Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][C:11]2[CH:12]=[N+:13]([O-])[CH:14]=[C:15]([F:18])[C:16]=2[N:17]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:12]1[C:11]2[S:10][C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])=[N:17][C:16]=2[C:15]([F:18])=[CH:14][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cc(F)c2nc(-c3c(Cl)cccc3Cl)sc2c1
Product: Fc1cnc(Cl)c2sc(-c3c(Cl)cccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49 %

Procedure:
A stirred solution of 2-(2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridine 5-oxide (0.095 g, 0.30 mmol) in phosphoryl chloride (3 mL) was heated under reflux for 0.5 hour and then at 110° C. for 15 minutes. The reaction was repeated on a larger scale by reacting 2-(2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridine 5-oxide (6.4 g, 17.0 mmol) with phosphoryl chloride (100 mL) and by heating the mixture under reflux for 30 minutes. After cooling to room temperature, the mixture was left standing at room temperature for 18 hours and then heated at reflux temperature for 15 minutes. The two crude reaction mixtures were combined and the volatiles were removed under reduced pressure. The crude residue was dissolved in EtOAc (200 mL) and washed with a saturated solution of potassium carbonate, followed by water, then dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-20% EtOAc in pentane to afford the title compound as a white solid (3.42 g, 49% yield). 1H NMR (400 MHz, CDCl3): δ 8.39 (d, J=1.9 Hz, 1H), 7.53-7.41 (m, 3H).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:24]([CH:34]2[CH2:37][CH2:36][CH2:35]2)[N:25]=[C:26]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:27]=1)=[O:4].[OH-].[Li+]>>[CH:34]1([N:24]2[C:23]([N:6]3[CH2:7][C@H:8]([S:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:19]([F:20])([F:22])[F:21])(=[O:11])=[O:12])[CH2:9][C@H:5]3[C:3]([OH:4])=[O:2])=[CH:27][C:26]([CH:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[N:25]2)[CH2:37][CH2:36][CH2:35]1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C2CCOCC2)nn1C1CCC1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C2CCOCC2)nn1C1CCC1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-[2-cyclobutyl-5-(tetrahydro-pyran-4-yl)-2H-pyrazol-3-yl]-4-(2-trifluorom ethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow oil which was used in the next step without further purification. MS (ESI): m/z=528.3 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:43])[C@@H:7]([NH:28][C:29]([O:31][CH2:32][C:33]12[CH2:42][CH:37]3[CH2:38][CH:39]([CH2:41][CH:35]([CH2:36]3)[CH2:34]1)[CH2:40]2)=[O:30])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:15][CH:16]=1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:33]12([CH2:32][O:31][C:29]([NH:28][C@@H:7]([CH2:8][NH:9][C:10]([C:12]3[S:13][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]4[NH:22][CH2:23][CH2:24][CH2:25][N:26]=4)=[CH:15][CH:16]=3)=[O:11])[C:6]([OH:43])=[O:5])=[O:30])[CH2:42][CH:37]3[CH2:38][CH:39]([CH2:41][CH:35]([CH2:36]3)[CH2:34]1)[CH2:40]2
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)s1)NC(=O)OCC12CC3CC(CC(C3)C1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCc1ccc(C(=O)NC[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)O)s1)NC1=NCCCN1

Procedure:
117 mg (0.19 mmol) of the product obtained in step c) were dissolved in 5 ml of dichloromethane and stirred for 3 hours with 1 ml of trifluoroacetic acid under an inert gas atmosphere at room temperature. The solvents were removed in vacuo, and the residue was dissolved in acetic acid and again evaporated to dryness. This procedure was repeated once. The resinous residue was triturated with diethyl ether. After filtration 90 mg of a colourless amorphous powder were obtained.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].C([O:12][C:13](=[O:27])[C:14](=[C:24]([CH3:26])[CH3:25])[N:15]1[C:18](=[O:19])[C:17]([Br:21])([Br:20])[CH:16]1[O:22][CH3:23])C1C=CC=CC=1.C1(OC)C=CC=CC=1.Cl>C(Cl)Cl.C(OCC)(=O)C>[Br:21][C:17]1([Br:20])[C:18](=[O:19])[N:15]([C:14](=[C:24]([CH3:26])[CH3:25])[C:13]([OH:27])=[O:12])[CH:16]1[O:22][CH3:23]
Reactant: COC1N(C(C(=O)OCc2ccccc2)=C(C)C)C(=O)C1(Br)Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Product: COC1N(C(C(=O)O)=C(C)C)C(=O)C1(Br)Br
Temperature: 25 °C

