Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-])=O)[CH:4]=1)[CH3:2].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)C.O>[NH2:10][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: CCc1ccc(O)c([N+](=O)[O-])c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1ccc(O)c(N)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 18.8 %

Procedure:
To a mixture of 4-ethyl-2-nitrophenol (5.5 g, 0.032 mol) in ethanol (180 mL) and water (90 mL) was added sodium thiosulfate (23 g, 0.131 mol) at room temperature. The heterogeneous mixture was stirred at 80° C. under an atmosphere of nitrogen for 16 hour. The reaction mixture was cooled to room temperature, and ethanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (3×100 mL), and the organic layer was washed with brine and dried under sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography on silica using 0%-25% methanol/dichloromethane as a mobile phase (×2). The solvent was removed under reduced pressure to give 2-amino-4-ethylphenol (0.89 g, 0.006 mol). 1H NMR (DMSO-d6, 400 MHz) δ 8.61 (br, 2H), 6.47 (d, 1H), 6.37 (s, 1H), 6.18 (d, 1H), 2.17 (q, 2H), 1.08 (t, 3H). MS: MH−: 137
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([OH:37])[C:18]3[C:27]([C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4F)=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][C:22]([OH:36])=[CH:23]4)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[Na+]>CN(C=O)C.O>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[O:37][C:29]4[C:28](=[CH:33][C:32]([F:34])=[CH:31][CH:30]=4)[C:27]4[C:18]3=[C:19]3[C:24](=[CH:25][CH:26]=4)[CH:23]=[C:22]([OH:36])[CH:21]=[CH:20]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(C(O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3cc(F)ccc3F)ccc2c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc2c3c(ccc2c1)-c1cc(F)ccc1OC3c1ccc(OCCN2CCCCCC2)cc1
Temperature: 50 °C

Procedure:
Dissolve 5-{[4-(2-azepan-1-yl-ethoxy)-phenyl]-hydroxymethyl}-6-(2,5-difluorophenyl)-naphthalen-2-ol (770 mg, 1.54 mmol) in 20 mL dry DMF and add sodium t-butoxide (1.18 g, 12.32 mmol). Heat the mixture to 50° C. for two hours. Dilute with water and extract multiple times with methylene chloride. Dry the organic layer and purify on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient. The yield is 370 mg (50%): 1H-NMR (CDCl3, 300 MHz) δ7.76 (dd, J=12.6, 8.4 Hz, 2H); 7.58 (d, J=9.0 Hz, 1H); 7.43-7.40 (m, 1H); 7.15 (d, J=2.4 Hz, 1H); 7.05-7.01 (m, 3H); 6.89 (s, 1H); 6.83-6.80 (m, 2H); 6.66-6.63 (m, 2H); 4.00-3.98 (m, 2H); 2.92-2.92 (m, 2H); 2.78-2.78 (m, 4H); 1.66-1.59 (m, 8H). The racemic compound is purified using chiral chromatography (conditions P). The two isomers eluted with retention times of 9.9 and 13.5 minutes.
Reaction SMILES: [CH2:1]([C:3]12[CH2:17][C:16](=[O:18])[CH:15]=[C:4]1[C:5]1[C:10]([CH2:11][CH2:12]2)=[CH:9][C:8]([O:13][CH3:14])=[CH:7][CH:6]=1)[CH3:2].C([O-])(O)=O.[Na+].[Br:24]Br>>[Br:24][C:15]1[C:16](=[O:18])[CH2:17][C:3]2([CH2:1][CH3:2])[CH2:12][CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=3)[C:4]=12
Reactant: BrBr
Reactant: CCC12CCc3cc(OC)ccc3C1=CC(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC12CCc3cc(OC)ccc3C1=C(Br)C(=O)C2
Reaction time: 0.03 h

