Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH3:17])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:18]([O:21][CH2:22][C:23]1[C:24]([N:38]2[N:47]=[CH:46][C:45]3[C:40](=[C:41]([F:52])[CH:42]=[C:43]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:44]=3)[C:39]2=[O:53])=[N:25][CH:26]=[CH:27][C:28]=1B1OC(C)(C)C(C)(C)O1)(=[O:20])[CH3:19].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:18]([O:21][CH2:22][C:23]1[C:24]([N:38]2[N:47]=[CH:46][C:45]3[C:40](=[C:41]([F:52])[CH:42]=[C:43]([C:48]([CH3:50])([CH3:49])[CH3:51])[CH:44]=3)[C:39]2=[O:53])=[N:25][CH:26]=[CH:27][C:28]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH3:17])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: Cc1cc(Nc2cc(Cl)nn(C)c2=O)nn1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C)n(C)n3)c(=O)n(C)n2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 100 °C
Yield: 65.3 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 127b (120 mg, 0.47 mmol), (2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl acetate 116c (536 mg, 1.3 mmol), Pd(dppf)Cl2 (34 mg, 0.047 mmol), K3PO4 (199 mg, 0.94 mmol), sodium acetate (77 mg, 0.94 mmol), acetonitrile (10 mL), and water (0.2 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (100:1 to 30:1) to afford 127c (180 mg, 65%) as a black oil. MS-ESI: [M+H]+ 587.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:9])[C:7]=1[Cl:8].[Mg].[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C:20]1([CH:27]=[O:28])[CH2:24][CH2:25][CH3:26])=[O:18])([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C:20]1([CH:27]([C:4]1[CH:5]=[C:6]([F:9])[C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[OH:28])[CH2:24][CH2:25][CH3:26])=[O:18])([CH3:14])([CH3:15])[CH3:13]
Reactant: Fc1cc(Br)cc(Cl)c1Cl
Reactant: CCCC1(C=O)CCCN1C(=O)OC(C)(C)C
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC1(C(O)c2cc(F)c(Cl)c(Cl)c2)CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
A stirred mixture of 3,4-dichloro-5-fluorophenyl bromide (1.38 g, 5.66 mmol) and magnesium turnings (0.145 g, 5.94 mmol) in THF (8 mL) was heated at reflux under nitrogen for 30 minutes, then cooled to 0° C. To the reaction mixture was added a solution of 2-formyl-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.682 g, 2.38 mmol) in THF (2 mL) dropwise over 15 minutes. The cold reaction mixture was stirred for one hour, then quenched by the addition of saturated aqueous NH4Cl (20 mL) and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to a yellow oil (1.7 g). Purification by chromatography (silica, 0 to 20% EtOAc in hexanes) gave 2-[(3,4-dichloro-5-fluoro-phenyl)-hydroxy-methyl]-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.571 g, 1.41 mmol, 50%) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([CH:10]=1)[C:8]#[N:9])=[O:2].N1C=CC=C(O)C=1.FC1C=CC(C=O)=CC=1C#N>>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: N#Cc1cc(C=O)ccc1Oc1cccnc1
Agent: N#Cc1cc(C=O)ccc1F
Agent: Oc1cccnc1
Product: N#Cc1cc(CO)ccc1Oc1cccnc1

Procedure:
The title compound was prepared by a procedure similar to that described for D5 starting from 5-formyl-2-(pyridine-3-yloxy)benzonitrile, which was prepared by reaction of pyridine-3-ol and 2-fluoro-5-formylbenzonitrile by the similar procedure to that described for D4.
Reaction SMILES: CN1[CH2:6][CH2:5][N:4]([CH3:7])C1=O.[CH3:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[CH:16]([OH:20])[CH:17]([CH3:19])[CH3:18]>C1COCC1>[NH:4]1[C:5]2[C:6](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:11]([C:16]([O:20][CH:16]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][N:10]2[CH3:9])[CH:17]([CH3:18])[CH3:19])=[O:20])=[CH:7]1
Reactant: CC(C)C(O)C1CCCCN1C
Reactant: CN1CCN(C)C1=O
Solvent: C1CCOC1
Product: CC(C)C(OC(=O)c1c[nH]c2ccccc12)C1CCCCN1C

