Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([C@@H:7]1[C:13]2[CH:14]=[CH:15][CH2:16][CH2:17][C:12]=2[CH2:11][CH:10]([NH2:18])[N:9]([CH3:19])[C:8]1=[O:20])=[O:6])[CH3:4].C([NH:28][CH:29]([CH2:33][C:34]([F:37])([F:36])[F:35])[C:30](O)=[O:31])(OC(C)(C)C)=O>>[NH2:28][CH:29]([CH2:33][C:34]([F:37])([F:36])[F:35])[C:30]([NH:2][C@H:3]([C:5]([C@@H:7]1[C:13]2[CH:14]=[CH:15][CH2:16][CH2:17][C:12]=2[CH2:11][CH:10]([NH2:18])[N:9]([CH3:19])[C:8]1=[O:20])=[O:6])[CH3:4])=[O:31]
Reactant: C[C@H](N)C(=O)[C@H]1C(=O)N(C)C(N)CC2=C1C=CCC2
Reactant: CC(C)(C)OC(=O)NC(CC(F)(F)F)C(=O)O
Agent: Cl
Product: C[C@H](NC(=O)C(N)CC(F)(F)F)C(=O)[C@H]1C(=O)N(C)C(N)CC2=C1C=CCC2

Procedure:
Following General Procedure D above using 1-(S)-[L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one hydrochloride (Example 7-30, below) and 2-(N-Boc-amino)-4,4,4-trifluorobutyric acid (Oakwood), the protected intermediate was prepared. The Boc-group was removed using 5.0 M HCl in dioxane and the resulting free-base purified by flash chromatography CHCl3/MeOH (97.3) yielding the title compounds.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:13][C:14]1[S:15][CH:16]=[C:17]([CH2:19][C:20]([OH:22])=O)[N:18]=1.[NH2:23][C@@H:24]1[C:31](=[O:32])[N:30]2[C@@H:25]1[S:26][CH2:27][C:28](/[CH:36]=[C:37]1/[C:38](=[O:46])[N:39]([CH2:42][CH:43]3[CH2:45][CH2:44]3)[CH2:40][CH2:41]/1)=[C:29]2[C:33]([OH:35])=[O:34]>CN(C)C=O>[NH2:13][C:14]1[S:15][CH:16]=[C:17]([CH2:19][C:20]([NH:23][C@@H:24]2[C:31](=[O:32])[N:30]3[C@@H:25]2[S:26][CH2:27][C:28](/[CH:36]=[C:37]2/[C:38](=[O:46])[N:39]([CH2:42][CH:43]4[CH2:45][CH2:44]4)[CH2:40][CH2:41]/2)=[C:29]3[C:33]([OH:35])=[O:34])=[O:22])[N:18]=1
Reactant: Nc1nc(CC(=O)O)cs1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC4CC4)C3=O)CS[C@H]12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Nc1nc(CC(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(/C=C4\CCN(CC5CC5)C4=O)CS[C@H]23)cs1

Procedure:
With 167.0 mg (1.03 mmol) 1,1′-carbonyldiimidazole, 163.0 mg (1.03 mmol) (2-aminothiazole-4-yl)-acetic acid and 300.0 mg (0.86 mmol) (E)-(6R,7R)-7-amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 6 ml N,N-dimethylformamide. The resulting solid was purified by reversed phase chromatography (RP-18 LiChroPrep gel, water:acetonitrile=9:1). The organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[NH2:10].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.CCN(CC)CC.[CH3:43][C:44]1([CH3:51])[C:48]([CH3:50])([CH3:49])[O:47][BH:46][O:45]1>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[Cl:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([B:46]2[O:47][C:48]([CH3:50])([CH3:49])[C:44]([CH3:51])([CH3:43])[O:45]2)=[C:3]([NH2:10])[CH:4]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: Cc1cc(Cl)cc(N)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)cc(N)c1B1OC(C)(C)C(C)(C)O1
Temperature: 80 °C

