Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:19][F:20])[CH:8]=[C:7]([C:9](=[S:11])[NH2:10])[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4]1.CO[CH:23](OC)[CH2:24]Br.[OH-].[K+].C1C=CC=CC=1>O>[F:20][CH2:19][C:3]1([CH2:2][F:1])[CH:8]=[C:7]([C:9]2[S:11][CH:23]=[CH:24][N:10]=2)[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4]1
Reactant: NC(=S)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Reactant: COC(CBr)OC
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)C(c1nccs1)=CC(CF)(CF)O2

Procedure:
A mixture of 600 mg of 2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-carbothioamide, 1.2 ml of bromoacetoaldehyde dimethylacetal, 11 mg of potassium hydroxide and 3 ml of benzene was refluxed with heating for 1 hour. Water was added thereto and the mixture was extracted with methylene chloride. The organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, hexane:ethyl acetate=2:1) to obtain 380 mg of 2-(2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-yl)thiazol represented by the following formula.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]2[CH2:12][C:7]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)([CH2:8]2)[C:6]1=[O:22])[CH2:2][CH2:3][CH3:4].C(OCC)(=O)C>C(O)C.[Pd]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:7]23[CH2:8][CH:9]([CH2:12]2)[C:10](=[O:11])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]3=[O:22])=[CH:18][CH:17]=1
Reactant: CCCCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 1, 2.08 g of 3-n-butyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 60 ml of ethanol are hydrogenated in the presence of 0.15 g of palladium-on-carbon and worked up. Melting point 178°-179° (from ethyl acetate).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]1([C:25]2[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][NH:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C)C=O>O>[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:27]2[CH:28]=[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:26]2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1c[nH]nc1-c1ccccc1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
Sodium hydride (60%, oily, 1.85 g) was added to a mixture of 4-benzyloxybenzyl chloride (10.8 g), ethyl 3-phenyl-1H-pyrazole-4-carboxylate (10.0 g) and N,N-dimethylformamide (50 ml) at 0° C., and the mixture was stirred for 1.5 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield ethyl 1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazole-4-carboxylate (15.3 g, yield: 80%). This was crystallized from ethyl acetate-diisopropyl ether. Melting point: 102–103° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[F:41][C:42]1[CH:43]=[N:44][C:45]2[C:50]([C:51]=1I)=[CH:49][CH:48]=[CH:47][CH:46]=2>>[F:41][C:42]1[CH:43]=[N:44][C:45]2[C:50]([C:51]=1[C:5]1[N:4]=[C:3]3[C:8]([N:9]=[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][CH:15]([C:18]([OH:21])([CH3:19])[CH3:20])[CH2:16][CH2:17]4)[N:2]3[CH3:1])=[C:7]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:6]=1)=[CH:49][CH:48]=[CH:47][CH:46]=2
Reactant: Fc1cnc2ccccc2c1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3c(F)cnc4ccccc34)nc21

Procedure:
Following the procedure for 165, 2-[1-(9-methyl-6-morpholin-4-yl-2-(tributylstannanyl)-9H-purin-8-ylmethyl)piperidin-4-yl]propan-2-ol and 3-fluoro-4-iodoquinoline were reacted to give 225. LCMS m/z: 520.2 (MH+)
Reaction SMILES: [CH:1]1([CH2:6][NH:7][CH2:8][C:9]2[C:10]3[C:15]([CH:16]=[C:17]4[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23](Br)[C:24]#[CH:25].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH:1]1([CH2:6][N:7]([CH2:25][C:24]#[CH:23])[CH2:8][C:9]2[C:10]3[C:15]([CH:16]=[C:17]4[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(CNCC3CCCC3)c3ccccc3cc2c1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C#CCN(Cc1c2ccccc2cc2ccccc12)CC1CCCC1
Yield: 88.4 %