Procedure:
The title compound was prepared by the procedures of Example 1 wherein the reaction solvent is changed to THF: 1,3-dimethyl-2-imidazolidinone using 1-(1-methyl-2-piperidyl)-2-methyl-1-propanol prepared in Reference Examples 5 and 6.
Reaction SMILES: NCC[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C1C([OH:19])=CC2C(CCN)=CNC=2C=1.CNCCC1C2C=C(O)C=CC=2NC=1.COC1C=C2C(NC=C2CCNC)=CC=1>>[OH:19][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: NCCc1c[nH]c2ccc(O)cc12
Reactant: NCCc1c[nH]c2ccccc12
Agent: CNCCc1c[nH]c2ccc(O)cc12
Agent: CNCCc1c[nH]c2ccc(OC)cc12
Product: On1ccc2ccccc21

Procedure:
1-hydroxyindole can be prepared in 2 stages from indole by reducing it to triethylsilane in trifluoroacetic acid then by treating the indoline obtained with an aqueous solution of H2O2 (30%) in the presence of a catalytic quantity (20%) of sodium tungstate dihydrate (Na2WO4.H2O) in methanol at 0° C. according to a procedure described in M. Somei, F. Yamada, T. Kurauchi, Y. Nagahama, M. Hasegawa, K. Yamada, S. Teranishi, H. Sato, C. Kaneko Chem. Pharm. Bull. 2001, 49, 87-96. This procedure was used in the preparation, from tryptamine derivatives, of several compounds oxygenated in position 5 of the indole ring such as for example serotonin, the N-methylserotonin and 5-methoxy-N-methyltryptamine.
Reaction SMILES: Cl.[CH2:2]([C@@H:9]1[CH2:13][NH:12][C@H:11]([C:14]([OH:16])=[O:15])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:24]([O:28][C:29](ON=C(C1C=CC=CC=1)C#N)=[O:30])([CH3:27])([CH3:26])[CH3:25]>O.O1CCOCC1>[CH3:25][C:24]([CH3:27])([O:28][C:29]([N:12]1[CH2:13][C@@H:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][C@H:11]1[C:14]([OH:16])=[O:15])=[O:30])[CH3:26]
Reactant: O=C(O)[C@@H]1C[C@H](Cc2ccccc2)CN1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](Cc2ccccc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of cis-4-benzyl-L-proline hydrochloride (3 g) and triethylamine (5 g) in water (10 ml) is added a solution of 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (3.5 g) in dioxane (10 ml). The mixture is stirred at ambient temperature for 4 hours. After the addition of water (30 ml), and washing with ether, the mixture is acidified to a pH of 3-4 with 10% citric acid. The oil that separates is extracted into ethyl acetate, washed with brine, and dried (MgSO4). After concentration in vacuo, the residue (3.7 g) solidifies at room temperature, melting point 145°-149° C. dec.
Reaction SMILES: [O:1]=[C:2]1[CH2:27][C@@H:26]2[C@:13]([CH3:30])([CH2:14][CH2:15][C@H:16]3[C@H:25]2[CH2:24][CH:23]=[C:22]2[C@:17]3([CH3:29])[CH2:18][CH2:19][C@H:20]([OH:28])[CH2:21]2)[C@H:3]1[C@H:4]([CH3:12])[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:11])[CH2:9][OH:10].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O>[OH:1][C@H:2]1[CH2:27][C@@H:26]2[C@:13]([CH3:30])([CH2:14][CH2:15][C@H:16]3[C@H:25]2[CH2:24][CH:23]=[C:22]2[C@:17]3([CH3:29])[CH2:18][CH2:19][C@H:20]([OH:28])[CH2:21]2)[C@H:3]1[C@H:4]([CH3:12])[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:11])[CH2:9][OH:10]
Reactant: C[C@@H](CO)CCC[C@@H](C)[C@H]1C(=O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Product: C[C@@H](CO)CCC[C@@H](C)[C@H]1[C@@H](O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 5 h
Yield: 160.7 %

