Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([Cl:54])[C:40]=1[OH:55]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:25]4)=[N:22][CH:23]=2)=[N:3][C:2]([C:43]2[CH:44]=[C:39]([Cl:38])[C:40]([OH:55])=[C:41]([Cl:54])[CH:42]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Cl)nc34)cn2)C1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)nc34)cn2)C1
Yield: 63.2 %

Procedure:
Following general procedure II, (R)-tert-butyl [1-(5-{[6-chloro-3-(cyclopropanecarbonyl)-1,5-naphthyridin-4-yl]amino}pyridin-2-yl)piperidin-3-yl]carbamate (150 mg, 0.29 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (120 mg, 0.43 mmol) to afford the product (119 mg, 64%) as an orange solid: ESI MS m/z 649 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH:12]=[CH2:13]>CO.[Pd]>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH3:13]
Reactant: C=Cc1c(Br)ccc2c1COC2=O
Agent: [Pd]
Solvent: CO
Product: CCc1c(Br)ccc2c1COC2=O
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-4-vinyl-2-benzofuran-1(3H)-one (2.0 g, 8.37 mmol) and Pd/C (400 mg) in 50 mL of MeOH was stirred at rt. under H2 (1 atm) overnight, and then filtered. The filtrate was concentrated. The resulting oil was purified by column chromatography to give 5-bromo-4-ethyl-2-benzofuran-1(3H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:25])[C:7]3[C:14](=[O:15])[N:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[C:12](=[O:24])[C:8]=3[NH:9][C:10]=2[CH:11]=1.CS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:25])[C:7]3[C:14]([OH:15])=[N:13][N:16]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[C:12](=[O:24])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: Cc1ccc(NN2C(=O)c3[nH]c4cc(Cl)ccc4c(=O)c3C2=O)cc1
Agent: CS(=O)(=O)O
Solvent: CO
Product: Cc1ccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 37.1 %

Procedure:
A stirred suspension of 6-chloro-2-(4-methylanilino)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (1.60 g, 4.53 mM) in a solution of methanol (128 mL) and methanesulfonic acid (32 mL) was refluxed for 4 hours and cooled to room temperature. The resulting yellow suspension was stirred at room temperature for five days and then filtered (the filtrate was saved for use in Example 19). The collected solids were washed with methanol and then ether to give the title compound (0.594 g, 37%) as a yellow powder, mp >400° C.; MS(CI): 354 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][S:18]([CH3:17])(=[O:20])=[O:19])=[C:5]([CH3:10])[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(N)c(C)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(NS(C)(=O)=O)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
To a solution of 6.85 gm (50 mmol) 4-methoxy-2-methylaniline in 70 ml of methylene chloride was introduced 8.5 gm (ml; mmol) pyridine followed by dropwise addition of 6.87 gm (60 mmol) methanesulfonylchloride. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with 1N HCl and then with saturated aqueous brine. The organics were dried with sodium sulfate and then evaporated in vacuo. The residue was triturated in diethyl ether to afford 7.5 gm (79%) of a light purple solid. Mass spectrum APCI (m/z) 216 (p+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][OH:9])[CH:2]=1.C(#[N+][O-])C1C=CC=NC=1.[CH3:19][Si:20]([CH3:28])([CH3:27])[C:21]#[C:22][Si:23]([CH3:26])([CH3:25])[CH3:24]>>[CH3:19][Si:20]([CH3:28])([CH3:27])[C:21]1[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:8][O:9][C:22]=1[Si:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: C[Si](C)(C)C#C[Si](C)(C)C
Reactant: ON=Cc1cccnc1
Agent: [O-][N+]#Cc1cccnc1
Product: C[Si](C)(C)c1onc(-c2cccnc2)c1[Si](C)(C)C

