Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][C@H:12]([CH3:14])[O:11][C@H:10]([CH3:15])[CH2:9]2)=[C:6]([CH:16]=O)[N:5]=[C:4]2[C:18]([CH3:21])=[N:19][O:20][C:3]=12.[NH:22]1[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]1=[O:30]>C(O)(C)C>[Cl:1][C:2]1[C:3]2[O:20][N:19]=[C:18]([CH3:21])[C:4]=2[N:5]=[C:6]2[C:7]=1[N:8]1[CH2:9][C@@H:10]([CH3:15])[O:11][C@@H:12]([CH3:14])[C@@H:13]1[C:26]1([C:25](=[O:29])[NH:24][C:23](=[O:30])[NH:22][C:27]1=[O:28])[CH2:16]2
Reactant: Cc1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(C=O)nc12
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CC(C)O
Product: Cc1noc2c(Cl)c3c(nc12)CC1(C(=O)NC(=O)NC1=O)[C@H]1[C@H](C)O[C@H](C)CN31
Temperature: 80 °C
Reaction time: 120 h
Yield: 42.7 %

Procedure:
Isopropanol (12 ml) was added to 7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)-3-methylisoxazolo[4,5-b]pyridine-5-carbaldehyde (Intermediate 471, 165 mg, 0.53 mmol) to give a yellow slurry; pyrimidine-2,4,6(1H,3H,5H)-trione (barbituric acid) (68.2 mg, 0.53 mmol) was added, and the mixture was heated to 80° C. After about 5 days, the mixture was concentrated. The crude was purified by chromatography using 10-50% EtOAc/CH2Cl2 to give 95 mg yellow solid which was subsequently recrystallized from EtOAc/hexanes. A total of 57 mg (19%) of the title product was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[NH2:22][C@H:23]([CH2:27][CH3:28])[CH2:24][C:25]#[N:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:17])[CH3:18])[C:13]([NH:22][C@H:23]([CH2:27][CH3:28])[CH2:24][C:25]#[N:26])=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Reactant: CC[C@@H](N)CC#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC[C@H](CC#N)NC(=O)[C@@H](C(C)C)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Yield: 23.4 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (10 mg, 0.032 mmol). THF (0.5 mL), (R)-3-aminopentanenitrile (3.19 mg, 0.032 mmol) and HATU (14.83 mg, 0.039 mmol) were added and the solution was stirred at 25° C. for 1 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (2.9 mg, 23.01%). 1H NMR (400 MHz, CD3OD) δ 0.82 (t, J=7.45 Hz, 3 H) 0.89-0.99 (m, 3 H) 1.11 (d, J=6.57 Hz, 3 H) 1.44-1.68 (m, 2 H) 2.41-2.56 (m, 1 H) 2.63 (dd, J=16.93, 7.33 Hz, 1 H) 2.76 (dd, J=16.93, 5.05 Hz, 1 H) 3.99 (d, J=10.61 Hz, 1 H) 4.95 (d, J=19.96 Hz, 1 H) 5.05 (d, J=11.37 Hz, 1 H) 5.35 (d, J=19.71 Hz, 1 H) 7.85 (s, 1 H) 8.20-8.27 (m, 1 H). [M+H] calc'd for C19H22ClN5O2, 388; found, 388.4.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:28])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:27])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37]>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:28])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:27])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCS(=O)(=O)Cl
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 82.9 %