Procedure:
To a solution of (25R)-26-hydroxy-16-oxocholesterol (9) (4.52 mmoles in pyridine (20 ml)), cooled in an ice bath, p-toluenesulfonyl chloride (3.44 g, 18.0 mmoles) is added mixture is stirred for 5 hours at room temperature. The reaction mixture is then poured into water and extracted with ether. The organic layer is washed with 2N HCl and water, dried over sodium sulfate, and evaporated under reduced pressure to yield 3.04 g (93%) of (25R)-16β, 26-dihydroxycholesterol 3β, 26-ditosylate (7) as an oil. The product is the same as the one in Example 8.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[CH2:5][C:6]([CH3:8])=[O:7].[CH2:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[O:25])=[CH:19][CH:18]=1)[CH3:16].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.N1C=CC=CC=1>[C:6]([CH:5]([C:24](=[O:25])[CH2:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:15][CH3:16])=[CH:18][CH:19]=1)[C:4]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(=[O:7])[CH3:8]
Reactant: CCc1ccc(CC(=O)Cl)cc1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ccc(CC(=O)C(C(C)=O)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A suspension of magnesium chloride (1.74 g) in dichloromethane (30 ml) was cooled to 0° C., and thereto were added t-butyl acetoacetate (3.03 ml) and pyridine (2.96 ml), and successively was added a solution of the above 4-ethylphenylacetyl chloride in dichloromethane (30 ml). The mixture was stirred at the same temperature for 2.5 hours, and an aqueous citric acid solution was added thereto. The mixture was extracted with chloroform. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to give t-butyl 2-acetyl-4-(4-ethylphenyl)-3-oxobutyrate (4.75 g) as pale yellow oil. APCI-Mass m/Z 322 (M+NH4).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=O)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC.[NH2:32][CH2:33][CH2:34][N:35]1[C:44]2[C:39](=[C:40]([F:49])[CH:41]=[CH:42][C:43]=2[O:45][CH2:46][CH2:47][CH3:48])[C:38](=[O:50])[C:37]([C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=2)=[CH:36]1>O.CN(C=O)C>[F:49][C:40]1[CH:41]=[CH:42][C:43]([O:45][CH2:46][CH2:47][CH3:48])=[C:44]2[C:39]=1[C:38](=[O:50])[C:37]([C:51]1[CH:52]=[CH:53][C:54]([O:57][CH3:58])=[CH:55][CH:56]=1)=[CH:36][N:35]2[CH2:34][CH2:33][NH:32][C:12]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][OH:11])=[O:14]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCN)c12
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCNC(=O)[C@H](CO)NC(=O)OC(C)(C)C)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.8 %

Procedure:
A DMF solution (0.5 ml) of N-(tert-butoxycarbonyl)-L-serine (174 mg, 0.85 mmol), triethylamine (198 mg, 1.96 mmol), diethyl phosphorocyanidate (DEPC, 176 mg, 0.97 mmol) and DMF (0.5 ml) were sequentially added to a DMF solution (1 ml) of 1-(2-aminoethyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (300 mg, 0.81 mmol) while ice-cooling, and stirred at room temperature for 20 hours. Water was added to the reaction mixture and then subjected to extraction using ethyl acetate. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution twice. The washed product was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=40:1→30:1). The purified product was concentrated to dryness under reduced pressure, giving a white amorphous solid of tert-butyl ((S)-1-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylcarbamoyl}-2-hydroxyethyl)carbamate (338 mg, yield: 75%).
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][CH2:21][CH2:22][CH2:23][C@H:24]([O:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([C:39]3[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][N:40]=3)[N:37]=[CH:38][C:31]=12)[C:25](OC)=[O:26])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:13]([O:20][CH2:21][CH2:22][CH2:23][C@H:24]([O:29][C:30]1[C:31]2[CH:38]=[N:37][N:36]([C:39]3[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][N:40]=3)[C:32]=2[N:33]=[CH:34][N:35]=1)[C:25]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:26])([C:16]([CH3:18])([CH3:19])[CH3:17])([CH3:15])[CH3:14]
Reactant: Cc1ccc(N)nc1
Reactant: COC(=O)[C@H](CCCO[Si](C)(C)C(C)(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Agent: C[Al](C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)[C@H](CCCO[Si](C)(C)C(C)(C)C)Oc2ncnc3c2cnn3-c2ncccc2Cl)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 37.3 %

Procedure:
A solution of trimethylaluminium (2M in hexane) (0.491 mL, 0.98 mmol) was added dropwise to a stirred solution of 5-methylpyridin-2-amine (92 mg, 0.85 mmol) in toluene (5 mL) cooled to 0° C., over a period of 1 minute under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. A solution of (2S)-methyl 5-(tert-butyldimethylsilyloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)pentanoate (Intermediate O2) (420 mg, 0.85 mmol) in toluene (5 mL) was added dropwise over a period of 2 minutes. The resulting solution was stirred at 0° C. for 10 minutes allowed to warm to ambient temperature and then heated at 60° C. for 20 hours. The mixture was cooled and 1M citric acid (10 mL) added with vigorous stirring. The mixture was diluted with ethyl acetate (35 mL), washed with water (10 mL) and brine (10 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 50 to 100% ethyl acetate in isohexane to give the product (180 mg, 37%). 1H NMR (400 MHz, CDCl3) δ 0.04 (3H, s), 0.05 (3H, s), 0.89 (9H, s), 1.78-1.81 (2H, m), 2.20-2.30 (2H, m), 2.29 (3H, s), 3.71 (2H, t), 5.90-5.93 (1H, m), 7.45 (1H, dd), 7.51 (1H, dd), 7.99 (1H, dd), 8.07-8.08 (1H, m), 8.14 (1H, d), 8.42 (1H, s), 8.53 (1H, s), 8.60 (1H, dd), 8.62 (1H, s); m/z (ESI+) (M+H)+=568; HPLC tR=3.33 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13](B2OCC(C)(C)CO2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][C:25]1[N:30]=[C:29](Cl)[CH:28]=[C:27]([Cl:32])[N:26]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]([C:29]2[CH:28]=[C:27]([Cl:32])[N:26]=[C:25]([NH2:24])[N:30]=2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cc1ccc(OCc2ccccc2)cc1B1OCC(C)(C)CO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc(OCc2ccccc2)cc1-c1cc(Cl)nc(N)n1
Temperature: 85 °C
Reaction time: 4 h
Yield: 39.5 %

