Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[N:30]1([S:34]([C:37]2[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:40]2[CH:41]=[CH:42][C:37]([S:34]([N:30]3[CH2:31][CH2:32][CH2:33]3)(=[O:36])=[O:35])=[CH:38][CH:39]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Reactant: O=S(=O)(c1ccc(B(O)O)cc1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(S(=O)(=O)N4CCC4)cc3)cc2)C(N)=O)CCOCC1
Temperature: 85 °C
Reaction time: 25 h
Yield: 77.9 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 350 mg) in acetonitrile (7 mL) under nitrogen was treated with 4-(azetidin-1-ylsulfonyl)phenylboronic acid (163 mg) followed by sodium carbonate (0.677 mL). Nitrogen was bubbled through the mixture and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (10 mg) was added. The mixture was stirred at 85° C. for 25 h. The solvent was partially evaporated and the solution was purified by chromatography on silica using ethyl acetate 50-100% in isohexane as eluent to afford the sub-titled compound as a solid (309 mg).
Reaction SMILES: C(O[C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1B1OC(C)(C)CCCCCO1)C.I[C:24]1[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][C:25]=1[NH2:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[O:22]=[C:4]1[C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:27]2[CH:28]=[C:29]([C:31]#[N:32])[CH:30]=[CH:24][C:25]=2[NH:26]1
Reactant: CCOC(=O)c1ccccc1B1OCCCCCC(C)(C)O1
Reactant: N#Cc1ccc(N)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: N#Cc1ccc2[nH]c(=O)c3ccccc3c2c1
Yield: 120.4 %

Procedure:
2-(4,4-Dimethyl-[1,3,2]dioxaboronan-2-yl)-benzoic acid ethyl ester (19.84 g), 2-iodo-4-cyanoaniline (18.47 g), tetrakis(triphenylphosphine)palladium (8.75 g) and potassium phosphate (35.36 g) were added to dioxane (360 ml), and the resulting mixture was heated under reflux overnight. The reaction solvent was cooled, and the produced solid was collected by filtration, washed with water and dried to thereby obtain 17.3 g (yield: quantitative) of the title compound as a yellow solid.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@H:11]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:9]2([CH3:10])[C@@H:8]([O:26][CH2:27][O:28][CH3:29])[CH2:7]1)[C:20]1[CH:19]=[CH:18][C:17]([O:24][CH3:25])=[CH:16][C:15]=1[CH2:14][CH2:13]3)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[OH:3][CH2:4][C@@H:6]1[C@H:11]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:9]2([CH3:10])[C@@H:8]([O:26][CH2:27][O:28][CH3:29])[CH2:7]1)[C:20]1[CH:19]=[CH:18][C:17]([O:24][CH3:25])=[CH:16][C:15]=1[CH2:14][CH2:13]3
Reactant: CCOC(=O)[C@H]1C[C@H](OCOC)[C@@]2(C)CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COCO[C@H]1C[C@H](CO)[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.5 %

Procedure:
A solution of 53.7 mg (0.125 mmol) of 56 in anhydrous Et2O (2 mL) was stirred at rt as 47.3 mg (1.25 mmol) of LiAlH4 was added and reaction was stirred at rt for 2 h. The reaction mixture was poured into saturated Na—K tartrate (100 mL) and extracted with EtOAc (3×, 70 mL). Combined organic extracts were dried over Na2SO4 and concentrated in vacuo giving 47.1 mg (87%) of 57 as a clear colorless oil which was a single isomer as judged by 1H NMR and used without further purification in the next step. Data for 57: TLC, T-2, Rf 0.31; 1H NMR (400 MHz, CDCl3) δ 0.88 (s, 3H, H-18), 1.05 (t, 1H, J=10.6 Hz, H-14), 3.38 (s, 3H, —CH2OCH3), 3.42 (dd, 1H, J=10.3, 8.2 Hz, CH2OH), 3.60 (t, 1H, J=8.9 Hz, H-17α), 3.78 (s, 3H, ArOCH3), 3.89 (dd, 1H, J=10.3, 3.2 Hz, —CH2OH), 4.66 & 4.69 (AB quartet, 2H, JAB=6.5 Hz, OCH2O), 6.62 (d, 1H, J=2.6 Hz, H-4), 6.72 (dd, 1H, J=8.7, 2.6 Hz, H-2), 7.22 (d, 1H, J=8.7 Hz, H-1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]2[S:20][C:11]3[C:12]([CH2:18][CH3:19])=[N:13][N:14]([CH3:17])[C:15](=[O:16])[C:10]=3[C:9]=2[C:21](N2C[C@H](O)CO2)=[O:22])=[C:5]([CH3:29])[NH:4][N:3]=1.FC(F)(F)C(O)=[O:33]>>[CH3:29][C:5]1[C:6]([CH2:7][C:8]2[S:20][C:11]3[C:12]([CH2:18][CH3:19])=[N:13][N:14]([CH3:17])[C:15](=[O:16])[C:10]=3[C:9]=2[C:21]([OH:22])=[O:33])=[C:2]([CH3:1])[NH:3][N:4]=1
Reactant: CCc1nn(C)c(=O)c2c(C(=O)N3C[C@H](O)CO3)c(Cc3c(C)n[nH]c3C)sc12
Reactant: O=C(O)C(F)(F)F
Product: CCc1nn(C)c(=O)c2c(C(=O)O)c(Cc3c(C)n[nH]c3C)sc12

Procedure:
Prepared from the product of example 3, part g) (1.0 g) in trifluoroacetic acid (10 ml) under reflux for 20 hrs. The resulting mixture was evaporated under reduced pressure, azeotroping with dichloromethane (×3). The residue was triturated with water and then with ether, and the solid was collected and dried to give the subtitle compound as a solid (580 mg).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:29]C(=O)OC(C)(C)C)[CH2:6][C@@H:5]1[CH3:37])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][OH:21])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:29])[CH2:6][C@@H:5]1[CH3:37])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cn(CCO[Si](C)(C)C(C)(C)C)nn3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1c2ccc(-c3cn(CCO)nn3)cc2[C@H](N)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of 1,1-dimethylethyl {(2S,4R)-1-acetyl-6-[1-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-1H-1,2,3-triazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (for a preparation see intermediate 46) (599 mg, 1.131 mmol) in dichloromethane (DCM) (20 mL) was treated with trifluoroacetic acid (TFA) (5.00 mL) and the resulting reaction mixture was stirred for 1 h at room temperature then concentrated in vacuovacuo. Purification of the residue on SP4 using a 50 G silica cartridge (gradient:0 to 12% MeOH in DCM) gave 2-{4-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-1H-1,2,3-triazol-1-yl}ethanol (396 mg, 0.885 mmol, 78% yield) as a yellow solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCCC.[C:14](=[O:16])=[O:15].Cl>C(OCC)C.O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:14]([OH:16])=[O:15])=[CH:2]1
Reactant: C1=Cc2ccccc2C1
Reactant: O=C=O
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CCCC