Procedure:
2-Bromo-5-chloro-3-methyl-phenylamine (595 mg, 2.7 mmol, Example 135: step c), Pd(OAc)2 (30.3 mg, 0.14 mmol), 2-(dicyclohexylphosphino)biphenyl (189.2 mg, 0.54 mmol) and Et3N (1.5 mL, 10.8 mmol) were dissolved into dioxane (10 mL). To this was added 4,4,5,5-Tetramethyl-[1,3,2]dioxaborolane (1.2 mL, 8.1 mmol) slowly. The reaction was heated to 80° C. overnight. The solvents were removed in vacuo and the resulting residue was dissolved into EtOAc and washed with brine. The combined organic layers were dried (MgSO4) and removal of the solvents in vacuo resulted in a mixture of the title compound and 3-Methyl-2,5-bis-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine were obtained and used with out further purification.
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>O1CCCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([N:17]2[CH2:18][CH2:19][N:14]([C:3]3[C:4](=[O:13])[C:5]4[C:10]([C:11](=[O:12])[C:2]=3[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:15][CH2:16]2)=[O:29])=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC1=C(N2CCNCC2)C(=O)c2ccccc2C1=O
Solvent: C1CCOC1
Product: CC1=C(N2CCN(C(=O)Nc3ccc(Cl)cc3)CC2)C(=O)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
A solution of 150 mg of 3-methyl-2piperazinyl-1,4-naphthoquinone in 50 ml of tetrahydrofuran was treated with a solution of 100 mg of 4-chlorophenylisocyanate in 10 ml of tetrahydrofuran. This mixture was stirred 1/2 hour, then evaporated in vacuo and the residue taken up in dichloromethane and filtered. The filtrate was evaporated and the residue recrystallized from dichloromethane/hexane, giving 200 mg of the desired product, mp 190°-192° C.
Reaction SMILES: [CH:1]1([N:4]2[C:11](=[O:12])[CH2:10][CH2:9][NH:8][C:7]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:6]=3[CH2:5]2)[CH2:3][CH2:2]1.C(O)(=O)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]=O)=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][N:8]2[CH2:9][CH2:10][C:11](=[O:12])[N:4]([CH:1]3[CH2:2][CH2:3]3)[CH2:5][C:6]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:7]2=3)=[CH:26][CH:25]=1
Reactant: COc1ccc2c(c1)CN(C1CC1)C(=O)CCN2
Reactant: O=CCc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CN(C1CC1)C(=O)CCN2CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a solution of 5-cyclopropyl-8-methoxy-2,3,5,6-tetrahydrobenzo[b][1,5]diazocin-4(1H)-one (50.0 mg, 0.203 mmol) from Example 1 in dichloroethane (2 ml) at 0° C. was added acetic acid (0.035 ml, 0.609 mmol), 2-(4-chlorophenyl)acetaldehyde (47.0 mg, 0.304 mmol) prepared as above and sodium triacetoxyborohydride (129.0 mg, 0.609 mmol). The mixture was stirred overnight at room temperature and then sodium bicarbonate was added followed by extraction with dichloromethane. The organic phases were dried over sodium sulfate, filtered and concentrated. Preparative thin layer chromatography (pentane/ethyl acetate: 1/1) of the obtained residue gave the desired compound as a yellow oil (59 mg, 76%).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:21][CH3:22])=[C:7]([CH:9]2[CH2:18][C:17]3[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=3[C:11](=O)[CH2:10]2)[CH:8]=1.[C:23]([NH:26][NH2:27])([NH2:25])=[NH:24].Cl.Cl>C(O)C>[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:21][CH3:22])=[C:7]([CH:9]2[CH2:18][C:17]3[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=3[C:11](=[N:27][NH:26][C:23]([NH2:25])=[NH:24])[CH2:10]2)[CH:8]=1
Reactant: N=C(N)NN
Reactant: COc1ccc(F)cc1C1CC(=O)c2c(C)ccnc2C1
Agent: Cl
Solvent: CCO
Product: COc1ccc(F)cc1C1CC(=NNC(=N)N)c2c(C)ccnc2C1
Temperature: 110 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a mixture of 7-(5-fluoro-2-methoxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one hydrochloride (1.2 g) and aminoguanidine hydrochloride (0.477 g) were added ethanol (15 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was stirred at 110° C. (bath temperature) for 2 hours. The reaction solution was cooled to room temperature, and the resulting crystals were filtered and dried to give 7-(5-fluoro-2-methoxyphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 168) (1.4 g) as colorless crystals.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6](=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[CH3:14][C:15]1[CH:19]=[C:18]([NH2:20])[N:17]([CH:21]([CH3:23])[CH3:22])[N:16]=1>C1C=CC=CC=1>[CH:1]1([C:4]2[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:19]3[C:15]([CH3:14])=[N:16][N:17]([CH:21]([CH3:23])[CH3:22])[C:18]=3[N:20]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(N)n(C(C)C)n1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C(C)C
Temperature: 25 °C