Procedure:
L-alanyl-L-prolyl-L-proline benzylester hydrochloride (4.09 g, 10.0 m mole) was added to methylene dichloride (40 ml) and triethyl amine (2.02 g, 20.0 m mole), was added thereto while stirring and cooling with ice. After that, ethanesulfonyl chloride (1.29 g, 10.0 m mole)-methylene dichloride (10 ml) solution was added dropwise over 1 hour thereto. The reaction solution was allowed to stand overnight at room temperature and then washed with two 20 ml portions of hydrochloric acid, 10% aqueous sodium chloride (20 ml), two 20 ml portions of 10% aqueous sodium bicarbonate and 10% aqueous sodium chloride (20 ml) in order. A methylene dichloride layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give a syrupy N-ethanesulfonyl-L-alanyl-L-prolyl-L-proline benzylester (3.85 g).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:45]=[CH:44][C:11]([CH2:12][CH:13](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH2:36][CH2:37][N:38]2[CH2:42][CH2:41][O:40][C:39]2=[O:43])[CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:7].Cl>C1COCC1.O>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH2:36][CH2:37][N:38]2[CH2:42][CH2:41][O:40][C:39]2=[O:43])[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[CH:44][CH:45]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCN2CCOC2=O)Cc2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(CCC(/C=C/c2ccccc2OCCCN2CCOC2=O)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
81.5 mg (1.94 mmol) of lithium hydroxide monohydrate are added to a solution of 370 mg (0.647 mmol) of methyl 4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[3-(2-oxo-1,3-oxazolidin-3-yl)-propoxy]phenyl}pent-4-en-1-yl]benzoate (Example 26A) in 2 ml of THF and 2 ml of water, and the mixture is stirred at room temperature for 18 h. The mixture is then adjusted to pH 2 using 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate. After filtration, the solvent is removed to dryness and the crude product is purified by preparative HPLC. This gives 114 mg (0.210 mmol, 32.4% of theory) of the title compound as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]Cl.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][O:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=1
Reactant: OCc1ccc(CCl)cc1
Reactant: COCCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOCc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.3 %

Procedure:
A 5 liter round bottom flask, fitted with a reflux condensor, dropping funnel and mechanical stirrer, was charged with p-hydroxymethylbenzyl chloride (255 g, 1.91 moles) in dichloromethane (2 liters). The flask was charged with 2-methoxyethoxymethyl chloride (300 g, 2.41 moles) and stirred at 20°-25° C. while N,N-diisopropylethylamine (500 mL, 2.86 moles) was slowly added. The reaction became exothermic and caused the dichloromethane solvent to reflux vigorously for 20 minutes. The contents were then stirred for 24 hours at room temperature. The dichloromethane extract was washed with water and brine. The remaining organics were dried over anhydrous magnesium sulfate. After removal of the solvent by rotary evaporation, the residue was passed through a plug of silica gel to provide 310 g (67% yield) of the desired product. 1H NMR spectral data were as follows: (CDCl3, 300 MHz): δ7.35 (m, 4H), 4.80 (s, 2H), 4.62 (s, 2H), 4.58 (s, 2H), 3.72 (m, 2H), 3.58 (m, 2H), 3.4 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][N:14]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]([C:21](O)=[O:22])=[CH:15]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:21]([C:16]3[CH:17]=[CH:18][C:19](=[O:20])[N:14]([CH3:13])[CH:15]=3)=[O:22])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: Cn1cc(C(=O)O)ccc1=O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cn1cc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)ccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
TEA (0.61 mL, 4.35 mmol) was added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.20 g, 0.87 mmol, Example 1, Step H), 1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.17 g, 1.13 mmol) and BOP-Cl (0.33 g, 1.30 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 1 hour, and then a LiOH solution (3 mL, 2N) was added. The mixture was stirred for 30 minutes, and water (10 mL) was added. The solid formed was collected by filtration, washed with DCM (10 mL) and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (0.22 g, 69% yield) as a solid.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:14]([NH:16][O:17]C3CCCCO3)=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].O>CO>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:14]([NH:16][OH:17])=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(C(=O)NOC3CCCCO3)cc2C1
Solvent: O
Solvent: CO
Product: CC(=O)N1CCc2ccc(C(=O)NO)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To 6.29 g of 2-acetyl-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide are added 57 ml water, 88 ml methanol and 1.4 g DowexWX2-100. The mixture is stirred overnight at ambient temperature and filtered. The filtrate is evaporated and 4.17 g of the title compound as a yellow solid are obtained. MP 177-181° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][C:12]=2[C:13]([NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:28][Mg]Br.S(=O)(=O)(O)O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[CH:25]=[CH:24][C:23]([CH:26]([OH:27])[CH3:28])=[CH:22][C:12]=2[C:13]([NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)Nc2cccnc2)c1
Reactant: C[Mg]Br
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CC(O)c1ccc(OCc2ccc(F)c(F)c2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-{[(3,4-difluorophenyl)methyl]oxy}-5-formyl-N-3-pyridinylbenzamide (may be prepared as described in Example 80; 100 mg, 0.27 mmol) in tetrahydrofuran (5 ml) was cooled to 0° C. and methylmagnesium bromide (0.18 ml, 0.54 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. An additional 3 eq of methylmagnesium bromide was added and the mixture was stirred at room temperature. 5 ml of 1M aqueous sulphuric acid was then added. After stirring for 30 min the mixture was extracted with ethyl acetate (3×10 ml). The organics were combined, evaporated under reduced pressure and the residue was purified by MDAP to yield the title compound. 48 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1.C(N(CC)C1C=CC=CC=1)C.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>C(OCC)(=O)C>[CH:29]([O:28][C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1)=[O:27])([CH3:31])[CH3:30]
Reactant: CCOc1ccc(N)nc1OCC
Reactant: CC(C)OC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Product: CCOc1ccc(NC(=O)OC(C)C)nc1OCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 83.2 %

