Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:12]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>O1CCCC1.O>[Cl:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[C:11]([CH2:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:29])=[O:2])=[CH:9][CH:8]=3)=[CH:12][N:13]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(Cc2cn(-c3ccccn3)c3cc(Cl)ccc3c2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Cc2cn(-c3ccccn3)c3cc(Cl)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.6 %

Procedure:
A solution of 4-(7-chloro-4-oxo-1-pyridin-2-yl-1,4-dihydro-quinolin-3-ylmethyl)-benzoic acid methyl ester (28 mg, 69.2 μmol) in tetrahydrofuran (553 μL) at 25° C. was treated with a solution of lithium hydroxide monohydrate (5.8 mg, 138 μmol) in water (138 μL). The reaction was stirred at 25° C. for 24 h. At this time, LCMS indicated that the reaction was incomplete. The reaction was treated with additional lithium hydroxide monohydrate (5.8 mg, 138 μmol). The reaction was stirred overnight at 25° C. At this time, LCMS still indicated that the reaction was incomplete. The reaction was treated with a third portion of lithium hydroxide monohydrate (5.8 mg, 138 μmol). The reaction was stirred overnight at 25° C. At this time, the reaction was diluted with water (30 mL) and extracted with methylene chloride (1×30 mL). The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution and extracted with a 10% solution of methanol/methylene chloride (3×50 mL). These organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 4-(7-chloro-4-oxo-1-pyridin-2-yl-1,4-dihydro-quinolin-3-ylmethyl)-benzoic acid (18 mg, 66.6%) as a light brown solid. ES+-HRMS m/e calcd for C22H15ClN2O3 [M+H+] 391.0844. Found 391.0835; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.79 (br. s., 1H) 8.73 (dd, J=4.8, 1.2 Hz, 1H) 8.29 (s, 1H) 8.17-8.25 (m, 1H) 7.77-7.86 (m, 3H) 7.68 (dd, J=7.1, 5.2 Hz, 1H) 7.41-7.48 (m, 3H) 7.22 (d, J=1.8 Hz, 1H) 3.88 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([N:13]1[C:21]2[C:16](=[C:17]([CH:22]=C)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)(=[O:12])=[O:11].I([O-])(=O)(=O)=[O:25].[Na+]>O1CCOCC1.O.O=[Os](=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([N:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:22]=[O:25])[C:16]=2[CH:15]=[CH:14]1)(=[O:12])=[O:11]
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1cc(C)ccc1OC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C)cc1S(=O)(=O)n1ccc2c(C=O)cccc21
Reaction time: 0.5 h

Procedure:
OsO4 (10 mg, 0.05 mmol) was added to a stirred mixture of 1-[(2-methoxy-5-methylphenyl)sulfonyl]-4-vinyl-1H-indole (262 mg, 0.80 mmol; Intermediate 7) and 2,6-2,6-lutidine (186 μL, 0.46 mmol) in dioxane (9 mL). The mixture turned from colorless to black in 1 minute. Sodium periodate (0.684 g, 3.2 mmol) in water (3 mL, warmed to dissolve) was added. A grey precipitation was immediately formed. The mixture was stirred for 30 min. and partitioned between 2M aqueous HCl (25 mL) and DCM (25 mL). The organic layer was dried, filtered and concentrated to give the title compound (290 mg, 110%, still some dioxane according to HNMR) as a black solid. MS (ESI+) for C17H15NO4S m/z 330 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]2[C:12]=1[CH2:13][CH2:14][C:15](=[O:23])[NH:16]2.O.[OH-].[Na+].[CH:27](O)=[O:28]>>[CH:27]([NH:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]2[C:12]=1[CH2:13][CH2:14][C:15](=[O:23])[NH:16]2)=[O:28]
Reactant: COc1ccc(-c2nc3ccccn3c2N)c2c1NC(=O)CC2
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(-c2nc3ccccn3c2NC=O)c2c1NC(=O)CC2