Procedure:
Commercially available 3-pyridinealdoxime (61) is converted to its chlorohydroxyimino derivative (US 2004/0157900) which is converted to nicotinonitrile oxide (Tetrahedron, 61, 2005, 4363-4371) “in situ” and reacted with 1,2-bis-trimethylsilanyl-ethyne (Chem. Ber., 107, 1974, 3717-3722) to afford the 1,3-dipolar cycloaddition product 3-(4,5-bis-trimethylsilanyl-isoxazol-3-yl)-pyridine (62). Halogen-induced ipso desilylation resulted in the 4-bromo-5-trimethylsilanyl derivative (63). Subsequent desilylation with NH4OH (Chem. Ber., 112, 1979, 2829-2836) generates 3-(4-bromo-isoxazol-3-yl)-pyridine (64).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15](SC(C)C)[N:14]=3)=[C:11]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:10]=[CH:9]2)[CH2:4][CH2:3]1.OOS([O-])=O.[K+].[CH3:36][OH:37]>>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([O:37][CH3:36])[N:14]=3)=[C:11]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[N:10]=[CH:9]2)[CH2:4][CH2:3]1
Reactant: CO
Reactant: CC(C)Sc1nccc(-c2c(-c3ccc(F)cc3)ncn2[C@H]2CC[C@H](O)CC2)n1
Agent: O=S([O-])OO
Agent: [K+]
Product: COc1nccc(-c2c(-c3ccc(F)cc3)ncn2[C@H]2CC[C@H](O)CC2)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The product of step (b) above, (10.8 g, 26.2 mmol) was dissolved in 43 mL of MeOH and Oxone™ (12.1 g, 19.6 mmol) was added and the resulting suspension was stirred at room temperature for 4-24 h. After HPLC confirmed that no starting material remained, the remaining Oxone™ salts were removed by filtration of the suspension through a Buchner funnel. A NaOMe/MeOH solution (25%, 16 mL) was added to the solution until the pH was about 12. After 20 min, HPLC confirmed that the reaction was complete and 100 mL of water was added to the reaction. The resulting solution was stirred at room temperature for 3 h, then filtered through a Buchner funnel and rinsed with 50 mL of water. The pale white solid was dried in the vacuum oven at 65° C. for 18 h to yield 6.0 h (62% yield) of title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.Cl.[OH:20][CH:21]1[CH2:24][NH:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:8][C:6]1[N:7]=[C:2]([N:23]2[CH2:24][CH:21]([OH:20])[CH2:22]2)[N:3]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:5]=1
Reactant: COc1ccc(CNc2nc(Cl)nc(Cl)n2)cc1
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(CNc2nc(Cl)nc(N3CC(O)C3)n2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 93 %

Procedure:
A 1.47 g (5.16 mmol) portion of 2,4-dichloro-6-(4-methoxybenzylamino)-1,3,5-triazine was suspended in 100 ml of ethanol, mixed with 568 mg (5.18 mmol) of 3-hydroxyazetidine hydrochloride and 1.43 g of potassium carbonate and stirred at room temperature for 7 hours. After evaporation of the solvent under a reduced pressure, water was added to the residue and the resulting precipitate was collected by filtration to obtain 1.54 g (93%) of the title compound as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:15])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.I[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[O:23][CH2:24][O:25][CH3:26].CC(C)([O-])C.[Na+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[O:23][CH2:24][O:25][CH3:26])[C:9](=[O:15])[C:10]2([CH3:13])[CH3:14])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Reactant: COCOc1cnccc1I
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCOc1cnccc1C1Cc2ccc(OC)cc2C(C)(C)C1=O
Temperature: 70 °C
Yield: 47.4 %