Procedure:
A mixture of 63.5 g of N-cyclopentylmethyl-9-anthracenemethylamine, 50 g of propargyl bromide, 200 ml of methylene chloride and 200 ml of 10% aqueous, potassium carbonate solution is stirred vigorously under nitrogen for two hours. The layers are separated and the aqueous layer is extracted once with methylene chloride. Removal of the solvent from the dried extract gives 63.5 g of N-cyclopentylmethyl-N-propargyl-9-anthracenemethylamine as an oil; nmr spectrum: τ 2.3-3.0 (m, 9); 5.5 (s, 2) 6.8 (d, 2.5Hz, 2); 7.5 (m, 2); 7.7 (t, 2.5Hz, 1) and 7.5-9.2 (m, 9). This product is cyclized by heating under reflux in 200 ml toluene for 1.25 hours. Removal of the solvent and crystallization of the residue from 150 ml of isopropyl alcohol gives 44.4 g of 2-cyclopentylmethyl-1,2,3,5-tetrahydro-5,9b-o-benzenobenz[e]isoindole, identical by infrared and nmr spectroscopy with the sample prepared by acylation of 1,2,3,5-tetrahydro-5,9b-o-benzenobenz[e]isoindole with cyclopentanecarbonyl chloride followed by reduction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH2:39][C:40](O)=[O:41])[C:34](=[O:43])[C:33]2=[O:44].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:40](=[O:41])[CH2:39][N:35]1[C:36]2[C:32](=[CH:31][C:30]([O:29][CH3:28])=[CH:38][CH:37]=2)[C:33](=[O:44])[C:34]1=[O:43]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2c(c1)C(=O)C(=O)N2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
A mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.2 g, 0.476 mmol), 2-(5-methoxy-2,3-dioxoindolin-1-yl)acetic acid (0.112 g, 0.476 mmol), DMAP (0.029 g, 0.238 mmol) and EDC (0.274 g, 1.428 mmol) in DCM (10 ml) was stirred at room temperature overnight. The reaction was washed with 1N HCl, aqueous 5% NaHCO3 and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography on silica gel (ethyl acetate:DCM=7:3) to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-methoxy-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.18635 g, 0.292 mmol, 61% yield). MS/ESI+ 637.19 [MH]+; [αD]=+60.39 c=0.155 in DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.41 (s, 2H), 7.22 (dd, 1H), 7.19-7.21 (m, 1H), 7.18 (d, 1H), 7.06 (d, 1H), 6.89-6.98 (m, 2H), 7.07 (t, 1H), 6.03 (dd, 1H), 4.62 (d, 1H), 4.54 (d, 1H), 3.89 (d, 2H), 3.81 (s, 3H), 3.40 (dd, 1H), 3.21 (dd, 1H), 1.09-1.37 (m, 1H), 0.51-0.67 (m, 2H), 0.28-0.47 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.[NH2:31][C:32]1[S:33][C:34]2[CH:40]=[C:39](Br)[CH:38]=[CH:37][C:35]=2[N:36]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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>[NH2:31][C:32]1[S:33][C:34]2[CH:40]=[C:39]([C:5]3[CH:6]=[C:7]([NH:8][S:9]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([F:20])[F:21])[CH:13]=4)(=[O:10])=[O:11])[C:2]([Cl:1])=[N:3][CH:4]=3)[CH:38]=[CH:37][C:35]=2[N:36]=1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3cccc(OC(F)F)c3)c2)OC1(C)C
Reactant: Nc1nc2ccc(Br)cc2s1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)cc2s1
Temperature: 100 °C
Reaction time: 5 h
Yield: 46.7 %

Procedure:
To a 50 mL round-bottomed flask was added N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-3-(difluoromethoxy)benzenesulfonamide (98 mg, 213 μmol), 2-amino-6-bromobenzothiazole (49 mg, 213 μmol), tetrakis(triphenylphosphine)palladium (25 mg, 21 μmol), sodium carbonate (213 μl, 425 μmol), dioxane (3 mL). The reaction mixture was stirred at 100° C. for 5 h. The mixture was cooled down to room temperature. The reaction mixture was diluted with water (2 mL) and extracted with EtOAc (3×20 mL). The organic extract was washed with saturated NaCl (10 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 80% EtOAc/hexanes to give N-(5-(2-aminobenzo[d]thiazol-6-yl)-2-chloropyridin-3-yl)-3-(difluoromethoxy)benzenesulfonamide (48 mg, 47% yield) as a white solid. MS (ESI pos. ion) m/z calc'd for C19H13ClF2N4O3S2: 482.0. found 483.0.1H NMR (300 MHz, MeOH) δ ppm 6.88 (t, J=73.08 Hz, 1H) 7.38-7.71 (m, 5H) 7.91 (d, J=1.17 Hz, 1H) 8.17 (d, J=2.19 Hz, 1H) 8.46 (d, J=2.34 Hz, 1H)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([O:13]C)[C:6](=[CH:9][CH:10]=[CH:11][CH:12]=1)[O:7][CH3:8].[Cl-].[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH:27]=[CH:26][CH:25]=[C:21]([C:22](O)=[O:23])[CH:20]=1.Cl>ClCCl>[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH:27]=[CH:26][CH:25]=[C:21]([C:22](=[O:23])[C:10]2[CH:11]=[CH:12][C:5]([OH:13])=[C:6]([O:7][CH3:8])[CH:9]=2)[CH:20]=1
Reactant: COc1ccccc1OC
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)c2ccc(O)c(OC)c2)c1