Procedure:
A solution of 5-(3-aminoimidazo[1,2-a]pyridine-2-yl)-8-methoxy-3,4-dihydrocarbostyril (5 g) in 90% formic acid (10 ml) was heated at 100° C. for 2 hours. After completion of reaction, water was added to the reaction mixture followed by neutralizing with 1 N sodium hydroxide. Crystals which precipitated were collected by filtration, washed with methanol and recrystallized from chloroform-methanol to give 3.05 g of 5-(3-formylaminoimidazo[1,2-a]pyridine-2-yl)-8-methoxy-3,4-dihydrocarbostyril.
Reaction SMILES: [S:1]1[C:8]2[CH:7]=[C:6]([C:9]([OH:11])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1.CN(C=O)C.[Cl:17]N1C(=O)CCC1=O>CCOC(C)=O>[Cl:17][C:7]1[C:8]2[S:1][CH:2]=[CH:3][C:4]=2[NH:5][C:6]=1[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cc2sccc2[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1[nH]c2ccsc2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.6 %

Procedure:
To a 20 mL vial fitted with a magnetic stir bar at 25° C. was added 4H-thieno[3,2-b]pyrrole-5-carboxylic acid (0.1 g, 0.599 mmol, 1 equiv) and 2 mL of anhydrous DMF. N-chlorosuccinimide (NCS) (0.08 g, 0.599 mmol, 1 equiv) was subsequently added and the reaction vessel contents stirred for 1 h at 25° C. before heating the reaction vial to 55° C. for 12 h. The reaction was then allowed to cool to 25° C. and was diluted with EtOAc (10 mL). The resulting mixture was then washed with water) 3×5 mL). The organic phase was dried over anhydrous MgSO4, filtered, and evaporated in vacuo. The resulting residue was dissolved in a small volume of methanol, filtered through a 0.45 micron syringe filter, and further purified via preparative HPLC using the Chromeleon purification system. A 0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 40% methanol and increasing to 100% over 7 min) afforded the desired 6-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid 70 (5.5 mg, 5%). LC/MS m/e 199.9 (M−H). tR of product: 2.3-2.7 min. 1H NMR (400 MHz, CD3OD) δ ppm 7.41 (d, J=5.32 Hz, 1H), 6.97 (d, J=5.27 Hz, 1H).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[CH2:8][CH2:7][O:6][CH:5]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:2]2[S:10][C:9]3[CH2:8][CH2:7][O:6][CH:5]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=3[CH:3]=2)[CH:21]=1
Reactant: CC(C)(C)OC(=O)NCC1OCCc2sc(Br)cc21
Reactant: OB(O)c1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCC1OCCc2sc(-c3cccnc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl (2-bromo-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methylcarbamate (500 mg, 1.44 mmol), pyridine-3-boronic acid (351 mg, 2.88 mmol), Pd(OAc)2 (33 mg), PPh3 (170 mg, 0.65 mmol) in 1,4-dioxane was purged with nitrogen. After stirring at room temperature for 0.5 hr, 457 mg of Na2CO3 in 3 mL of H2O was added. The reaction mixture was stirred at 100° C. for 2 hr. After cooling to room temperature, the reaction mixture was poured into 100 mL of water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography to give the desired product.
Reaction SMILES: N[C:2]1[N:6]([CH2:7][CH:8]=[CH2:9])[N:5]=[C:4]([CH3:10])[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].N([O-])=O.[Na+].[ClH:20]>O.[Cu](Cl)Cl>[Cl:20][C:2]1[N:6]([CH2:7][CH:8]=[CH2:9])[N:5]=[C:4]([CH3:10])[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Cl
Reactant: C=CCn1nc(C)c(C(=O)OCC)c1N
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: C=CCn1nc(C)c(C(=O)OCC)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6.7 g (0.032 mole) of ethyl 5-amino-3-methyl-1-(2-propenyl)-1H-pyrazole-4-carboxylate (XV) in 30 mL of concentrated hydrochloric acid was added 8.6 g (0.064 mole) of copper (II) chloride. The mixture was cooled to 0° C. and 2.65 g (0.038 mole) of sodium nitrite was added portionwise over 20 minutes. The mixture was stirred at room temperature for 1 hour, and then at 40° C. for 2 hours. The mixture was diluted with 50 mL of water and extracted twice with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-hexane (1:4) to give 5.0 g of ethyl 5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole-4-carboxylate (XVI) as a light yellow oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([O:25]C)=O)[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](=[O:25])[NH:35][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:17]=[CH:16]4)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc21
Reactant: NCc1ccccc1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2CC(=O)NCc2ccccc2)c1