Procedure:
A solution of 3a-ethyl-7-methoxy-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one (415 mg, 1.7 mol) in CCL4 (5.1 mL) was treated with NaHCO3 (714 mg, 8.5 mmol). The mixture was cooled in an ice bath, purged with N2, stirred, and treated with Br2 (0.088 mL, 1.7 mmol) to give an unstirrable orange gum. The mixture was sonicated for one minute, swirled in an ice bath for two minutes, and then stirred at 0-5° C. for 75 minutes. The mixture was then partitioned between CH2Cl2 and water (50 mL each). The organic phase was washed with saturated aqueous Na2S2O3 and brine, dried over MgSO4, filtered, and evaporated under vacuum. The crude product was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40M (4×15 cm) silica gel column, eluting with 5:1 hexane-EtOAc, to provide 1-bromo-3a-ethyl-7-methoxy-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one as a white foam.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19](=[CH:27]O)[C:20](=[O:26])[NH:21]2>>[CH2:14]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][CH:27]=[C:19]2[C:18]3[C:22](=[CH:23][CH:24]=[CH:25][C:17]=3[CH3:16])[NH:21][C:20]2=[O:26])=[CH:11][CH:12]=1)[CH3:15]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: Cc1cccc2c1C(=CO)C(=O)N2
Product: CCN(CC)CCOc1ccc(NC=C2C(=O)Nc3cccc(C)c32)cc1
Yield: 22.7 %

Procedure:
In a manner similar to that describe in Example 231, 4-(2-diethylamino-ethoxy)-phenylamine (713 mg, 1.2 equiv.) and 4-methyl-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.86 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (237 mg, 23%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].N1C=CC=CC=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.Cl>C(Cl)Cl>[CH3:20][O:19][C:17](=[O:18])[C:16]1[CH:21]=[CH:22][C:13]([NH:12][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A solution of methanesulfonyl chloride (15.2 g, 132 mmol) in methylene chloride (50 mL) was added dropwise to a stirring slurry of pyridine (41.8 g, 529 mmol) and methyl 4-aminobenzoate (20.0 g, 132 mmol) in methylene chloride (110 mL) cooled by a dry ice/acetone bath. The reaction mixture was allowed to warm to ambient temperature and was stirred overnight. The reaction mixture was added to 400 mL of 4% aqueous HCl solution and the solid that formed was collected by filtration. The orange solid was recrystallized from methanol to give 28.8 g (91.5%) of an orange-pink solid, mp 147°-150° C.
Reaction SMILES: [CH:1]([S:3]([CH3:6])(=[O:5])=[O:4])=[CH2:2].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:20]([CH2:21][C:22]([CH3:25])([OH:24])[CH3:23])[C:19]([CH2:26][O:27][CH2:28][CH3:29])=[N:18][C:13]=3[CH:14]=[N:15][C:16]=2[CH:17]=1.[H-].[Na+].O>C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:20]([CH2:21][C:22]([O:24][CH2:2][CH2:1][S:3]([CH3:6])(=[O:5])=[O:4])([CH3:23])[CH3:25])[C:19]([CH2:26][O:27][CH2:28][CH3:29])=[N:18][C:13]=3[CH:14]=[N:15][C:16]=2[CH:17]=1
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CC(C)(C)O
Reactant: C=CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCc1nc2cnc3cc(Br)ccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
A solution of methyl vinyl sulfone (3.0 g, 29 mmol) and 1-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (5.4 g, 14 mmol) in anhydrous THF (57 mL) was purged with nitrogen; solid sodium hydride (available as a 60% dispersion in mineral oil, 57 mg, 1.4 mmol) was added. The reaction was stirred for 70 minutes at ambient temperature, at which time an analysis by HPLC indicated a ratio of product to starting material of 3:1. The reaction mixture was combined with material from another run, and water (100 mL) was added. The aqueous layer was separated and extracted with ethyl acetate (100 mL, 50 mL). The combined organic fractions were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol) to provide 7-bromo-2-ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][C:40]([N:43]2[CH:47]=[CH:46][N:45]=[C:44]2[CH3:48])=[N:41][CH:42]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:38]=[N:39][C:40]([N:43]4[CH:47]=[CH:46][N:45]=[C:44]4[CH3:48])=[N:41][CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1nccn1-c1ncc(Br)cn1
Product: Cc1nccn1-c1ncc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromo-2-(2-methyl-1H-imidazol-1-yl)-pyrimidine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=0.932 min, m/z=512.3; 1H NMR (CD3OD) 0.86 (s, 3H), 1.16 (s, 3H), 1.49 (m, 3H), 2.15 (m, 2H), 2.18 (m, 1H), 2.37-2.49 (m, 2H), 2.79 (s, 3H), 3.03 (m, 1H), 5.53 (m, 1H), 7.01-7.06 (m, 3H), 7.21-7.29 (m, 5H), 7.44 (m, 2H), 7.97 (m, 1H), 8.95 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[N:14][NH:15][CH:16]=1)[C:6]([OH:8])=[O:7].[CH3:17]C1C(B2OC(C)(C)C(C)(C)O2)=CNN=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[C:16]([CH3:17])=[N:15][NH:14][CH:13]=1)[C:6]([OH:8])=[O:7]
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(C(=O)O)ccc1-c1cn[nH]c1
Product: COc1cc(C(=O)O)ccc1-c1c[nH]nc1C