Procedure:
To 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 924 mg), 4-iodo-3-methoxymethoxy-pyridine (1 g), sodium t-butoxide (906 mg), Pd2dba3 (173 mg) and S-Phos (185 mg), toluene (19 ml) was added, and the mixture was stirred and heated at 70° C. for 2 hrs under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and filtered through Celite. The organic layer was washed with saturated aqueous solution of sodium bicarbonate and saturated brine, and then concentrated under reduced pressure. The resulting residues were purified by silica gel column (ethyl acetate/hexane) to obtain the title compound (610 mg, 47%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])=[O:2].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:2]
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)c(C=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-formyl-4-hydroxybenzoate (3.55 g, 19.7 mmol) in DMF (20 ml) was added benzyl bromide (3.70 g, 21.67 mmol) and K2CO3 (4.1 g, 29.6 mmol). The reaction was stirred at ambient temperature overnight and the solvent evaporated to dryness (at reduced pressure). The residue was partitioned between ethyl ether and water and the aqueous layer extracted a second time with ethyl ether. The organic extracts were combined, washed with brine, dried (MgSO4 ) and evaporated to give methyl 3-formyl-4-benzyloxybenzoate as an off-white solid which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)CCC>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Prepared according to procedure E using 2,4-dichloro-5,7-difluoro-3-methylquinoline (1.94 g, 7.8 mmol) (described herein), 2-(tributylstannyl)pyridine (2.9 mL, 7.8 mmol), and tetrakis(triphenylphosphine)palladium(o) (0.69 g, 0.59 mmol) in toluene. The reaction was stirred at 100° C. for 18 h, then cooled to rt, concentrated, and the resulting residue triturated with hexanes. Column chromatography afforded 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinoline as a white solid. Mass Spectrum (ESI) m/e=291 (M+1).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][N:16]([CH2:25][CH3:26])[CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[ClH:27].[CH2:28](O)[CH3:29]>>[ClH:27].[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[CH2:15][N:16]([CH2:25][CH3:26])[CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][O:24][CH2:28][CH3:29])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: CCO
Reactant: CCN(CCCNCCCO)Cc1c2ccccc2cc2ccccc12
Agent: Cl
Product: CCOCCCNCCCN(CC)Cc1c2ccccc2cc2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
A solution of compound 18 (200 mg, 0.57 mmole) was dissolved in absolute ethanol (13 mL) and stirred at 0° C. for 10 minutes. A 4N HCl solution (22 mL) was added to the reaction mixture dropwise and stirred at 0° C. for 20 minutes and then at room temperature overnight. The solution was concentrated in vacuo to give 20 as a yellow solid in 95% yield. 1H NMR (D2O) δ 8.50 (s, 1H), 8.06 (m, 4H), 7.73 (m, 2H), 7.62 (m, 2H), 4.98 (s, 2H), 3.64 (t, 2H), 3.39 (q, 2H), 3.13 (t, 2H), 2.90 (t, 2H), 2.76 (t, 2H), 1.79 (q, 2H), 1.44 (m, 5H); 13C NMR (D2O): δ 133.8, 133.4, 132.4, 130.8, 128.3, 125.1, 121.8, 61.4, 52.4, 52.1, 52.0, 48.0, 47.0, 30.5, 23.4, 11.3. HRMS (FAB) calcd for C23H3ON2O.2HCl (M+H−2HCl)+ 351.2431, Found 351.2428.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32](C)=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[Cl:36]C1C=CC=CC=1S(N=C=O)(=O)=O>>[Cl:36][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[S:26]([NH:25][C:23]([NH:22][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:6]3=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]3[N:4]=[C:3]2[CH2:1][CH3:2])=[CH:15][CH:16]=1)=[O:24])(=[O:28])=[O:27]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccccc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 10 of Example 1 from 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine (step 9 of Example 1) and 2-chlorobenzenesulfonyl isocyanate.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([C:63]1[CH:95]=[CH:94][C:66]([CH2:67][O:68][C:69]([NH:71][CH2:72][C@@H:73]([S:91][S:92][CH3:93])[CH2:74][CH2:75][C@H:76]([NH:83][C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[C:77](OCC#N)=[O:78])=[O:70])=[CH:65][CH:64]=1)=[N+:61]=[N-:62]>C(#N)C>[N:60]([C:63]1[CH:64]=[CH:65][C:66]([CH2:67][O:68][C:69]([NH:71][CH2:72][C@H:73]([S:91][S:92][CH3:93])[CH2:74][CH2:75][C@@H:76]([NH:83][C:84]([O:86][C:87]([CH3:89])([CH3:90])[CH3:88])=[O:85])[C:77]([O:40][C@H:39]2[C@@H:38]([OH:41])[C@@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36][C@H:35]2[CH2:34][O:33][P:30]([O:29][C@H:28]2[CH2:27][C@H:26]([N:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]3=[O:59])[O:25][C@@H:24]2[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:78])=[O:70])=[CH:94][CH:95]=1)=[N+:61]=[N-:62]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CSS[C@@H](CC[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N)CNC(=O)OCc1ccc(N=[N+]=[N-])cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CSS[C@H](CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O)CNC(=O)OCc1ccc(N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (49.2 mg, 0.077 mmol) and (2S,5S)-cyanomethyl 6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-5-(methyldisulfanyl)hexanoate (Compound tk9) (125 mg, 0.232 mmol) in acetonitrile (0.5 mL) was added to buffer A (13 mL), and the mixture was stirred at room temperature for 2 hours. Acetonitrile (0.5 mL) was added and the mixture was stirred for 1.25 hours, followed by addition of acetonitrile (0.5 mL). After stirring for a further 1.25 hours, acetonitrile (0.5 mL) was added and the mixture was stirred for 1.5 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S,5S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-5-(methyldisulfanyl)hexanoate (Compound tk10) (14.0 mg, 16%).
Reaction SMILES: [OH:1][CH:2]1[N:6]([CH3:7])[C:5](=[O:8])[NH:4][C:3]1=[O:9].[CH2:10](N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>CO>[CH3:10][O:1][CH:2]1[N:6]([CH3:7])[C:5](=[O:8])[NH:4][C:3]1=[O:9]
Reactant: CN1C(=O)NC(=O)C1O
Reactant: CCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CO
Product: COC1C(=O)NC(=O)N1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
5.0 g of 5-hydroxy-1-methylhydantoin (compound 1) were dissolved in absolute methanol and 6.7 g of triethylamine were added to the solution. 10.9 g (1.5 equivalent) of p-toluenesulfonyl chloride were then added to the solution, and was stirred at room temperature for 3 hours. After the reaction mixture was evaporated to dryness, a small amount of water was added to the residue and was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness, and the residue was purified by column chromatography on silica gel (ethyl acetate). The obtained crude compound was recrystallized from a mixture of ethyl acetate and hexane to give 3.8 g of 5-methoxy-1-methylhydantoin (compound 5) in the form of white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=[O:12].[C:13]1([CH3:22])[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1>>[C:13]1([CH3:22])[CH:18]=[CH:17][CH:16]=[C:15]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]=[O:12])[CH:14]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Product: Cc1cccc(-c2ccc3[nH]cc(C=O)c3c2)c1
Yield: 85 %