Procedure:
Example 125 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 117) and benzylamine to give the title compound (0.002 g),
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][C:28]([CH:34]=O)=[CH:29][CH:30]=2)[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:28]3[CH:27]=[C:26]4[C:31]([CH2:32][CH2:33][C:24](=[O:23])[NH:25]4)=[CH:30][CH:29]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1ccc2c(c1)NC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(c4)NC(=O)CC5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
To 20 mL of a chloroform solution containing 176 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 102 mg of 2-oxo-1,2,3,4-tetrahydroquinoline-7-carbaldehyde, 34 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 200 mg of sodium triacetoxyborohydride was added, and stirred for 2.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=100:1] to give 178 mg of 7-methoxy-1-(2-(4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethyl)amino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as a pale brown foam.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[C:11]1(=[O:16])[O:15][CH:13]([CH3:14])[CH2:12]1.Cl>O>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH:13]([CH3:14])[CH2:12][C:11]([OH:16])=[O:15]
Reactant: Oc1cccc(F)c1
Reactant: CC1CC(=O)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)O)Oc1cccc(F)c1
Temperature: 23 °C

Procedure:
To a solution of 35.72 g (0.893 mol) sodium hydroxide in 357 ml water was added 100 g (0.893 mol) 3-fluorophenol. The reaction was heated to reflux and to the gently refluxing solution was added 72.8 ml (0.893 mol) beta-butyrolactone dropwise over 1.5 hours. The reaction was cooled to 23° C. and the pH brought to 2 with concentrated hydrochloric acid. The reaction was extracted with 300 ml diethyl ether and the ether layer was separated, washed with brine and then extracted with 3×200 ml saturated sodium bicarbonate. The combined bicarbonate layers were washed with 200 ml diethyl ether, acidified with 50 ml concentrated hydrochloric acid and extracted with 300 ml diethyl ether. The latter ether extract was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the product as a red oil, 31.6 g (17.9%).
Reaction SMILES: Cl.[CH2:2]([NH:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C@@H:23]([C:25]([O:27][CH3:28])=[O:26])[NH2:24])[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)=[O:7])[CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[NH4+].[Cl-].[C:40]([O:43][CH2:44][CH3:45])(=[O:42])C>C1COCC1>[CH2:44]([O:43][C:40]([NH:24][C@H:23]([C:25]([O:27][CH3:28])=[O:26])[CH2:22][O:21][C:17]1[CH:16]=[C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]([NH:5][CH2:2][CH2:3][CH3:4])=[O:7])[CH:10]=2)[CH:20]=[CH:19][CH:18]=1)=[O:42])[CH3:45]
Reactant: CCOC(C)=O
Reactant: CCCNC(=O)Nc1cccc(-c2cccc(OC[C@H](N)C(=O)OC)c2)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCNC(=O)Nc1cccc(-c2cccc(OC[C@H](NC(=O)OCC)C(=O)OC)c2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound of Example 6 (256.0 mg, 0.63 mmol, 1 equiv) was suspended in THF (3 mL) and cooled to 0° C. Ethyl chloroformiate (88.5 mg, 0.82 mmol, 1.3 equiv) was added dropwise followed by N,N diisopropylethylamine (234.3 mg, 1.88 mmol, 3 equiv). The reaction mixture was allowed to warm to room temperature and stirred for one hour. It was worked up by addition of sat. aqueous NH4Cl soln. and ethyl acetate. The phases were separated and the organic layer was dried over NaSO4. After filtration and evaporation of the solvents the crude product was purified by chromatography (SiO2 CH/EtOAc 90:10). Yield 210.0 mg, 75.4% of a white solid. 1H NMR (CDCl3, 300 MHz) δ 7.50 (s, 1H); 7.39-7.25 (m, 3H); 7.21 (d, 1H), 7.12 (d, 1H); 7.05 (s, 1H); 6.90 (brs, 1H); 6.81 (d, 1H); 5.80 (d, 1H); 5.10 (m, 1H); 4.75-4.65 (m, 1H); 4.42 (dd, 1H); 4.25 (dd, 1H); 4.20-4.10 (m, 2H); 3.79 (s, 3H); 3.20 (dd, 2H); 1.52 (sext, 2H); 1.22 (t, 3H); 0.95 (t, 3H). MS (DCI/NH3) 461 (M+NH4), 444 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:11]([OH:12])=[C:5]2[N:6]=[CH:7][N:8]=[C:9]([SH:10])[C:4]2=[N:3]1.[CH2:13](Br)[CH2:14][CH2:15][CH3:16]>N>[CH3:1][N:2]1[C:11]([OH:12])=[C:5]2[N:6]=[CH:7][N:8]=[C:9]([S:10][CH2:13][CH2:14][CH2:15][CH3:16])[C:4]2=[N:3]1
Reactant: CCCCBr
Reactant: Cn1nc2c(S)ncnc2c1O
Agent: N
Product: CCCCSc1ncnc2c(O)n(C)nc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.2 g of 2-methyl-3-hydroxy-7-mercapto-pyrazolo [4,3-d]pyrimidine was dissolved in 50 ml of aqueous ammonia, and after an addition of 1.08 g of n-butyl bromide, the mixture was stirred at room temperature for 5 hours. By means of a rotary evaporator, ammonia gas was distilled off at room temperature. Then, the aqueous solution was acidified with hydrochloric acid and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and then evaporated to dryness. The remaining solid was recrystallized from acetone.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]([CH3:10])=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[C:7]([O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[N:6]2)[CH2:3][CH2:2]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>CC1C=C(C)C=C(C)N=1>[CH:1]1([CH2:4][N:5]2[C:9]([CH3:10])=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[C:7]([O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][O:33][C:34](=[O:37])[CH2:35][CH3:36])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[N:6]2)[CH2:3][CH2:2]1
Reactant: CCC(=O)Cl
Reactant: Cc1c(Cc2ccc(OC(C)C)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1CC1CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: CCC(=O)OC[C@H]1O[C@@H](Oc2nn(CC3CC3)c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 3 h
Yield: 405.5 %