Procedure:
Intermediate 3 was synthesized by following a similar route to Intermediate 1 using 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1A. LCMS (ESI) m/z: 233.0 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:10][OH:11]>>[OH:11][C:10]1[CH:2]=[CH:1][CH:4]=[CH:5][C:6]=1[CH:7]=[CH:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CO
Reactant: CC(=O)c1ccccc1
Product: O=C(C=Cc1ccccc1O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The previous product was mixed with acetophenone (2 g) suspended in methanol at −10° C. and stirred for 5 hr at room temperature. After neutralization with 5% hydrochloric acid solution, the product was extracted with 200 Ml of ethylacetate. The extracted organic phase was dried with anhydrous magnesium sulfate, and resulting 1-phenyl-3-(2-methoxymethyloxyphenyl)-prophenone was hydrolyzed with dilute alkaline solution. The reaction mixture was extracted with 200 Ml of ethylacetate. Extracted organic phase is dried with anhydrous magnesium sulfate and evaporated under vacuum. About 0.9 g of white solid (1-phenyl-3-(2-hydroxyphenyl)prophenone was obtained and subjected to silica gel column chromatography (5×3 cm, Merk). After being eluted with n-hexane:ethylacetate (v/v, 1:7), 0.7 g of purified compound was recovered and identified as follows:
Reaction SMILES: N1C(C)=CC=CC=1C.[Si:9]([O:16]S(C(F)(F)F)(=O)=O)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[C:24]([O:28][C:29]([N:31]1[CH2:35][C@H:34]([F:36])[CH2:33][C@@H:32]1[C@@H:37](O)[C@H:38]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:39]([N:41]1[C@@H:45]([CH:46]([CH3:48])[CH3:47])[CH2:44][O:43][C:42]1=[O:49])=[O:40])=[O:30])([CH3:27])([CH3:26])[CH3:25].Cl>ClCCl>[C:24]([O:28][C:29]([N:31]1[CH2:35][C@H:34]([F:36])[CH2:33][C@@H:32]1[C@@H:37]([O:16][Si:9]([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11])[C@H:38]([CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:39]([N:41]1[C@@H:45]([CH:46]([CH3:47])[CH3:48])[CH2:44][O:43][C:42]1=[O:49])=[O:40])=[O:30])([CH3:26])([CH3:27])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](Cc1ccccc1)[C@H](O)[C@H]1C[C@@H](F)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](Cc1ccccc1)[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C[C@@H](F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
Add 2,6-lutidine (5.3 mL, 54 mmol) and tert-butyl-dimethylsilyl-trifluoromethylsulfonate (1.62 mL, 7.08 mL) to a solution of 2-(R)-[2-(S)-benzyl-1-(S)-hydroxy-3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)-3-oxopropyl]-4-(R)-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (2.585 g, 5.4 mmol) in dichloromethane (40 mL) at −78° C. Stir 3 h, warm to room temperature, stir 5 min and cool in an ice bath. Add 1 N HCl (100 mL), wash with 1 N HCl (2×100 mL), saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with hexanes and ethyl acetate) to give the title compound as a white foam (2.779 g, 87%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](S(C)(=O)=O)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)n(C)c(=O)c1OCc1ccccc1
Reactant: C1CNCCN1
Product: CCOC(=O)c1nc(N2CCNCC2)n(C)c(=O)c1OCc1ccccc1
Yield: 0.6 %