Procedure:
To an ice-cooled suspension of aluminum trichloride (0.400 g; 0.003 mole) in methylene chloride (15 mL) in a nitrogen stream a solution of 2-methoxy-3,3-dibromo-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid benzyl ester (0.447 g; 0.001 mole) and anisole (0.648 g; 0.65 mL, 0.006 mole) in methylene chloride (15 mL) was added and then it was stirred for half an hour at room temperature. Ethyl acetate (15 mL) and 0.1N hydrochloric acid (5 mL) were added to the reaction mixture and the layers were separated. The ethyl acetate layer was extracted with a 5% sodium hydrogen carbonate solution (2×20 mL) and the layers were separated. The aqueous layer was acidified with 0.1N hydrochloric acid to pH 1, then fresh ethyl acetate (20 mL) and sodium chloride were added and the layers were again separated. The ethyl acetate layer was washed with a saturated salt solution, dried and evaporated to a dry residue to obtain 3,3-dibromo-2-methoxy-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid, which was identical to the one disclosed under 2a.
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4].Br[C:31]1[CH:32]=[CH:33][C:34]([CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[N:35][CH:36]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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]>[F:29][CH:2]([F:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:31]3[CH:32]=[CH:33][C:34]([CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[N:35][CH:36]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4]
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
To a solution of the product of Step 3, Example 22 (1000 mg, 2.4 mmol) in toluene/ethanol (30:20 mL) is added commercially available tert-butyl (5-bromopyridin-2-yl)methylcarbamate (695 mg, 2.42 mmol), sodium bicarbonate (5 mL of a saturated solution) and Pd(dppf)2Cl2 (90 mg, 0.12 mmol). The reaction mixture is heated to 80° C. while stirring under nitrogen for 4 hours. The reaction mixture is cooled and diluted with water. Contents are extracted with ethylacetate (2×75 mL) and the combined organic phase is dried (Na2SO4) and concentrated under vacuum. Crude material is chromatographed (80 g Redi-Sep column) eluting from 100% hexanes to 90:10 ethylacetate:hexanes to afford the title compound (912 mg): m/z (CI) M+H 494.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[C@@H:14]([S:15][CH2:16][C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)=[O:18])[NH:13][C:12]2=[O:25])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])[CH:27]=[O:28].C(N(CC)CC)C.C(OCC)(=O)C>ClCCCl>[OH:28][CH:27]([N:13]1[C@H:14]([S:15][CH2:16][C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[O:18])[C@H:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]1=[O:25])[C:26]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N[C@@H]1SCC(=O)C1CCCCO1
Reactant: CC(C)(C)OC(=O)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(O)N1C(=O)[C@@H](NC(=O)Cc2ccccc2)[C@H]1SCC(=O)C1CCCCO1
Yield: 82 %