Product: O=C(O)C1=CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a stirred solution of indene (21.9 mL, 188 mmol) in 150 mL of dry ethyl ether was added 129 mL (200 mmol) of η-BuLi dropwise at room temperature over 30 minutes with the evolution of butane. The rust colored mixture was refluxed for 2 h, and then poured in a thin stream onto 40 g of Dry Ice. The mixture was shaken at room temperature for 2 h, after which time 1 L of H2O was cautiously added. The aqueous layer was acidified with 10% HCl and then extracted with ethyl ether. Recrystallization from benzene gave 20 g (80%) of indene-3-carboxylic acid as yellowish crystals.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[NH:7][CH2:6][CH2:5]2.C1(C)C=CC(S(O[CH2:24][CH:25]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=3)[CH2:26]2)(=O)=O)=CC=1>>[CH:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:41]=[CH:42][C:33]=1[CH2:32][CH2:31][CH2:30][N:27]1[CH2:28][CH2:29][CH:25]([CH2:24][N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][C:11]([CH3:12])=[C:2]([CH3:1])[CH:3]=3)[C:8]2=[O:13])[CH2:26]1
Reactant: CC1=C(C)CC2CCNC(=O)C2=C1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(CCCc3ccc4ccccc4c3)C2)cc1
Product: Cc1cc2c(cc1C)C(=O)N(CC1CCN(CCCc3ccc4ccccc4c3)C1)CC2

Procedure:
Prepared from 6,7-dimethyl-1-oxo-1,3,4,5-tetrahydro-isoquinoline and 3-(p-toluenesulphonyloxymethyl)-N-[3-(naphth-2-yl)-propyl]-pyrrolidine analogously to Example 2.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][N:14](CC3C=CC=CC=3)[CH2:13][CH2:12][N:11]2[CH2:23][CH:24]=[CH2:25])=[CH:6][CH:5]=1.C1(C)C=CC=CC=1.[OH-].[Na+].[C:35](Cl)(=[O:39])[O:36][CH2:37][CH3:38]>O.CCCCCC>[CH2:37]([O:36][C:35]([N:14]1[CH2:13][CH2:12][N:11]([CH2:23][CH:24]=[CH2:25])[C@H:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[CH2:15]1)=[O:39])[CH3:38]
Reactant: C=CCN1CCN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: C=CCN1CCN(C(=O)OCC)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 7.3 %

Procedure:
In distilled water (5 mL), (R)-2-(4-Chlorophenyl)-4-(phenylmethyl)-1-(2-propenyl)hexahydropyrazine dihydrochloride (400 mg, 1.0 mmol) produced in Example 18 was dissolved. To the solution, toluene (5 mL) and 30 wt % aqueous solution of sodium hydroxide (401 mg, 3.0 equivalents) were added. After the organic layer and aqueous layer were separated, the organic layer was washed twice with distilled water (5 mL) and then concentrated. To the concentrate, hexane (5 mL) and ethyl chlorocarbonate (163 mg, 1.5 equivalents) were added. The mixture was stirred at 25° C. for 24 hours. Further, ethyl chlorocarbonate (328 mg, 3.0 equivalents) was added, and the mixture was stirred at 40° C. for 24 hours. After the mixture was cooled to 5° C., the precipitated crystals were collected by filtration under reduced pressure, washed with hexane (2 mL), and dried under vacuum, to obtain 22.5 mg of the title compound as while crystals (yield: 7%, chemical purity: 92.5 area %). Further, the filtrate was concentrated. To the concentrate, toluene (5 mL) was added and the toluene was distilled away. The operation was repeated 3 times. The obtained concentrate was dried under vacuum, to obtain 212 mg of the title compound as while turbid oil (yield: 69%, chemical purity: 95.9 area %). The retention time in the chemical purity analysis method was 22.7 min.
