH:36])=O.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C(N(CC)CC)C>ClCCl>[N:47]1([C:34]([C:37]2[CH:38]=[C:39]3[C:43](=[CH:44][CH:45]=2)[NH:42][C:41](=[O:46])[CH2:40]3)=[O:36])[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1
Reactant: C1COCCN1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1Cc2cc(C(=O)N3CCOCC3)ccc2N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
PyBOP (3.5 g, 6.72 mmol) was added to a mixture of 5-carboxy-2-oxindole (1 g, 5.6 mmol), morpholine (0.5 mL, 6.2 mmol) and triethylamine (2.0 mL, 14 mmol) in dichloromethane. After stirring at room temperature for 4 hours, the reaction was diluted with more dichloromethane, washed with saturated sodium bicarbonate and brine, dried and concentrated. The residue was purified by column chromatography to give 5-(morpholine-4-carbonyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[CH2:7][C:8](O)=[O:9])=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:34][CH2:35][CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1>ClCCl>[CH2:1]([O:3][C:4](=[O:5])[CH:6]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[CH2:7][C:8](=[O:9])[NH:34][CH2:35][CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1)[CH3:2]
Reactant: CCOC(=O)C(CC(=O)O)Cc1cccc2ccccc12
Reactant: NCCc1c[nH]c2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCOC(=O)C(CC(=O)NCCc1c[nH]c2ccccc12)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 1.45 g of the butyric acid obtained in 30 ml of dichloromethane was added 0.86 g of 1,1'-carbonyldiimidazole. The mixture was stirred for 1 hour at room temperature. Then, 0.82 g of triptamine was added to the reaction mixture, and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed successively with water, diluted hydrochloric acid and water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: ethyl acetate/benzene=1/1 by volume) to obtain 1.41 g of 3-[2-(3-indolyl)ethylcarbamoyl]-2-(1-naphthylmethyl)propionic acid ethyl ester as a light brown powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:10][C:11]1[C:12](Cl)=[N:13][CH:14]=[C:15]([CH3:17])[CH:16]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:22][C:23](=[O:42])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=1)[CH3:21]>>[CH2:20]([O:22][C:23](=[O:42])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([C:12]2[C:11]([CH2:10][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:19])[CH2:8][CH3:9])=[CH:16][C:15]([CH3:17])=[CH:14][N:13]=2)[CH:26]=1)[CH3:21]
Reactant: CCN(Cc1cc(C)cnc1Cl)C(=O)OC(C)(C)C
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ncc(C)cc2CN(CC)C(=O)OC(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 6, using the following starting materials: (2-chloro-5-methyl-pyridin-3-ylmethyl)-ethyl-carbamic acid tert-butyl ester and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]([NH2:22])=O)[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1>CN(C=O)C.P(Cl)(Cl)(Cl)=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]#[N:22])[C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)=[CH:7][C:6]=2[CH:17]=1
Reactant: NC(=O)C=Cc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#CC=Cc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Yield: 10.5 %

Procedure:
A solution of 3-[5-hydroxy-2-(4-hydroxyphenyl)-benzofuran-7-yl]-acrylamide 61 (0.07 g, 0.24 mmol) in DMF (5 mL) and phosphorous oxychloride (0.11 mL) was heated at 65° C. for 2 hours. Then ice was added to the reaction mixture and the product extracted into ethyl acetate. The organic layer was dried over MgSO4 and the solvent removed in vacuo. The crude product was submitted for reverse phase prep HPLC. The product was isolated to give 0.007 g of 3-[5-hydroxy-2-(4-hydroxy-phenyl)-benzofuran-7-yl]-acrylonitrile 64: 1H NMR (DMSO-d6) δ 9.90 (s, 1 H), 9.48 (s, 1 H), 7.82 (d, 2 H, J=8.6 Hz), 7.79 (d, 1 H, J=16.7 Hz), 7.13 (s, 1 H), 7.03 (d, 1 H, J=2.3 Hz), 6.92 (d, 1 H, J=2.4 Hz), 6.88 (d, 2 H, J=8.7 Hz), 6.71 (d, 1 H, J=16.8 Hz); MS 276 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([C:7]([O:22][C@@H:23]2[C@@H:27]([CH2:28][OH:29])[O:26][C@@H:25]([N:30]3[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]3=[O:32])[CH2:24]2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H:43]([OH:44])C1.C1CCC(N=C=NC2CCCCC2)CC1.N1C=CC=CC=1>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([C:7]([O:22][C@@H:23]2[C@@H:27]([CH:28]([CH:43]=[O:44])[OH:29])[O:26][C@@H:25]([N:30]3[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]3=[O:32])[CH2:24]2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: COc1ccc(C(O[C@H]2C[C@H](n3cc(C)c(=O)[nH]c3=O)O[C@@H]2CO)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: COc1ccc(C(O[C@H]2C[C@H](n3cc(C)c(=O)[nH]c3=O)O[C@@H]2C(O)C=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 5 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