Procedure:
2-(5-Benzyloxy-2-methylphenyl)-5,5-dimethyl[1,3,2]dioxaborinane (41.5 g) obtained in Step 2 above, 2-amino-4,6-dichloropyrimidine (13.8 g, 84.2 mmol), and dichloroditriphenylphosphine palladium (5.0 g, 7.12 mmol) were placed in a reaction vessel, and then dimethoxyethane (800 ml) and 2N aqueous sodium carbonate solution (63.1 ml, 126.2 mmol) were sequentially added thereto. The resulting mixture was stirred at 85° C. for 4 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (1000 ml), and washed with water (600 ml) and then with a saturated aqueous sodium chloride solution (60 ml). The ethyl acetate solution was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=6:1 to 3:1) to yield 4-(5-benzyloxy-2-methylphenyl)-6-chloropyrimidin-2-ylamine (10.84 g, 40%) as a pale yellow solid material.
Reaction SMILES: C[Li].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:16][C@H:15](C(OCC)=O)[CH2:14][CH2:13][C@H:12]1[NH:22][C:23]([C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([Cl:34])=[CH:29][CH:28]=2)=[O:24])=[O:9])([CH3:6])([CH3:5])[CH3:4].[Cl-].[NH4+]>O1CCCC1>[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:16][C@H:15]([C:3]([OH:7])([CH3:5])[CH3:4])[CH2:14][CH2:13][C@H:12]1[NH:22][C:23]([C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([Cl:34])=[CH:29][CH:28]=2)=[O:24])=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCOC(=O)[C@@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](C(C)(C)O)CC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1 h
Yield: 118.6 %

Procedure:
Methyllithium (1.14N solution, 2.27 ml) was added to a tetrahydrofuran solution (10 ml) of (1R*,2S*,4R*)-N2-tert-butoxycarbonyl-N1-[(5-chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-1,2-cyclohexanediamine (200 mg) at −78° C., and the mixture was stirred for 1 hour and then 2 hours under ice cooling. An aqueous solution of ammonium chloride was added to the reaction mixture to extract the reaction mixture with chloroform, and the resultant organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:3) to obtain the title compound (115 mg) as a colorless solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[CH3:16][O:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:6]=1[C:4]([OH:3])=[O:5]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1OC
Reactant: BrCc1cccc2ccccc12
Product: COc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccccc12

Procedure:
Using general procedure B, 3-methoxy-1H-indole-2-carboxylic acid ethyl ester (Lit. 1) was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 332.1 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[Mg].[CH3:11]/[C:12](/[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])=[CH:13]\[CH2:14][O:15][C:16](=[O:30])[C:17](OC/C=C(\C)/CCC=C(C)C)=[O:18].[NH4+].[Cl-].C1(C=CC(O)=CC=1)O>C1COCC1.CCCCCCC.CCOCC>[O:18]=[C:17]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1)[C:16]([O:15][CH2:14]/[CH:13]=[C:12](\[CH3:11])/[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])=[O:30]
Reactant: C=Cc1ccc(Br)cc1
Reactant: CC(C)=CCC/C(C)=C/COC(=O)C(=O)OC/C=C(\C)CCC=C(C)C
Agent: Oc1ccc(O)cc1
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCCC
Product: C=Cc1ccc(C(=O)C(=O)OC/C=C(\C)CCC=C(C)C)cc1
Temperature: 25 °C
Yield: 20.9 %