Procedure:
Following the procedure described for the synthesis of compound 67A 5-Benzyloxy-2-methanesulfonyl-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (7.0 g, 19.2 mmol) was reacted with piperazine (17.0 g, 192 mmol) and to yield the title compound as a pale yellow oil (0.0418 g, 42% yield). 1H NMR (500 MHz, CDCl3) δ: 7.45 (2H, d, J=6.7 Hz), 7.34–7.27 (3H, m), 5.13 (2H, s), 4.30 (2H, q, J=7.2 Hz), 3.49 (3H, s), 3.15–3.13 (4H, m), 2.98–2.96 (4H, m), 1.89 ( 1H, bs), 1.27 (3H, J=7.2 Hz). HRMS (M+H) calcd for C19H25N4O4: 373.21414. found: 373.1866.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1>C(Cl)Cl>[F:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:39])=[CH:33][CH:32]=1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.36 mmol, example 9 (step 3) and DIEA (62.8 μL, 0.36 mmol) in DCM (2 mL) was added 4-fluorophenyl isocyanate (40.5 μL, 0.36 mmol). The resulting mixture was reacted under the same conditions as described for example 10 to give the title compound as a white solid. MS (ESI, positive ion) m/z: 415 (M+H).
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:8][C:7]=2[CH:31]=1.[Li]CCCC.[CH:37]([C:39]1[CH:40]=[C:41]([CH:45]([S:53][CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])[S:46][CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])[CH:42]=[CH:43][CH:44]=1)=O>O1CCCC1.CCCCCC>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]=[CH:37][C:39]3[CH:40]=[C:41]([CH:45]([S:46][CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])[S:53][CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])[CH:42]=[CH:43][CH:44]=3)=[N:8][C:7]=2[CH:31]=1
Reactant: Clc1ccc2oc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2c1
Reactant: COC(=O)CCSC(SCCC(=O)OC)c1cccc(C=O)c1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CCSC(SCCC(=O)OC)c1cccc(C=Cc2nc3cc(Cl)ccc3o2)c1
Reaction time: 0.25 h

Procedure:
To a solution of phosphonium bromide (780 mg) (Step 4) in tetrahydrofuran (THF) (8 mL) at -78° was added dropwise 1 eq. of n-BuLi in hexane. The solution was stirred at -78° for 15 min. Then (545 mg) of the aldehyde (Step 1) in THF (4 mL) was added dropwise and the reaction mixture was stirred at -78° for 1 hour. The reaction mixture was poured into pH 7 buffer, extracted with ethyl acetate, dried and evaporated. The residue was chromatographed on a column of SiO2 using 10:1 toluene/ethyl acetate to afford the title compound, m.p. 66°-67° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:30]([S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[CH:29][CH:28]=[CH:27][C:26]=2[F:37])[C:21]([Cl:38])=[CH:20][N:19]=1>>[Cl:38][C:21]1[C:22]([NH:24][C:25]2[C:30]([S:31]([CH:34]([CH3:35])[CH3:36])(=[O:33])=[O:32])=[CH:29][CH:28]=[CH:27][C:26]=2[F:37])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4S(=O)(=O)C(C)C)n3)cc2CC1

Procedure:
Title compound was prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 1221d.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][OH:13])[CH2:6][CH2:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:33][C:34]1[C:42]([O:43][C:44]2[C:53]3[C:48](=[CH:49][C:50](O)=[C:51]([O:54][CH3:55])[CH:52]=3)[N:47]=[CH:46][N:45]=2)=[CH:41][CH:40]=[C:39]2[C:35]=1[CH:36]=[C:37]([CH3:57])[NH:38]2>ClCCl>[F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:50]2[CH:49]=[C:48]3[C:53]([C:44]([O:43][C:42]4[C:34]([F:33])=[C:35]5[C:39](=[CH:40][CH:41]=4)[NH:38][C:37]([CH3:57])=[CH:36]5)=[N:45][CH:46]=[N:47]3)=[CH:52][C:51]=2[O:54][CH3:55])[CH2:6][CH2:5]1
Reactant: OCCCN1CCN(CCF)CC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(CCF)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.2 %

Procedure:
Diisopropyl azadicarboxylate (230 μl, 1.17 mmol) was added dropwise to a solution of 3-[4-(2-fluoroethyl)piperazin-1-yl]propan-1-ol (203 mg, 1.07 mmol), triphenylphosphine (357 mg, 1.36 mmol) and 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazoline (330 mg, 0.97 mmol), (prepared as described for the starting material in Example 7), in dichloromethane (8.5 ml). The reaction mixture was stirred at ambient temperature for 1.5 hours and then loaded directly onto a silica column, eluting with a mixture of methanol in methylene chloride (11/89) to give 7-{3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy}-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (413 mg, 83%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]2[S:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][C:15]=3[CH3:22])=[CH:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]>CO>[CH3:1][O:2][C:3]([C:5]1[C:10]2[S:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:22])=[CH:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2cc(-c3ccc(OC)cc3C)sc12
Solvent: CO
Product: COC(=O)c1cccc2cc(-c3ccc(O)cc3C)sc12
Yield: 69 %