Procedure:
A solution of ethyl 4-cyclopropyl-2,4-dioxobutanoate (700 mg, 3.76 mmol), 3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine (523 mg, 3.76 mmol) and benzene (20 mL) were heated at 65° C. for 6 hr, and then allowed to cool to room temperature for 2 d. The solvent was removed under reduced pressure and the residue purified via silica gel chromatography (eluent: 0 to 25% EtOAc:Hex). The final product was collected as 0.77 g (71%). LCMS E-S (M+H)=288.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.04-1.11 (m, 2H), 1.13-1.20 (m, 4H), 1.47 (t, J=7.20 Hz, 6H), 1.55 (d, J=6.82 Hz, 12H), 2.16-2.25 (m, 2H), 2.68 (s, 6H), 4.49 (q, J=7.07 Hz, 4H), 5.20 (spt, J=6.78 Hz, 2H), 7.41 (s, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH2:13]([O:15][C:16](=[O:19])[NH:17][NH2:18])[CH3:14]>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:18][NH:17][C:16]([O:15][CH2:13][CH3:14])=[O:19]
Reactant: CCOC(=O)NN
Reactant: O=Cc1ccc2ccccc2n1
Solvent: CO
Product: CCOC(=O)NN=Cc1ccc2ccccc2n1
Yield: 19.6 %

Procedure:
A mixture of 3.93 gm (0.025 mole) of 2-quinolinecarboxaldehyde, 2.60 gm (0.025 mole) of ethylcarbazate and 100 ml of methanol is refluxed for 8 hrs. The hot solvent is evaporated in vacuo to give a solid. The crude product is crystallized from ethyl acetate/Skellysolve B to yield 1.19 gm (20%) of the title compound, having a melting point of 163°-165° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][C:40]([S:43]([NH2:46])(=[O:45])=[O:44])=[CH:39][CH:38]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.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>[CH3:17][O:16][C:12]1[C:11]2[C:7]([C:37]3[CH:42]=[CH:41][C:40]([S:43]([NH2:46])(=[O:45])=[O:44])=[CH:39][CH:38]=3)=[N:8][N:9]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[C:10]=2[CH:15]=[CH:14][N:13]=1
Reactant: COc1ccc(Cn2nc(OS(=O)(=O)C(F)(F)F)c3c(OC)nccc32)cc1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(-c3ccc(S(N)(=O)=O)cc3)c3c(OC)nccc32)cc1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To a solution of 4-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (100 mg) in DMF (4 mL)/water (0.30 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (102 mg), tetrakis(triphenylphosphine)palladium(0) (27.7 mg) and potassium carbonate (66.2 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (45.0 mg).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:5]2[O:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15]>CN(C)C=O.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>[CH2:15]([C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:5]2[O:6][CH:7]=[CH:8][C:4]=2[CH:3]=1)[CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc(Br)cc2ccoc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1cc(OC)c2occc2c1

Procedure:
A solution of 10 g (0.044 mol) of 5-bromo-7-methoxybenzo[b]furan, 17.5 g (0.053 mol) of allyltributyltin and 1.02 g (0.00088 mol) of tetrakis(triphenylphosphine)palladium(0) in 80 ml of dimethylformamide is heated at 90° C. for 15 hours under an inert atmosphere. After returning to room temperature, the dimethylformamide is evaporated off in vacuo. The reaction mass is taken up in 200 ml of diethyl ether and washed in succession with 100 ml of water and 100 ml of a saturated sodium chloride solution. Customary treatment of the organic phase yields an oil, which is purified by chromatography on a silica column using a dichloromethane/heptane (6/4) mixture as eluant.
Reaction SMILES: C([O:4][CH:5]([CH:26]1[CH2:28][CH2:27]1)[C@H:6]1[O:10][C@@H:9]([N:11]2[C:15]3[N:16]=[C:17]([NH2:20])[N:18]=[CH:19][C:14]=3[S:13][C:12]2=[O:21])[C@@H:8](CC([O-])=O)[CH2:7]1)(=O)C.C(OC([C@H]1O[C@@H](N2C3N=C(N)N=CC=3SC2=O)[C@@H](CC([O-])=O)C1)CC)(=[O:31])C>>[NH2:20][C:17]1[N:18]=[CH:19][C:14]2[S:13][C:12](=[O:21])[N:11]([C@H:9]3[C@H:8]([OH:31])[CH2:7][C@@H:6]([CH:5]([CH:26]4[CH2:28][CH2:27]4)[OH:4])[O:10]3)[C:15]=2[N:16]=1
Reactant: CCC(OC(C)=O)[C@@H]1C[C@H](CC(=O)[O-])[C@H](n2c(=O)sc3cnc(N)nc32)O1
Reactant: CC(=O)OC(C1CC1)[C@@H]1C[C@H](CC(=O)[O-])[C@H](n2c(=O)sc3cnc(N)nc32)O1
Product: Nc1ncc2sc(=O)n([C@@H]3O[C@H](C(O)C4CC4)C[C@H]3O)c2n1