Procedure:
2-Amino-5,6-diethoxypyridine (1.83 g) and N,N-diethylaniline (1.49 g) were dissolved in ethyl acetate (30 ml). To the resultant solution, there was dropwise added isopropyl chloroformate (1.23 g) in 5 minutes under ice-cooling. The resulting mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic alumina chromatography using a mixture of toluene and ethyl acetate as an eluent to give 2-isopropyloxycarbonylamino-5,6,-diethoxypyridine (2.24 g) in a yield of 83.5%.
Reaction SMILES: [I:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([CH3:10])[N:5]=[C:4]2[N:11]([CH3:14])[CH:12]=[CH:13][C:3]=12.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[I:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([CH3:10])[N:5]=[C:4]2[N:11]([CH3:14])[CH:12]=[CH:13][C:3]=12
Reactant: Cc1nc2c(ccn2C)c(I)c1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1nc2c(ccn2C)c(I)c1C=O
Reaction time: 3 h
Yield: 84 %

Procedure:
A solution of (4-iodo-1,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol in dichloromethane (DCM) (300 mL) was treated with PCC (11.96 g, 55.5 mmol) and Celite™ (17 g) in one portion. After 3 h, the mixture was diluted with DCM (100 mL) and filtered through a pad of celite and washed with DCM/ethyl acetate (10:1). The filtrate was concentrated in vacuo to afford the title compound (10.8 g, 36.0 mmol, 84% yield) as a yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.88 (s, 3H) 3.88 (s, 3H) 6.48 (d, J=3.52 Hz, 1H) 7.22 (d, J=3.52 Hz, 1H) 10.36 (s, 1H). LC/MS (m/z) ES+=301 (M+1)+
Reaction SMILES: Br[CH:2]([CH3:10])[C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:11][C:12]([NH2:14])=[S:13]>>[NH2:14][C:12]1[S:13][C:2]([CH3:10])=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:11]=1
Reactant: CCOC(=O)C(=O)C(C)Br
Reactant: NC(N)=S
Product: CCOC(=O)c1nc(N)sc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.4 %

Procedure:
Ethyl 3-bromo-2-oxobutanoate (Intermediate 177, 12.2 g; 58.7 mmol) and thiourea (4.46 g; 76.1; 58.7 mmol) were combined and heated to reflux. The solution was allowed to cool to room temperature and stir for 12 hours. The reaction was monitored by LC/MS. The base was precipitated with 20% NH4OH (10 ml) and then redissolved with 1N HCl (100 ml) and then finally reprecipitated with 20% NH4OH. The precipitate was collected and washed with H2O. The crude product was then crystallized from 9:1 ethanol/water to give 5.95 g of product in 55% yield. MS (ES) MH+: 187 for C7H10N2O2S.
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:26]Br>C(Cl)Cl>[C:1]([NH:8][C:9]1[S:10][C:11]([Br:26])=[C:12]([C:14]([O:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[N:13]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: BrBr
Reactant: CCOP(=O)(COC(=O)c1csc(NC(=O)OC(C)(C)C)n1)OCC
Solvent: ClCCl
Product: CCOP(=O)(COC(=O)c1nc(NC(=O)OC(C)(C)C)sc1Br)OCC