Procedure:
The title compound (85 mg, 69%) is prepared essentially as described in the synthesis of 2-(4-Hydroxy-2-methyl-phenyl)-benzo[h]thiophene-5-carboxylic acid ethyl ester, utilizing 2-(4-Methoxy-2-methyl-phenyl)-benzo[b]thiophene-7-carboxylic acid methyl ester and methanol. ES/MS m/e 297 (M−1).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:19][C:20]1[C:24](B(O)O)=[C:23]([CH3:28])[O:22][N:21]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[C:24]2[C:20]([CH3:19])=[N:21][O:22][C:23]=2[CH3:28])=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2c(Br)[nH]c3ccccc23)cc1
Reactant: Cc1noc(C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2c(-c3c(C)noc3C)[nH]c3ccccc23)cc1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
2-bromo-3-(4-methoxyphenyl)-1H-indole (93 mg, 0.31 mmol), 3 mol % tetrakis(triphenylphosphine)palladium and 3,5-dimethylisoxazol-4-ylboronic acid (3 eq) were mixed in 1.5 ml degassed DME under nitrogen. 1.24 ml sodium hydrogen carbonate (1 M) was added drop wise over 5 min. The resulting mixture was stirred at 90° C. for 45 min and then cooled to rt. The solvent was evaporated under nitrogen flow and the residue was taken up in DCM. Filtering through a short plug of silica gave a crude product which was purified again on silica (EtOAc/n-Heptane 1:9-3:7). 40.5 mg 4-(3-(4-methoxyphenyl)-1H-indol-2-yl)-3,5-dimethylisoxazole was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:10])=[N:4][C:5]([F:9])=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[P:17](=[S:25])(Cl)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>CN(C)C=O>[P:17](=[S:25])([O:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[C:5]([F:9])[N:4]=1)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]
Reactant: CCOP(=S)(Cl)OCC
Reactant: Oc1nc(F)c(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=S)(OCC)Oc1nc(F)c(Cl)cc1Cl
Temperature: 25 °C

Procedure:
A mixture was prepared by admixing, with stirring, 9.7 g (0.053 m) of 3,5-dichloro-6-fluoro-2-pyridinol, 5.6 g (0.053 m) of sodium carbonate and 100 ml of dimethylformamide. To this mixture was added all at once, at room temperature, with stirring, 9.9 g (0.053 m) of O,O-diethyl phosphorochloridothioate. The resulting mixture was heated at 60°-65° C. with stirring for one hour. The mixture was cooled to room temperature and filtered to remove insolubles. The solvent was removed by distillation under reduced pressure and the residue dissolved in 100 ml of benzene. The mixture was washed with water and the organic layer separated, dried and filtered. The benzene was removed by evaporation under reduced pressure. The residue (15 g) was crystallized from 15 ml of hexane giving 5.9 g of the desired O,O-diethyl O-(3,5-dichloro-6-fluoro-2-pyridinyl) phosphorothioate. The product melted at 31°-33° C. and upon analysis, was found to have carbon, hydrogen and nitrogen contents of 32.30, 3.30 and 4.19 percent, respectively, as compared with the theoretical contents of 32.36, 3.32 and 4.19 percent, respectively, as calculated for the above named compound.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].[CH:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:7][O:6][C:4]([CH:3]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:15][CH:2]=[N:1]1)=[O:5]
Reactant: O=Cc1ccccc1
Reactant: [C-]#[N+]CC(=O)OC
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1N=COC1c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
39/3 mg (0.55 mmole) of (S)-N-methyl-N-[3-(diethylamino) -propyl]-1-[(R)-1',2-bis(diphenylphosphino)ferrocenyl] -ethylamine and 14.1 mg (0.055 mmole) of silver trifluoromethane-sulfonate was stirred in methylene chloride (5.5 ml) at room temperature for 30 minutes, and then, 0.549 g (5.54 mmole) of methyl isocyano-acetate and 0.642 g (6.05 mmole) of benzaldehyde was added thereto and stirred for 20 hours at 25° C. in nitrogen After being distilled under conditions of 110° C./0.3 mmHg, 1.0 g of 4- methoxycarbonyl-5-phenyl-2-oxazoline (trans/cis =87/13) was obtained. Yield: 91%. The trans-form and the cis-form were separated from each other by column chromatography, and the optical purity of the transform was determined by means of 1H NMR spectroscopy with the same shift reagent Eu(dcm)3 as Example 1, which was 51% ee. After acid-hydrolysis with 6N HC1, L-threo-β-phenylserine, which is a known compound, was obtained.