Procedure:
A Grignard reagent prepared from 4-bromostyrene (2.78 g, 15.2 mmol) and magnesium (0.39 g, 15.9 mmol) in THF (23 mL) was added dropwise (during 20 min) to a stirred solution of (E)-bis(3,7-dimethylocta-2,6-dien-1-yl)oxalate (5.00 g, 13.8 mmol) in THF (40 mL) at −60° C. The mixture was left warming to room temperature, and then poured into a mixture of ice (70 g) and a saturated solution of NH4Cl (60 mL). Extraction with diethyl ether (200 mL), washing with a saturated solution of NaCl (100 mL, 3×), drying (Na2SO4), adding of hydroquinone (10 mg) and concentrating afforded 6.44 g of the crude compound. Repetitive column chromatography (SiO2, heptane/ether 9:1 and 98:2), addition of hydroquinone to the product fraction, concentration and drying under vacuum (0.2 mbar, 1 h) gave 0.90 g (21%) of an oil.
Reaction SMILES: [CH3:1]O.B(F)(F)F.[Br:7][C:8]1[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=1>CO>[Br:7][C:8]1[O:12][C:11]([C:13]([O:15][CH3:1])=[O:14])=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CO
Agent: FB(F)F
Product: COC(=O)c1ccc(Br)o1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Boron trifluoride methanol (6.3 ml, 7.6 g) was added to a stirred solution of 5-bromofuran-2-carboxylic acid (10 g) in methanol (90 ml) and heated under reflux under nitrogen for 5 hours. More boron trifluoride methanol (5 ml) was added and the mixture heated under reflux for 5 hours, allowed to cool to room temperature and stand for 10 hours before the solvent was removed in vacuo and the residue poured into saturated sodium hydrogen carbonate solution (300 ml) and extracted with ethyl acetate (3×200 ml). The extract was washed with saturated sodium hydrogen carbonate solution (2×100 ml), dried over MgSO4, and the solvent removed in vacuo to give methyl 5-bromofuran-2-carboxylate, m.p. 62° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=2)=[CH:6][N:5]=1)([O-:3])=[O:2].C=O.[C:18](O)(=O)C>CO>[CH3:18][N:13]1[CH2:12][CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[N:5][CH:6]=2)[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(C2=CCNCC2)cn1
Reactant: CC(=O)O
Agent: C=O
Solvent: CO
Product: CN1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 232a (1.2 g, 5.8 mmol) in CH3OH (25 mL) was added HCHO (1 mL, 35 mmol) and acetic acid (1 mL), followed by the addition of NaBHCN3 (1.0 g, 12 mmol). The mixture was stirred at room temperature for 2 h. It was then evaporated under reduced pressure and the residue was purified by reverse-phase Combiflush eluting with 0.3% NH4HCO3 in water/acetonitrile to afford 232b as a yellow solid (1.0 g, 78%). MS-ESI: [M+H]+ 220.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH3:13])[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH2:13][Br:14])[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnn(C(=O)OC(C)(C)C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1cc(CBr)cn1
Temperature: 25 °C
Yield: 29.2 %

Procedure:
To a solution of 4-methylpyrazole-1-carboxylic acid tert-butyl ester (1.0 g, 5.5 mmol) in carbon tetrachloride (20 mL) was added N-bromosuccinimide (1.0 g, 5.6 mmol) and benzoyl peroxide (50 mg), and the reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:4 EtOAc/hexanes) provided 4-bromomethylpyrazole-1-carboxylic acid tert-butyl ester as a light yellow oil (0.42 g, 30%): 1H NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.74 (s, 1H), 4.39 (s, 2H), 1.65 (s, 9H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=[C:11]([C:19]3(O)[CH2:25][CH:24]4[N:26]([CH3:27])[CH:21]([CH2:22][CH2:23]4)[CH2:20]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:19]3[CH2:25][CH:24]4[N:26]([CH3:27])[CH:21]([CH2:22][CH2:23]4)[CH:20]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C2(O)CC3CCC(C2)N3C)c(-c2ccncc2)c1-c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC[SiH](CC)CC
Agent: [F-]
Solvent: O=C(O)C(F)(F)F
Product: CN1C2C=C(c3c[nH]c(-c4ccc(F)cc4)c3-c3ccncc3)CC1CC2
Yield: 83 %

Procedure:
In a similar manner to that described in Example 9(iii) above, 2-(4-fluorophenyl)-4-(3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-3-(pyridin-4-yl)-1-triisopropylsilyl-1H-pyrrole (a mixture of isomers A and B, prepared as described in step 43(i) above] was subjected to dehydration using triethylsilane and trifluoroacetic acid followed by desilylation (deprotection) with tetrabutylammonium fluoride to give the title compound (yield 83%) as a white powder.