Procedure:
(3R,4R)-3-Phenylacetamido-4-[(RS)-tetrahydropyran-2-yl-carbonylmethylthio]azetidin-2-one (1.7 g) in 1,2-dichloroethane (20 ml) was successively treated with 0.5M t-butyl glyoxylate in 1,2-dichlorethane (10 ml) and triethylamine (50 mg, 70 μl) and monitored by t.l.c. (ethyl acetate) until no starting material remained. The reaction mixture was concentrated and flash chromatography (70% ethyl acetate in hexane, ethyl acetate) to afford the title compound as a yellow foam (1.9 g, 82%); νmax (CH2Cl3) 3400 (w), 1780, 1736, 1687 cm-1 ; δH (CDCl3) 1.49 (9H, s) overlapping 1.44-1.61 (4H, m), 1.8-2.0 (2H, m), 3.35-3.58 (3H, m), 3.65 (2H, s), 3.81-3.92 (1H, m), 4.01-4.06 (1H, m), 4.28-4.43 (1H, m), 4.99, 5.00, 5.07 (together 1H, 3d, J4.7 Hz), 5.21, 5.32, 5.33 (together 1H, 3d, J6.8, 7.7, 7.6 Hz), 5.42, 5.50 (together 1H, 2dd, J4.8, 8.7 Hz, 6.35, 6.36, 6.61 (together 1H, 3d, J8.7 Hz) and 7.27-7.38 (5H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][N:31]3[CH2:30][CH2:29][N:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[O:21][CH3:20])[CH2:33][CH2:32]3)[O:13][N:12]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-c2cc(CCC=O)on2)cc1OC
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccccc4OC)CC3)on2)cc1OC
Yield: 108 %

Procedure:
About 2 min after dissolving 3-[3-(3,4-dimethoxyphenyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-(2-methoxyphenyl)piperazine (7.4 mg, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (24 mg, 0.12 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 22.6 hr and followed the same processes as in Example 1 to obtain 18.9 mg (100%) of the target compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:5]2.[Li]CCCC.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:33]2[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=2)=[O:32])=[CH:27][CH:26]=1>O1CCCC1>[Cl:12][C:7]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:31]([C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=3)([C:33]3[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=3)[OH:32])[CH:3]=2)[N:8]=1
Reactant: Clc1nc2ccc(Br)cc2cc1-c1ccccc1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)c(-c3ccccc3)cc2c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a 50-mL round-bottom flask containing a solution of 6-bromo-2-chloro-3-phenylquinoline (210 mg, 0.66 mmol, Intermediate 31: step b) in tetrahydrofuran (10 mL) was added 2.5 M n-BuLi in hexanes (0.29 mL, 0.72 mmol) dropwise with stirring at −78° C. After 45 minutes at −78° C., a solution of (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (132 mg, 0.60 mmol, Intermediate 8: step b) in tetrahydrofuran (2 mL) was added dropwise. The resulting solution was stirred at −78° C. for an additional 2 hours, then quenched with 30 mL of aqueous NH4Cl and extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by FCC (20:1 DCM/MeOH) to provide the title compound as a white solid. MS (ES): mass calcd. for C26H19Cl2N3O, 459.1; m/z found, 460.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.96 (d, J=3.9 Hz, 1H), 8.33 (s, 1H), 8.05 (d, J=6.0 Hz, 1H), 7.94 (s, 1H), 7.88 (d, J=6.6 Hz, 1H), 7.42-7.56 (m, 9H), 6.93 (s, 1H), 3.71 (s, 3H).
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:11])=O)[C:4]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.[CH2:18]([C:25]1([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[CH2:18]([C:25]1([OH:31])[CH2:30][CH2:29][N:28]([C:9]([C:5]2[C:4]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:3][CH:8]=[CH:7][CH:6]=2)=[O:11])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1cccnc1-c1ccncc1
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1cccnc1-c1ccncc1)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
A suspension of 2,4′-bipyridine-3-carboxylic acid dihydrochloride (5.0 g), 4-benzyl-4-hydroxypiperidine (3.9 g), HATU (10 g) and triethylamine (13 mL) in DMF (50 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (3.2 g).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[N:21]1([CH2:26][C@@H:27]2[CH2:31][CH2:30][CH2:29][NH:28]2)[CH2:25][CH2:24][CH2:23][CH2:22]1.C(OCC)(=O)C>C(O)C>[N:21]1([CH2:26][C@@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2[CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1Nc2cccnc2N(C(=O)CN2CCC[C@H]2CN2CCCC2)c2ccccc21