Procedure:
To a solution of 1-(cyclopropylmethyl)-3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (0.40 g) in 2,4,6-trimethylpyridine (1.5 mL) was added propionyl chloride (0.0088 g) at 0° C., and the mixture was stirred for 3 hours. Citric acid monohydrate (3.3 g) and water were added to the reaction mixture, and the mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol), and successively by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 1-(cyclopropylmethyl)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(6-O-propionyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.20 g).
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][N:6]=[C:7]1[S:12][CH2:11][S:10](=[O:13])[CH2:9][S:8]1)=[O:4].C(OO)(=[O:16])C>>[CH3:1][NH:2][C:3]([O:5][N:6]=[C:7]1[S:12][CH2:11][S:10](=[O:16])(=[O:13])[CH2:9][S:8]1)=[O:4]
Reactant: CC(=O)OO
Reactant: CNC(=O)ON=C1SCS(=O)CS1
Product: CNC(=O)ON=C1SCS(=O)(=O)CS1
Reaction time: 18 h

Procedure:
2-(Methylcarbamoyloximino)-1,3,5-trithiane-5-oxide prepared by the method of Example IV was further reacted with 5 ml of peracetic acid and left standing for 18 hours at room temperature. Concentrating under reduced pressure yielding 0.15g of a solid residue. Crystallization from acetonitrile yielded a solid, m.p. 174°-177° C (decomp.)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:19])[C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([O-:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[NH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[N:30][CH:29]=[CH:28]2>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C:10](=[O:12])[C@H:9]([N:8]([CH3:19])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:34][CH:33]=2)[CH:28]=[CH:29][N:30]=1
Reactant: Nc1ccc2cnccc2c1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](C(=O)[O-])c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@@H](C(=O)Nc1ccc2cnccc2c1)c1ccccc1
Reaction time: 4 h