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:13]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[N:18]([CH2:22][CH:23]([O:25]C(=O)C)[CH3:24])[N:17]=2)=[O:14])[C:9](=[O:11])[CH:10]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:40][C:36]1[CH:37]=[CH:38][CH:39]=[C:2]([F:1])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:29][CH:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[C:13]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[N:18]([CH2:22][CH:23]([OH:25])[CH3:24])[N:17]=2)=[O:14])[C:9](=[O:11])[CH:10]=1
Reactant: CC(=O)OC(C)Cn1nc(NC(=O)C(CC2CCOCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(NC(=O)C(CC2CCOCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)nn1CC(C)O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 70.4 %

Procedure:
A solution of acetic acid 2-{3-[2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionylamino]-5-methyl-pyrazol-1-yl}-1-methyl-ethyl ester (Example 131, 170 mg, 0.31 mmol) in tetrahydrofuran (10 mL) and water (2 mL) at 25° C. was treated with lithium hydroxide monohydrate (40 mg, 0.93 mmol). The reaction was stirred at 25° C. for 4.5 h. At this time, the reaction was concentrated in vacuo. Silica gel column chromatography (0 to 60% tetrahydrofuran/hexanes) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-propyl)-5-methyl-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide as a white solid (113 mg, 70%); ES+-HRMS m/e calcd for C25H29N5O5F2 [M+H+] 518.2210 found 518.2207. 1H NMR (300 MHz, CDCl3) δ ppm 1.21 (d, J=6.0 Hz, 3H), 1.28-1.51 (m, 3H), 1.54-1.74 (m, 2H), 1.86 (br. s., 1H), 2.14-2.22 (m, 2H), 2.25 (s, 3H), 3.34 (q, J=10.8 Hz, 2H), 3.72-3.84 (m, 1H), 3.88-4.01 (m, 3H), 4.14 (br. s., 1H), 5.64-5.75 (m, 1H), 6.01 (br. s., 1H), 6.49 (s, 1H), 7.09 (t, J=8.5 Hz, 2H), 7.29-7.36 (m, 1H), 8.02 (br. s., 1H), 8.67 (br. s., 1H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(O)[C:4]([F:7])([F:6])[F:5]>O=P(Cl)(Cl)Cl>[CH3:22][N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]([C:4]([F:7])([F:6])[F:5])([C:2]([F:24])([F:23])[F:1])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: CN(c1ccccc1)c1ccccc1C(O)(C(F)(F)F)C(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Product: CN1c2ccccc2C(C(F)(F)F)(C(F)(F)F)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
1,1,1,3,3,3-hexafluoro-2-(2-(methyl(phenyl)amino)phenyl)propan-2-ol (0.2 g, 0.57 mmol) was dissolved in 15 mL POCl3 and the solution refluxed under argon for 3 d. Excess POCl3 was distilled off using a short path distillation head, the residue was dissolved in CHCl3, poured into a 10% (v/v) aqueous ammoniacal solution and the biphasic system stirred at room temperature for one hour. The organic layer was separated and the aqueous layer extracted with Et2O (3×50 mL). The organic layers were combined, washed with brine and water and dried over MgSO4, and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography using 10% dichloromethane in hexanes as the eluent to yield 0.15 g (80%) of the desired compound as a light-blue oil. 1H NMR (400 MHz, CHCl3) δ 3.46 (s, 3H), 7.00 (m, 4H), 7.42 (m, 2H), 7.89 (m, 2H). 13C NMR (100 MHz, CHCl3) δ 29.8, 35.1, 111.8, 114.7, 120.3, 130.3 (quintet), 130.7, 141.8. 19F NMR (380 MHz, CHCl3) δ −65.9. HRMS (EI) calc for C16H11F6N [M]+ 332.0868, found 332.0874. IR (KBr plate) 479 (m), 693 (s), 709 (s), 758 (s), 848 (m), 954 (s), 1116 (s), 1163 (m), 1192 (s), 1260 (s), 1489 (s), 1573 (m), 1594 (m), 2840 (m), 2972 (m), 3054 (m) cm−1.