Procedure:
The title compound is prepared analogously to Example 31 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and (S)-(+)-2-[(1-pyrrolidinyl)methyl]pyrrolidine to give colorless crystals, mp. 192°-193° C. (ethyl acetate). [α]D20 =-18.1° (ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][O:6][CH:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:15]#[N:16])[CH2:8]1.[OH-:32].[K+]>C(O)(C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][O:6][CH:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:15]([NH2:16])=[O:32])[CH2:8]1
Reactant: [OH-]
Reactant: N#CC(CCN1CCC(OCc2cccc(Cl)c2)C1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)C(CCN1CCC(OCc2cccc(Cl)c2)C1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 83.7 %

Procedure:
To 1.80 g of 4-[3-(3-chlorobenzyloxy)pyrrolidine-1-yl]2,2-diphenylbutyronitrile was added 1.41 g of potassium hydroxide and 15 ml of tert-butanol, and the mixture was refluxed for 48 hours. The reaction mixture was poured into ice water, then extracted with methylene chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=10:1) to obtain 1.57 g of the aimed compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:11][C:12](=[O:48])[NH:13][C:14]1[N:19]=[CH:18][C:17]2[C:20]([C@@H:42]3[CH2:44][C@H:43]3[C:45](O)=[O:46])=[N:21][N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:16]=2[CH:15]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[CH3:67][CH2:68][N:69](C(C)C)C(C)C.C(N)C.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH2:68]([NH:69][C:45]([C@@H:43]1[CH2:44][C@H:42]1[C:20]1[C:17]2[CH:18]=[N:19][C:14]([NH:13][C:12]([NH:11][C@@H:4]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:3][O:2][CH3:1])=[O:48])=[CH:15][C:16]=2[NH:22][N:21]=1)=[O:46])[CH3:67]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC[C@@H](NC(=O)Nc1cc2c(cn1)c([C@@H]1C[C@H]1C(=O)O)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CCN
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)[C@@H]1C[C@H]1c1n[nH]c2cc(NC(=O)N[C@H](COC)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
A mixture of trans-2-(6-(3-((S)-2-methoxy-1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)cyclopropanecarboxylic acid (13 mg, 0.020 mmol), 1-propanephosphonic acid cyclic anhydride (50% in EtOAc, 18.20 μl, 0.031 mmol), DIEA (10.68 μl, 0.061 mmol) and ethylamine (2M in THF) (102 μl, 0.204 mmol) in DCM (0.5 ml) was stirred at room temperature overnight and then concentrated. The residue was treated with TFA (500 μl, 6.49 mmol) and triethylsilane (7 μl, 0.044 mmol). The mixture was stirred at room temperature for 6 h and then concentrated. The residue was purified by preparative HPLC (Reverse phase C-18, Waters SunFire PrepODB, 150×19 mm, 5u), eluting with 10-90% Acetonitrile/Water+0.1% TFA (20 mL/min) over 15 min. to give trans-N-ethyl-2-(6-(3-((S)-2-methoxy-1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)cyclopropanecarboxamide (4.5 mg, 52% yield). MS ESI calc'd. for C22H26N6O3[M+1]+ 423, found 423. MS ESI calc'd. for C22H26N6O3[M−1]− 421, found 421.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH:13]3[CH2:15][CH2:14]3)[C:7]=12.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH:13]3[CH2:15][CH2:14]3)[C:7]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCc1ccccc1
Reactant: Cc1c(C)n(C2CC2)c2c(Cl)nncc12
Product: Cc1c(C)n(C2CC2)c2c(OCc3ccccc3)nncc12
Yield: 78.6 %

Procedure:
The title compound was prepared as a white powder in 78.6% yield in a similar procedure to that described in Example 1 by using 7-chloro-1-cyclopropyl-2,3-dimethylpyrrolo[2,3-d]pyridazine and benzyl alcohol.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:3]#[C:4][C:5]([O:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[O:6]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:2]([C:3]#[C:4][C:5]([O:7][CH2:8][CH:9]=[C:10]([CH3:11])[CH3:12])=[O:6])=[O:1])=[CH:18][CH:17]=1
Reactant: COc1ccc(C(O)C#CC(=O)OCC=C(C)C)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(C(=O)C#CC(=O)OCC=C(C)C)cc1
Reaction time: 1 h