Procedure:
5-Bromo-1H-indole-3-carbaldehye was reacted with m-tolylboronic acid as described for 3-6 and 3-7. Yield: 85%; 1H NMR (300 MHz, CDCl3): δ 9.91 (s, 1 H), 8.43 (s, 1 H), 7.66 (s, 1 H), 7.36 (d, J=7.5 Hz, 1 H), 7.20 (d, J=8.7, 1 H), 4.11 (t, J=7.2 Hz, 2 H), 1.85 (t, J=6.3 Hz, 2 H), 1.30-1.24 (m, 10 H), 0.86 (t, J=6 Hz, 3 H); 13C NMR (75 MHz, CDCl3): δ 184.1, 138.7, 135.8, 126.8, 126.8, 124.7, 117.3, 116.4, 111.4, 47.4, 32.7, 31.6, 29.6, 29.0, 26.7, 22.5, 14.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([F:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2].[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][C:12]([F:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cc(F)cc2c1Cl
Reactant: CCCCN
Product: CCCCNc1c(C(=O)OCC)cnc2c(OC)cc(F)cc12

Procedure:
4-Chloro-6-fluoro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.88 mmol) was treated with butylamine following general procedure B to afford 4-butylamino-6-fluoro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (282 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (170 mg) following general procedure E. The above ethylamide (0.170 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 1-butyl-3-ethyl-9-fluoro-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (105 mg). LCMS: m/z 346 [M+1]+.
Reaction SMILES: [SH:1][CH:2]([CH3:23])[CH:3]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:31]([S:1][CH:2]([CH3:23])[CH:3]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5])(=[O:33])[CH3:32]
Reactant: CC(S)C(Cc1ccccc1)C(=O)Nc1cccc(C(=O)O)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)SC(C)C(Cc1ccccc1)C(=O)Nc1cccc(C(=O)O)c1
Yield: 31.3 %

Procedure:
3-[(3-Mercapto-2-benzylbutanoyl)amino]benzoic acid (compound of Example 194) (1.7 g) is suspended in dichloromethane (17 ml), and thereto is added triethylamine (0.52 g)with stirring under ice cooling. To the mixture are further added dropwise acetyl chloride (0.51 g) and triethylamine (0.52 g) simultaneously, and the mixture is stirred at room temperature for one hour. The reaction mixture is diluted with dichloromethane and washed with 10% hydrochloric acid and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then dichloromethane is distilled off under reduced pressure. The residue is dissolved in acetonitrile and purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated into dryness under reduced pressure to give the title compound (0.6 g).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:14])=[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=1)=[O:3].C(N(C(C)C)CC)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[CH:40]1([C:43]([CH:45]2[CH2:47][CH2:46]2)=O)[CH2:42][CH2:41]1>C(Cl)Cl>[C:15]([C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[C:43]([CH:45]2[CH2:47][CH2:46]2)[CH:40]2[CH2:42][CH2:41]2)[CH:9]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[C:7]=1[OH:14])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=C(C1CC1)C1CC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(C(=O)C=C(C2CC2)C2CC2)cc(C(C)(C)C)c1O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 4 g of 3,5-di-tert-butyl-4-hydroxyacetophenone in 250 ml of dry methylene chloride is cooled to -78° C. and 7.3 ml di-iso-propyl ethylamine (i-Pr2EtN) is added followed by 8.1 ml of trimethylsilyl trifluoromethanesulphonate (TMSOTf). The mixture is stirred at -78° C. for 10 minutes and is allowed to warm to ambient temperature over 1 hour. The mixture is cooled again to -78° C., and 3.6 ml of dicyclopropylketone is added followed by 32 ml of 1M titanum tetrachloride solution in methylene chloride. After stirring for 1 hr, the mixture is washed with 1N aqueous hydrochloric acid and the solvents are removed under reduced pressure. The residue is dissolved in 50 ml of methanol-1N aqueous hydrochloric acid and stirred for 1 hr at room temperature. The mixture is concentrated under reduced pressure and partitioned between methylene chloride and water. The organic phase is washed with aqueous sodium bicarbonate, brine and dried over sodium sulphate. The solvents are evaporated and the residue is purified by flash chromatography (10% ethyl acetate in hexane), and the product is recrystallized from hexane to give 1-(3,5-di-tert-butyl-4-hydroxyphenyl-3,3-dicyclopropylprop-2-en-1-one as an orange solid.