Reaction SMILES: [CH:1]1[N:5]([C@@H:6]2[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:13])[C@H:7]2[OH:14])[C:4]2[N:15]=[CH:16][NH:17][CH2:18][C@@H:19]([OH:20])[C:3]=2[N:2]=1.[CH:21]1[N:29]=[C:28](N)[C:27]2[C:23](=[C:24]([C@@H:31]3[O:35][C@H:34]([CH2:36][OH:37])[C@@H:33]([OH:38])[C@H:32]3[OH:39])[NH:25][N:26]=2)[N:22]=1>>[CH:21]1[NH:29][C:28](=[O:10])[C:27]2[NH:26][N:25]=[C:24]([C@@H:31]3[O:35][C@H:34]([CH2:36][OH:37])[C@@H:33]([OH:38])[C@H:32]3[OH:39])[C:23]=2[N:22]=1.[CH:1]1[N:5]([C@@H:6]2[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:13])[C@H:7]2[OH:14])[C:4]2[N:15]=[CH:16][NH:17][CH2:18][C@@H:19]([OH:20])[C:3]=2[N:2]=1
Reactant: Nc1ncnc2c([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)[nH]nc12
Agent: OC[C@H]1O[C@@H](n2cnc3c2N=CNC[C@H]3O)[C@H](O)[C@@H]1O
Product: O=c1[nH]cnc2c([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)n[nH]c12

Procedure:
A culture broth filtrate (2000 ml, pH 7.4, containing 26 mg of coformycin, 120 mg of formycin A and an unknown amount of formycin B) obtained from the submerged cultivation of a coformycin-producing microorganism, Nocardia interforma (ATCC No. 21072) was passed through a column (28 mm diameter) of 110 ml of a strong cation-exchange resin consisting of a polystyrene sulfonic acid (available as "Amberlite" IR-120, a commercial product of Rohm & Haas Co., U.S.A.) which had been converted into the 50% NH4+ -form prepared as described in Example 1. Coformycin and formycin A in the culture filtrate were adsorbed on the resin, but formycin B was not adsorbed. The resin column was washed with 550 ml of water and then eluted with 1 N aqueous ammonia. The first running (70 ml) was discarded, and the eluate was recovered (250 ml) after its pH increased to 9.6 or more. The recovered eluate containing coformycin and formycin A was concentrated to dryness under reduced pressure to give 725 mg of a crude powder. This crude powder was dissolved in 4 ml of water and the resulting aqueous solution (pH 9.0) was subjected to a column chromatography with a column (15 mm diameter) of 40 ml of "Amberlite" CG-50 (I-type) of 50% the NH4+ -form. The development was done with water. The eluate was collected in 4 ml-fractions. Each fraction was analysed by silica gel thin-layer chromatography in the same manner as described in Example 1. Fraction Nos. 28-34 containing coformycin alone were combined and concentrated to dryness under reduced pressure to give 43 mg of a colorless powder. This powder was crystallised from 0.6 ml of warm water, affording 19 mg of colorless crystals of coformycin. mp. 182°-184° C. Yield 73%. Fraction Nos. 35-61 containing formycin A alone were combined and concentrated to dryness under reduced pressure to give 135 mg of a colorless powder. This powder was crystallised from 4 ml of warm water, affording 90 mg of colorless crystals of formycin A. mp. 141°-142° C. Yield 75%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH:18]([CH3:20])[CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:47](=O)([O-])[O-:48].[Cs+].[Cs+]>CO.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH:18]([CH3:20])[CH3:19])=[N:15][C:16]([O:48][CH3:47])=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Agent: [Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CO
Product: COc1nc(C(C)C)n2c1C(CCc1ccc(C(F)(F)F)cc1)N(C(=O)OC(C)(C)C)CC2

Procedure:
A solution of 1-iodo-3-isopropyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (150 mg; 0.266 mmol) in anhydrous MeOH (3 ml) was treated successively with copper(I) iodide (5 mg; 0.026 mmol), 1,10-phenanthroline (10.5 mg; 0.053 mmol), and cesium carbonate (138.8 mg; 0.426 mmol). The resulting brown suspension was sealed and put in the microwave oven (35 W; 100° C.; 6 bars; 1 h). This microwave-assisted methoxylation was repeated two additional times with the same amount of starting material. The resulting mixed brown suspension was concentrated to dryness under reduced pressure and the crude was purified by preparative HPLC. The expected product 3-isopropyl-1-methoxy-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester was obtained as a yellow oil (107.5 mg; 29%). LC-MS: tR=0.94 min.; [M+H]+=468.55 g/mol.