Procedure:
The title compound was prepared in analogy to Example 2, by using [(2R,3R,5S)-5-[acetoxy(cyclopropyl)methyl]-2-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-3-yl] acetate (compound 16a) instead of [(2R,3R,5S)-5-(1-acetoxypropyl)-2-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-3-yl]acetate (compound 2a). Example 17 was purified and separated by preparative HPLC to afford Example 17-A and Example 17-B as white solid.
Reaction SMILES: [CH3:1]C1C=CC([N+]([O-])=O)=CC=1O.C(Br)C=C.[CH2:16]([C:19]1[C:24]([OH:25])=[C:23](Cl)[CH:22]=[CH:21][C:20]=1[N:27]1[C:31](=[O:32])[C:30]2[CH2:33][CH2:34][CH2:35][CH2:36][C:29]=2[C:28]1=[O:37])[CH:17]=[CH2:18].ClC1C=CC([N+]([O-])=O)=CC=1O>>[CH2:16]([C:19]1[C:24]([OH:25])=[C:23]([CH3:1])[CH:22]=[CH:21][C:20]=1[N:27]1[C:31](=[O:32])[C:30]2[CH2:33][CH2:34][CH2:35][CH2:36][C:29]=2[C:28]1=[O:37])[CH:17]=[CH2:18]
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Reactant: C=CCc1c(N2C(=O)C3=C(CCCC3)C2=O)ccc(Cl)c1O
Agent: O=[N+]([O-])c1ccc(Cl)c(O)c1
Solvent: C=CCBr
Product: C=CCc1c(N2C(=O)C3=C(CCCC3)C2=O)ccc(C)c1O

Procedure:
N-(2-allyl-3-hydroxy-4-methylphenyl)-3,4,5,6-tetrahydrophthalimide (5A) was prepared, as yellow crystals, m.p.: 141°-143° C., from 2-methyl-5-nitrophenol and allyl bromide by the procedures described in Example 3 for preparing 3D from 2-chloro-5-nitrophenol and allyl bromide.
Reaction SMILES: [C@@H:1]1(N2C3N=CN=C(O)C=3N=C2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[NH:19]1[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]1=[O:21].N1C(=O)C2NC=NC=2NC1=O>C([O-])(=O)C.[NH4+]>[C@@H:1]1([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)C[C@@H]1O
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: CC(=O)[O-]
Agent: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Agent: [NH4+]
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 1 h
Yield: 68 %

Procedure:
The assay mixture contained 2 g (wet weight) of Bacillus stearothermophilus cells, 5 mM 2′-deoxyinosine, 5 mM thymine, 20 units of xanthine oxidase (from buttermilk) in 10 ml of 50 mM ammonium acetate buffer (pH 5.5). The conversions were run at 55° C. for 1 hour. The reaction mixture was centrifuged and then filtered using an Amicon Ultrafiltration device (YM-3 membrane) and the products were separated and analyzed by HPLC (C-18 column) in 5% methanol and 5 mM phosphate buffer at pH 4.6 using a flow rate of 0.5 ml/ min. Thymidine was isolated in 68% yield (90% conversion).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH:10]C(OC(C)(C)C)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:18][C:19]1[C:24]([C:25]([N:27]=[C:28]=[O:29])=O)=[C:23]([F:30])[C:22]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:21][CH:20]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:23]([F:30])[C:24]=1[C:25]1[NH:27][C:28](=[O:29])[N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:10]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Reactant: CC(C)(C)OC(=O)NNc1ccc(Cl)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(Cl)c(Cl)c3)c(=O)[nH]2)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 7.1 %