Procedure:
A solution of 2-[N-Boc(amino)]-4-diethylphosphonomethoxycarbonylthiazole (1 mmole) in CH2Cl2 (5 mL) was treated with bromine (2 mmole) at room temperature for 4 h. Evaporation and extraction gave 2-[N-Boc(amino)]-5-bromo-4-diethylphosphonomethoxycarbonylthiazole as an orange oil which was subjected to Step D of Example 18 followed by Step C of Example 3 to give 2-amino-5-bromo-4-phosphonomethoxycarbonylthiazole (18.2) as a solid. Mp>230° C. (decomp). Anal. Calcd. for C5H6N2O5PSBr: C: 18.94; H: 1.91; N: 8.84. Found: C: 19.08; H: 1.76; N: 8.67.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCCCc1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(CCCCC(=O)O)c1
Yield: 85 %

Procedure:
A mixture of ethyl 5-(3-methoxyphenyl)pentanoate (1 equivalent) and sodium hydroxide (3 equivalents) in THF/H2O was heated at reflux overnight. THF was evaporated, the aqueous phase acidified with 6N HCl to pH<5, and then extracted with a mixture of chloroform:isopropyl alcohol (3:1, 5 times). The organic phase was dried over anhydrous sodium sulfate. A light yellow oil was obtained in more than 85% yield after removal of the solvent: 1H NMR δ 7.20 (m, 1H), 6.79-6.73 (m, 3H), 3.80 (s, 3H), 2.62 (m, 2H), 2.38 (m, 2H), 1.68 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH:13]1([C:16]2[C:17]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:29]2[CH2:30][CH2:31][N:26]([C:17]3[C:16]([CH:13]4[CH2:15][CH2:14]4)=[CH:21][C:20]([C:22]([F:25])([F:23])[F:24])=[CH:19][N:18]=3)[CH2:27][CH2:28]2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Agent: Cl
Product: O=C(c1ccc(Br)cc1F)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Yield: 85.5 %

Procedure:
Using 4-bromo-2-fluorobenzoyl chloride (2.5 g) and 1-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazine hydrochloride (3.2 g) described in Preparation Example 89 and by the reaction and treatment in the same manner as in Preparation Example 108, the title compound (4.2 g) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.II.[C:18]1([C:26]([CH2:28][C:29]2[CH:36]=[CH:35][C:32]([O:33][CH3:34])=[CH:31][CH:30]=2)=O)[CH:25]=[CH:24][C:21]([O:22][CH3:23])=[CH:20][CH:19]=1.OS(O)(=O)=O>C1COCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]([C:29]2[CH:36]=[CH:35][C:32]([O:33][CH3:34])=[CH:31][CH:30]=2)=[CH:26][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[CH:24][CH:25]=2)=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: COc1ccc(C=C(c2ccc(OC)cc2)c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
Benzyl 4-bromophenyl ether (13.155 g; 50 mmol), prepared in Example 2, in 20 mL THF was added to Mg turnings (1.17 g; 48 mg-atom) in 20 mL THF. Grignard reagent formation was facilitated by addition of a few drops of EtBr2, one crystal of I2, and heat. This mixture was stirred and heated to reflux for 2 h. 11.54 g (45 mmol) desoxyanisoin was added under reflux as a slurry in 60 mL THF. The resulting mixture was stirred at reflux for 18 h, cooled to room temperature, poured onto 200 g 2N H2SO4 and ice (1:1), and stirred at room temperature until the ice melted. The resulting mixture was placed in a separatory funnel and extracted with 200 mL Et2O. The organic layer was washed with aqueous Na2SO5 (100 mL), and brine (2×100 mL). The combined aqueous layers were extracted with Et2O (50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to give 19 g of a wine colored oil, which was dissolved in Et2O and refrigerated to precipitate any unreacted deoxyanisoin. After filtration and concentration of the solution, the resulting oil was purified on 60 g flash SiO2 (7:3 petroleum ether-CH2Cl2) to yield 12.4 g (65%) of 1-(4-Benzyloxyphenyl)-2,2-bis(4-methoxyphenyl)ethene as a yellow oil. NMR δ7.41 (s, 5H, O-benzyl C6H5), 7.35 to 6.57 (m, 13H, ArH and C=CH), 5.07 (s, 2H, PhCH2O), 3.78 (s, 1.5H, geminal ring OCH3), 3.77 (s, 1.5H, central ring OCH3), 3.72 (s, 3H, vicinal ring OCH3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH:16]=1)=[O:4].[H][H]>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]1)=[O:4]
Reactant: COC(=O)c1cnccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC(=O)c1cnccc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.6 %