Reaction SMILES: [P:1]([O-])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(Cl)(=O)C([Cl:23])=O.CN(C=O)C>C(Cl)Cl>[P:1]([Cl:23])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=P(Cl)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of dibenzyl phosphate (3.76 g, 13.5 mmol) in CH2Cl2 (10 mL) was treated with oxalyl chloride (1.17, 13.5 mmol) and DMF (0.5 mL). The mixture was stirred at room temperature for 1 h, the solvent was removed by rotary evaporation and the residue was dried in vacuo for 2 h to afford dibenzyl chlorophosphate as a yellowish solid. The residue was suspended in CH2Cl2 (5 mL), cooled to 0° C., treated with a solution of benzylic alcohol M (1.7 g, 6.7 mmol) in CH2Cl2 (5 mL) then DBU (2.02 mL, 13.5 mmol, added dropwise). The mixture was stirred at room temperature for 1 h30, and the solvent was removed by rotary evaporation. The residue was purified by column chromatography over silica gel using a gradient of 0-10% EtOAc/hexane as eluent.
Reaction SMILES: C(#N)C.[NH2:4][C:5]1[NH:9][N:8]=[CH:7][C:6]=1[C:10]#[N:11].C(N(CC)CC)C.Br[C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[C:20]([NH:4][C:5]1[C:6]([C:10]#[N:11])=[CH:7][NH:8][N:9]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: N#Cc1cn[nH]c1N
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC#N
Product: N#Cc1c[nH]nc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.5 %

Procedure:
To a solution of dry acetonitrile (10 mL) and dry tetrahydrofuran (30 mL) was added 5-amino-1H-pyrazole-4-carbonitrile (1.0 g, 9.25 mmol) followed by triethylamine (1.08 mL, 1.74 mmol). The resulting suspension was allowed to stir at room temperature for five minutes and then cooled to 0° C. A solution of (bromomethanetriyl)tribenzene (1.89 g, 5.84 mmol) in dry tetrahydrofuran (10 mL) was added drop-wise via an addition funnel equipped with a nitrogen inlet, at such a rate that the temperature did not rise above 5° C. The addition funnel was then rinsed with dry tetrahydrofuran (5 mL) and the reaction mixture was stirred at 0° C. for 10 minutes, then allowed to warm to room temperature and stirred for 2 hours. The volatiles were removed in vacuo and residue was dissolved in EtOAc (150 mL) and washed once water (100 mL), once with saturated aqueous sodium chloride, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was applied to an 80 g silica gel cartridge using methylene chloride, and the column was eluted with a 10-30% EtOAc/hexanes gradient. The product containing fractions were combined to give 3-(Trityl-amino)-1H-pyrazole-4-carbonitrile (1.3 g, 41%) as an off-white semi-crystalline solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:17])=[C:8]([NH:10]C2C=CC=CC=2)[CH:9]=1)(=[O:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:17])=[C:8]([NH:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccc(Cl)c(Nc2ccccc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1ccc(Cl)c(NS(C)(=O)=O)c1
Temperature: 0 °C
Yield: 56.6 %

Procedure:
To a stirred solution of 5-acetyl-2-chloro-phenylaniline (which was obtained in Example 22) (7.40 g, 43.5 mmol) in CH2Cl2 (200 mL) and pyridine (40 mL) at 0˜5° C. was added dropwise methanesulfonyl chloride (5.0 g, 43.6 mmol) in 50 mL of CH2Cl2. After 1 hour at 0° C. the mixture was warmed to room temperature and stirred at room temperature for another hour. The solvents were removed and the residue was dissolved in CH2Cl2(500 mL). The reaction mixture was washed with water and the organic layer was dried (MgSO4) and concentrated. The product was purified by flash silica gel chromatography eluting with ethyl acetate and hexanes to give the title compound as a white solid (6.1 g, 57%); 1H NMR (300 MHz, DMSO-d6) δ 2.58 (s, 3H), 3.08 (s, 3H), 7.69 (d, J=8.3 Hz, 1H), 7.83 (dd, J=8.3, 2.1 Hz, 1H), 7.94 (d, J=2.1 Hz, 1H), 9.69 (s, 1H); MS (ES) m/z: 245.9 ((M−H)−, 100%); HRMS Calcd. for C9H11ClNO3S(MH+): 248.0148. Found: 248.0135.