Procedure:
To a solution of tert-butyl 2-(3,4-dichlorophenyl)hydrazinecarboxylate (Intermediate-52, 0.060 g, 0.21 mmol) in DCM (10 mL) was added solution of 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.101 g, 0.32 mmol) in DCM and the reaction mixture was stirred for 20 h at room temperature, followed by addition of TFA (3 mL) and further stirred for 20 h at room temperature. The reaction mass was quenched in water, extracted with DCM and concentrated to afford crude product which was purified by column chromatography eluting with MeOH:DCM to afford 0.007 g of pure product. 1H NMR (300 MHz, CDCl3): δ 1.20 (s, 9H), 4.44 (d, J=5.4 Hz, 2H), 6.20 (m, 1H), 7.29 (m, 1H), 7.41-7.49 (m, 2H), 7.91 (d, J=8.1 Hz, 1H), 8.15 (s, 1H); MS (m/z): 471.26 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([NH:17][CH3:18])[C:14]([N+:19]([O-:21])=[O:20])=[CH:13][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=1.[C:22](Cl)(=[O:24])[CH3:23].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([NH:17][CH3:18])[C:14]([N+:19]([O-:21])=[O:20])=[CH:13][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:22](=[O:24])[CH3:23])[CH:7]=1
Reactant: CNc1cc(OC)c(Oc2ccnc(N)c2)cc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CNc1cc(OC)c(Oc2ccnc(NC(C)=O)c2)cc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, 4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridin-2-amine (1 eq) and disopropylethylamine (4 eq) in methylene chloride was brought to 0° C. Acetyl chloride (1.1 eq) was added dropwise and mixture stirred for 5 minutes. Reaction brought to room temperature and water added. Organic layer washed with brine, dried over sodium sulfate and concentrated to yield N-(4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridin-2-yl)acetamide. HPLC=3.21 min; MS: MH+=333.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:28]1[CH2:31][CH2:30][CH2:29]1>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][N:28]3[CH2:31][CH2:30][CH2:29]3)[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: C1CNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(Cl)c2c(c1)O[C@@H](CN1CCC1)CO2

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), azetidine (0.1 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 317 (M+, 1), 85 (3), 71 (5), 70 (bp), 68 (2), 63 (3).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]1[CH2:16][O:15][CH2:14][CH2:13][NH:12][CH2:11]1.Cl.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:12]2[CH2:11][CH2:10][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: C1CNCCOC1
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Brc1ccc(CN2CCCOCC2)cc1
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a solution of 4-bromobenzaldehyde (616 mg, 3.3 mmol) in dichloroethane (50 mL) was added homomorpholine hydrochloride (548 mg, 4 mmol) and acetic acid (0.1 mL). Sodium triacetoxyborohydride (3.4 g, 16 mmol) was added and the reaction was stirred overnight. The reaction was quenched with sat. NH4Cl (30 mL). Ethyl acetate (250 mL) was added and the solution was washed with sat. NaHCO3 (2×50 mL), brine (50 mL), dried over MgSO4 and concentrated to dryness. The residue was flushed through a silica plug with (5% MeOH/CH2Cl2) to give a white solid (850 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J=7.3 Hz, 2H), 7.10 (d, J=7.3 Hz, 2H), 3.66-3.57 (m, 2H), 3.55-3.50 (m, 2H), 3.46-3.42 (m, 2H), 3.16-3.10 (m, 2H), 2.55-2.45 (m, 4H), 1.75-1.65 (m, 2H).
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][C:18](=[O:34])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[N:20]=2)[CH2:6][C@H:5]1[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N+:2]=[N-:3].C.[CH:44]#[C:45][CH3:46].C(N(CC)CC)C>O1CCOCC1.[Cu]>[F:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([F:33])[C:26]=1[C:21]1[N:20]=[C:19]([C:18]([NH:17][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:11]=2[N:7]2[CH2:8][C@H:9]([CH3:10])[C@H:4]([N:1]3[CH:44]=[C:45]([CH3:46])[N:3]=[N:2]3)[C@H:5]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:6]2)=[O:34])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Reactant: C#CC
Agent: [Cu]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cn([C@H]2[C@@H](C)CN(c3ccncc3NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)C[C@H]2NC(=O)OC(C)(C)C)nn1
Temperature: 60 °C
Yield: 95 %

Procedure:
In a high pressure vial was added tert-butyl (3R,4S,5S)-4-azido-1-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-5-methylpiperidin-3-ylcarbamate (1.0 equiv.), copper in charcoal (0.2 equiv.), prop-1-yne (10.0 equiv.) and triethylamine (1.5 equiv.), in dioxane (0.15 M) to give a black suspension. The pressure tube was sealed and the mixture was stirred with heating to 60° C. for 48 hrs. The reaction was cooled to RT, filtered through celite, concentrated to yield tert-butyl (3R,4S,5S)-1-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-5-methyl-4-(4-methyl-1H-1,2,3-triazol-1-yl)piperidin-3-ylcarbamate in 95% yield. LC/MS (m/z)=623.2 (MH+), Rt=0.87 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][NH:29][CH2:30]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][N:29]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:30]2
Reactant: Nc1cccc2c1CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1cccc2c1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c1F)C2
Yield: 43.1 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 81 mg of 4-amino isoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 98 mg of the target compound.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][CH2:28][O:29][C:22]=3[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][CH2:28][O:29][C:22]=4[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CCc1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: CCc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-ethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-ethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.