To a stirred, cold solution of 3′-O-(4,4′-dimethoxy-trityl)thymidine (prepared from thymidine by the common procedures, 40.4 g, 0.072 mol) in anhydrous DMSO was added a solution of DCC (45.86 g, 0.224 mol) in DMSO (180 ml). The resulting solution was stirred at 5° C. for 5 min. pyridine (2.94 g, 3.0 ml, 0.0371 mol) was added and after stirring for another 5 min. a solution of trifluorocaetic acid (2.11 g, 1.43 ml, 0,0185 mol) in DMSO (2 ml) was added dropwise. The resulting reaction mixture was stirred at 5° C. for 10 min. and at room temperature for 6 h. Water (20 ml) was added dropwise under cooling and the mixture stirred at room temperature for 1 h. Precipitates were filtered and washed with DMSO. The combined DMSO solution was poured onto crashed ice (4 L) with stirring. After standing for 1 h, the precipitates were filtered and washed thoroughly with water. The cake was dissolved in methylene chloride (5 00 ml), and the organic layer separated, dried (Na2SO4), and concentrated. The crude was purified by chromatography on silica (3% methanol in methylene chloride) to give 32.6 g (81%) of 3′-O-(4,4′di-methoxytrityl)-5′-formylthymidine as a colorless powder.
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[Cl:37][C:38]1[CH:43]=[C:42]([O:44][C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)[CH:41]=[CH:40][C:39]=1[C:52](=O)[CH3:53].[OH-].[K+]>C(O)C>[Cl:37][C:38]1[CH:43]=[C:42]([O:44][C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)[CH:41]=[CH:40][C:39]=1[C:52]1[CH:53]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]3[N:22]([CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[C:21]4[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=4[N:19]=3)[CH:14]=2)[N:9]=1
Reactant: CC(=O)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc(Oc5ccc(Cl)cc5)cc4Cl)ccc3c1)n2C1CCCCC1
Yield: 49 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-[2-chloro-4-(4-chloro-phenoxy)-phenyl]-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (75 mg, 49% yield). MS: 608.17 (M+H+); HPLC Procedure B, retention time=8.44 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30]O>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([O:1][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH3:24])[CH:3]=3)[N:8]=[CH:7][N:6]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(CNc2ncnc3cc(OC)c(O)cc23)cc1
Reactant: COCCOCCO
Product: COCCOCCOc1cc2c(NCc3ccc(OC)cc3)ncnc2cc1OC

Procedure:
6-Hydroxy-4-(4-methoxybenzylamino)-7-methoxyquinazoline was reacted with 2-(2-methoxyethoxy)ethanol using an analogous procedure to that described in the second last paragraph of Note [1] immediately above that is concerned with the preparation of starting materials. There was thus obtained (4-(4-methoxybenzylamino)-7-methoxy-6-[2-(2-methoxyethoxy)ethoxy]quinazoline; NMR Spectrum: (CDCl3) 3.51 (m, 2H), 3.68 (m, 2H), 3.82 (s, 3H), 3.88 (m, 2H), 3.96 (s, 3H), 4.26 (m, 2H), 4.76 (d, 2H), 5.87 (t, 1H), 6.89 (d, 2H), 7.13 (s, 1H), 7.19 (s, 1H), 7.34 (d, 2H), 8.59 (s, 1H); Mass Spectrum: M+H+ 414.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([F:13])[C:7]=1[F:14])[CH2:2][CH2:3][CH3:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:24][CH:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[C:33]([F:40])[C:32]=2[F:41])[CH2:27][CH2:26]1>CN(C=O)C>[F:41][C:32]1[C:33]([F:40])=[C:34]([O:37][CH2:38][CH3:39])[CH:35]=[CH:36][C:31]=1[C@H:28]1[CH2:29][CH2:30][C@H:25]([CH2:24][O:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[C:7]([F:14])[C:8]=2[F:13])[CH2:26][CH2:27]1
Reactant: CCOc1ccc(C2CCC(CCl)CC2)c(F)c1F
Reactant: CCCCOc1ccc(O)c(F)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc(OC[C@H]2CC[C@H](c3ccc(OCC)c(F)c3F)CC2)c(F)c1F
Temperature: 30 °C
Reaction time: 7 h

Procedure:
4-Butoxy-2,3-difluorophenol (24) (4.6 g) and tripotassium phosphate (K3PO4) (14.0 g) were added to DMF (100 ml) under a nitrogen atmosphere, and the stirring was continued at 70° C. The compound (20) (3.0 g) was added thereto, and the stirring was continued at 70° C. for 7 hours. After the reaction mixture obtained had been cooled to 30° C. and separated from solid materials by filtration, toluene (100 ml) and water (100 ml) were added thereto, and mixed. The mixture was then allowed to separate into organic and aqueous phases, and the extraction into an organic phase was carried out. The organic phase obtained was washed with brine and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off, and the residue obtained was purified by means of column chromatography (silica gel; heptane/toluene=1/2 by volume). The product was further purified by means of recrystallization (Solmix A-11: heptane=1:2 by volume), giving 4.02 g of 2,3-difluoro-4-ethoxy-[trans-4-(2,3-difluoro-4-butoxyphenoxymethyl)cyclohexyl]benzene (No. 831). The yield based on the compound (20) was 85.1%.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([O:7][CH2:8][CH2:9][CH3:10])[NH:4][C:3]=1[CH:11]=[O:12].[C:13]([O:17][C:18]([C:20]1[C:21]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32]Br)=[CH:28][C:27]=2[F:34])=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:13]([O:17][C:18]([C:20]1[C:21]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][N:4]3[C:3]([CH:11]=[O:12])=[C:2]([Br:1])[N:6]=[C:5]3[O:7][CH2:8][CH2:9][CH3:10])=[CH:28][C:27]=2[F:34])=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1F
Reactant: CCCOc1nc(Br)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)c(F)c1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
5-Bromo-2-propoxy-3H-imidazole-4-carbaldehyde (3.7 g, 15.7 mmol), 4′-bromomethyl-2′-fluorobiphenyl-2-carboxylic acid t-butyl ester (5.7 g, 15.7 mmol) and potassium carbonate (6.5 g, 47.0 mmol) were dissolved in DMF (50 mL, 646 mmol), and stirred at room temperature until the reaction was complete, as determined by HPLC. Water (100 mL) was added and the mixture was extracted with EtOAc (2×), washed with saturated aqueous NaCl (2×), dried over MgSO4, filtered and concentrated to yield a yellow oil. The oil was purified by flash chromatography (2-20% EtOAc/hexanes) to yield compound A (4.8 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:15]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][C:11]([CH:12]=O)=[CH:10][N:9]=2)[S:5][CH:6]=1.[CH3:23][O:24][C:25](=[O:46])[CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[N:9]=[CH:10][C:11](/[CH:12]=[CH:26]/[C:25]([O:24][CH3:23])=[O:46])=[CH:14][C:15]=2[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:5][CH:6]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1csc(Nc2ncc(C=O)cc2Oc2ccccc2)n1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cnc(Nc2nc(C)cs2)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of mL 6-(4-methylthiazol-2-ylamino)-5-phenoxynicotinaldehyde (311 mg, 1.00 mmol) and THF (10 mL) was added methyl(triphenylphosphoranylidene)acetate (500 mg, 1.5 mmol) and the reaction mixture was stirred at room temperature. After 4 hours, additional methyl(triphenylphosphoranylidene)acetate (500 mg, 1.5 mmol) was added and the reaction mixture was stirred overnight. Filtered, concentrated the filtrate, and purified by silica gel chromatography (1:1 EtOAc in hexanes) to afford (E)-methyl 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-yl)acrylate.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[Br:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[N+:14]([O-:16])=[O:15])=[CH:8][CH:7]=1.CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([C@H:12]([CH2:13][N+:14]([O-:16])=[O:15])[C@H:2]([CH3:3])[CH:1]=[O:4])=[CH:10][CH:11]=1
Reactant: CCC=O
Reactant: O=[N+]([O-])/C=C/c1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: CCCCCC
Product: C[C@H](C=O)[C@@H](C[N+](=O)[O-])c1ccc(Br)cc1

Procedure:
The title compound was prepared from propionaldehyde and (E)-1-bromo-4-(2-nitrovinyl)benzene according to the general procedure. Both enantiomeric excess and diastereomeric ratio were determined by HPLC with an AD-H column at 230 nm (2-propanol:hexane=5:95), 1.0 mL/min; major enantiomer tmajor=18.59 min, tminor=13.77 min. [α]D20=−24.6 (c=2.1, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CCO.[Pd]>[CH3:15][N:13]([CH2:12][C:5]1[CH:6]=[CH:7][C:8]([NH2:9])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:14]
Reactant: COc1cc(CN(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(CN(C)C)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
10% Pd on carbon (12 mg, 0.866 mmol) was added to a solution of 1-(3-methoxy-4-nitrophenyl)-N,N-dimethylmethanamine (Preparation 109, 160 mg, 0.76 mmol) in EtOH (3 mL). The reaction mixture was degassed and then stirred for 1 hour at room temperature under an atmosphere of hydrogen before being filtered on a pad of Celite and concentrated under reduced pressure to afford the title compound (0.135 g, 98%).