Procedure:
A solution of Pd(OH)2/C (5.2 g, 7.4 mmol, 0.3 eq., 20%) in EtOAc (100 mL) was stirred for 10 minutes at room temperature under nitrogen. 3,6-Dihydro-2H-[4,4′]bipyridinyl-1,3′-dicarboxylic acid 1-t-butyl ester 3′-methyl ester (8.7 g, 27.3 mmol, 1.0 eq.) was added. Hydrogen gas was introduced into the reaction vessel (at 1 atm) and the solution was stirred for 5 hours at room temperature. The solids were filtered and the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:5) to yield 3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1,3′-dicarboxylic acid 1-t-butyl ester 3′-methyl ester (6.7 g) as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][S:20]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)=[O:12])[N:10]=2)[CH2:3]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1csc(N2CC(O)C2)n1)N1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCCCC3)cs2)C1
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a solution of 3-hydroxy-1-(4-piperidinocarbonyl-1,3-thiazol-2-yl)azetidine (310 mg, 1.16 mmol) (obtained as described in Reference Example 27(2)) in methylene chloride (10 ml) were added methanesulfonyl chloride (0.27 ml, 3.48 mmol) and triethylamine (0.49 ml, 3.48 mmol) in an ice bath, and then the mixture was stirred for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-methanesulfonyloxy-1-(4-piperidinocarbonyl-1,3-thiazol-2-yl)azetidine (346 mg, yield 86%) as a pale yellow solid.
Reaction SMILES: C[Si]([CH:5]=[N+:6]=[N-:7])(C)C.CN(C)C.[Br:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[N:20]([CH3:22])[C:19]([C:23](Cl)=[O:24])=[CH:18]2.[Cl-].[NH4+]>O1CCCC1.C(#N)C>[Br:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[N:20]([CH3:22])[C:19]([C:23](=[O:24])/[CH:5]=[N:6]/[NH2:7])=[CH:18]2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cn1c(C(=O)Cl)cc2cccc(Br)c21
Agent: CN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cn1c(C(=O)/C=N/N)cc2cccc(Br)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a dichloromethane (2 mL) solution of 7-bromo-1-methyl-1H-indole-2-carboxylic acid (200 mg), oxalyl dichloride (0.10 mL) and N,N-dimethylformamide (5 mL) were added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, azeotroped twice with toluene to obtain a crude product of 7-bromo-1-methyl-1H-indole-2-carboxylic acid chloride. Separately, a solution was prepared by dissolving 2M trimethylsilyldiazomethane (0.60 mL) and trimethylamine (0.16 mL) in tetrahydrofuran (2 mL)-acetonitrile (2 mL) and a tetrahydrofuran (1 mL)acetonitrile (1 mL) solution of 7-bromo-1-methyl-1H-indole-2-carboxylic acid chloride was added thereto, and then the mixture was stirred at room temperature for 4 hours. To the reaction mixture, an aqueous saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10 85:15) to obtain the titled compound having the following physical properties (72 mg).