Procedure:
A solution of 10.7 g (39 mmol) of 3-methyl-2-butenyl 4-hydroxy-4-(4-methoxyphenyl)-2-butynoate in 150 ml of methylene chloride was added dropwise at 0° to a suspension of 101.7 g (1.17 mol) of manganese dioxide in 200 ml of methylene chloride. The reaction mixture was stirred at 0° for 1 hour, filtered over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 700 g of silica gel (elution agent methylene chloride/ether 4:1). There was obtained 3-methyl-2-butenyl 3-(4-methoxybenzoyl)propiolate as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].BrBr.[CH3:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1>O1CCOCC1.C(#N)C>[CH3:14][C:15]1[N:16]([CH2:2][C:1]([C:4]2[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=2)[C:7]#[N:8])=[O:3])[CH:17]=[CH:18][N:19]=1
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: Cc1ncc[nH]1
Agent: BrBr
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1nccn1CC(=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-acetylbenzonitrile (50 g, 0.345 mol) is dissolved in dioxane (600 ml) with stirring at room temperature, bromine (17.7 ml, 0.345 mol) is added in and the mixture is stirred for 30 minutes. The dioxane is removed in vacuo to give a solid which is dissolved in acetonitrile (300 ml). 2-Methylimidazole (28.3 g, 0.345 mol) is added to the solution and the mixture is stirred for 1 hour, the temperature of the mixture rising to 45° C. The precipated solid is filtered off, washed with acetonitrile, and slurried with methanol for 1 hour. After filtering to remove undissolved solid, the filtrate is evaporated in vacuo to leave a solid which is dried in vacuo at 40° C. to give the title compound, m.s. 369 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)=[CH:5][CH:4]=1)[CH3:2].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(O[C@@H:31]1[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[C@@H:42]([O:43][C:44](=[O:46])[CH3:45])[C@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]1[O:33][C:34](=[O:36])[CH3:35])(=O)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(#N)C.ClC(Cl)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:11]=[N:12][N:13]([C@@H:31]3[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[C@@H:42]([O:43][C:44](=[O:46])[CH3:45])[C@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]3[O:33][C:34](=[O:36])[CH3:35])[CH:14]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCc1ccc(Cc2cn[nH]c2)cc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CC(Cl)Cl
Product: CCc1ccc(Cc2cnn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2)cc1
Temperature: 60 °C
Yield: 44.4 %

Procedure:
To a solution of 4-(4-ethylphenylmethyl)pyrazole 36 (495 mg) in acetonitrile (2.0 ml) was added N,O-bis(trimethylsilyl)acetamide (1.05 ml), and the mixture was stirred under heating at 60° C. for 2.5 hours under argon atmosphere. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give crude 4-(4-ethylphenylmethyl)-1-trimethylsilylpyrazole 37, which was used in the subsequent reaction without further purification. (2) The above N-silyl compound 37 was dissolved in dichloroethane (7.0 ml), and added thereto were molecular sieve 4A powder (500 mg), 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose 38 (1.04 g) and trimethylsilyl trifluoromethanesulfonate (0.51 ml). The mixture was stirred under heating at heating at 80° C. for 3 hours under argon atmosphere. The reaction mixture was cooled to room temperature, and insoluble materials were filtered off. Subsequently, the filtrate was poured into a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted twice with dichloromethane, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20-50:50) to give 4-(4-ethylphenylmethyl)-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) pyrazole 39 (610 mg) as a colorless semisolid. APCI-Mass m/Z 517 (M+H). (3) From the above tetraacetate compound 39, the desired 4-(4-ethylphenylmethyl)-1-(β-D-glucopyranosyl)pyrazole 40 was prepared in a manner similar to Example 106-(3) as colorless oil. APCI-Mass m/Z 349 (M+H).