Procedure:
To (R)-2-(tert-butoxycarbonyl(methyl)amino)-2-phenylacetate (E6) in DMF was added EDC, DMAP and 6-aminoisoquinoline. This mixture was stirred for 4 hours and the reaction was washed with NaHCO3 (sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, Hexanes/EtOAc) gave pure (R)-tert-butyl 2-(isoquinolin-6-ylamino)-2-oxo-1-phenylethyl(methyl)carbamate (E7).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][CH2:11]Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][O:10][CH3:11])[CH:3]=1
Reactant: COCCl
Reactant: Oc1cccc(F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc(F)c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A solution of 22.4 g (200 mmole) of 3-fluorophenol in 400 mL of CH2Cl2 under N2 was prepared and cooled to 5° C. The stirred mixture was treated with 23.1 g (267 mmole) of chloromethyl methyl ether. The reactor was equipped with a thermocouple and an addition funnel. To the stirred mixture was added dropwise 34.8 mL of DIEA (25.8 g, 200 mmole) such that the temperature did not exceed 10° C. After 30 min, an additional 18 mL of DIEA was added dropwise. After a total of 1 h, an additional 18 mL of DIEA was added. The mixture was allowed to stand overnight. The solution was washed with 500 mL of 1N HCl and the aqueous layer extracted two times with CH2Cl2. Combined extracts were dried with Mg2SO4, carefully concd and distilled in vacuo 61-68° C. @ 15 torr to afford 28.7 g (75.3%) of a clear, colorless liquid: (lit. bp 25-26° C. @ 0.6 torr); 1H NMR (CDCl3/400 MHz) 3.46 (s, 3H), 5.14 (s, 2H), 6.70 (tdd, 1H, J=8.3 Hz, J=2.4 Hz, 0.8 Hz), 6.75-6.82 (m, 2H), 7.21 (q, 1H, J=7.7 Hz); 19F NMR (CDCl3/400 MHz) −112.0 (m, 1F); 113C NMR (CDCl3/100 MHz) 56.1, 94.5, 104.1 (d, J=25.0 Hz), 108.6 (d, J=21.3 Hz), 111.9 (d, J=2.9 Hz), 130.2 (d, J=9.9 Hz), 158.6 (d, J=11.0 Hz), 163.5 (d, J=245.3 Hz).
Reaction SMILES: II.[CH:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:4].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].Cl>[Zn].O1CCCC1>[C:26]([O:25][C:23](=[O:24])[CH2:22][CH:3]([OH:4])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=CCCCCCCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(O)CCCCCCC(=O)OCc1ccccc1

Procedure:
A stirred suspension of 59 g. (0.75 g-atom) of activated zinc in 500 ml. of dry tetrahydrofuran containing a crystal of iodine is brought to reflux under nitrogen. To this is added slowly a solution of 12.1 g. (0.50 mol.) of benzyl 7-formylheptanoate and 117 g. (0.60 mol.) of t-butyl bromoacetate in 500 ml. of dry tetrahydrofuran. Within a few minutes, the solution becomes cloudy and the iodine color disappears, indicating that the reaction has started. After the addition is complete (30 minutes), the mixture is stirred and refluxed for an additional hour. The cooled solution is then poured into 0.1 N hydrochloric acid and the pH adjusted to 2 with 2 N hydrochloric acid. The excess zinc is filtered off and the filtrate thoroughly extracted with ethyl acetate. The combined extracts are dried and concentrated in vacuo to give crude 3-hydroxydecanedioic acid 10-benzyl ester-1-t-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([NH2:9])[N:3]=1.[NH:10]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([NH2:9])[N:3]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: C1CNCCNC1
Solvent: CCO
Product: Nc1cc(N2CCCNCC2)nc(N)n1

Procedure:
The analogous 1-(2,6-diamino-4-pyrimidinyl)homopiperazine was prepared by reaction of 2,6-diamino-4-chloropyrimidine with unprotected homopiperazine (5 mol equivalents) in ethanol in a sealed tube, following the procedure of Example 19. Yield of the obtained base: 91.3%, mp. 62°-72° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][N:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:28])=[CH:14][CH:13]=1)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[CH3:42]
Reactant: CCOC(=O)CBr
Reactant: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCN(CCC)CCCCN(CC(=O)OCC)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound (28.58 g) obtained in Example 23-4 was dissolved in anhydrous DMF (560 ml) and added with triethylamine (20.35 ml) and ethyl bromoacetate (12.14 ml) and the whole was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in ethyl acetate and washed with water, followed by drying with magnesium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (21.265 g) as a colorless oily substance.