Procedure:
14.8g of aluminum chloride and 5g of veratrole are added to a solution of 7.34g of isophthalic acid monomethyl ester chloride in 160 ml of dichloromethane under ice cooling. The reaction mixture is refluxed for 8 hours, poured on ice water, acidified with 2 n of hydrochloric acid and shaken out with dichloromethane. The organic phase is dried on sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel with hexane/ethyl acetate=8/2. 3.5g of 3-(4-hydroxy-3-methoxybenzoyl)-benzoic acid methyl ester of melting point of 133°-134° C. is obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2O.CN(C=O)C.S(Cl)([Cl:20])=O>>[Cl:20][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: Oc1ncnc2ccc(I)cc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1ncnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99 %

Procedure:
To a solution of 6-Iodo-quinazolin-4-ol (5.0 g, 18 mmol) in thionyl chloride (10 mL) was added slowly DMF (0.5 mL) and the mixture is heated immediately to reflux. Heating is continued for 4.5 hours, followed by cooling to room temperature. The reaction mixture was then evaporated under reduced pressure to dryness. The residue was then redesolved in DCM (20 mL), and to it was added toluene (50 mL), and the mixture was then evaporated under reduced pressure to dryness. The procedure was repeated one more time to rid the product of thionyl chloride to yield 5.2 g (99%) of desired product as a tan solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[C:17](=[CH:18][CH2:19][S:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:16][CH:15]2[N:12]1[C:13](=[O:28])[CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:37])C=1>C(Cl)Cl>[CH2:1]([O:8][C:9]([CH:11]1[C:17](=[CH:18][CH2:19][S:20]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:37])[O:16][CH:15]2[N:12]1[C:13](=[O:28])[CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)C1C(=CCSCc2ccccc2)OC2CC(=O)N21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C1C(=CCS(=O)Cc2ccccc2)OC2CC(=O)N21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Benzyl3-(2-benzylthioethylidene)-7-oxo-4-oxa-1-azabicyclo[3,2,0]heptane-2-carboxylate (39.5 mg) was dissolved in methylene chloride (5 ml) and treated with m-chloroperbenzoic acid (19 mg) at 0° C. The solution was stirred at 0° C. for 1/2 hour and washed with 3% bicarbonate solution (3×5 ml). The solvent was evaporated and the gum chromatographed to yield the title product as a mixture of R and S sulphoxides (30 mg; 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[I:17]I.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([I:17])[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1ccc2ccc(Cl)cc21
Reactant: II
Agent: O=S([O-])[O-]
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CCOCC
Product: Cn1c(I)cc2ccc(Cl)cc21
Reaction time: 0.25 h

Procedure:
A solution of 6-chloro-l-methylindole (0.83 g, 5.0 mmole) in diethyl ether is treated with 1.7 M t-butyl lithium in hexanes (3.5 mL, 6.0 mmole) at 0° C., stirred at ambient temperatures for 0.25 hour, treated with I2 (1.52 g, 6.0 mmole), stirred at room temperature until reaction is complete by TLC analysis, treated with aqueous sodium sulfite and extracted with diethyl ether. The combined ether extracts are dried over MgSO4 and concentrated in vacuo to afford the title product as a brown solid, 1.52 g (contains ether). The product is used as is in Example 9.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C1(N=C=NC2CCCCC2)CCCCC1.C1(N=C=NC2CCCCC2)CCCCC1.N(C(OC(C)(C)C)=O)[C@H](C(O)=O)C(C)C.[CH:61]1[N:65]([CH2:66][O:67][CH2:68][CH2:69]O)[C:64]2[N:71]=[C:72]([NH2:76])[N:73]=[C:74]([OH:75])[C:63]=2[N:62]=1>CN(C)C=O>[CH3:5][CH:3]([C@H:2]([NH2:1])[C:6]([O:8][CH2:69][CH2:68][O:67][CH2:66][N:65]1[C:64]2[NH:71][C:72]([NH2:76])=[N:73][C:74](=[O:75])[C:63]=2[N:62]=[CH:61]1)=[O:7])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1nc(O)c2ncn(COCCO)c2n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)[C@H](N)C(=O)OCCOCn1cnc2c(=O)nc(N)[nH]c21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of Boc-Val and dicyclohexyl carbodiimide (DCC) in dimethylformamide (DMF) in a ratio of 1:2 DCC/Boc-Val was stirred for 1 hr at 0° C. under nitrogen atmosphere. A solution of acyclovir (1) and 4-N,N(dimethylamino)pyridine (DMAP) was added to the reaction mixture, stirred for 18 hrs and then filtered. The solvent of the filtrate was partially removed in vacuo and the impure solution was added dropwise to cold diethyl ether. The resulting precipitate (2) was filtered and dried, followed by acidolytic removal (treating Boc-Val-ACV with trifluoroacetic acid (TFA) for 30 min at 0° C.) of the Boc protecting group to yield Val-ACV (3). Compound (3) was neutralized by triethylamine (TEA) and treated with the amino acid anhydride of Boc-Val for about 5 hrs. The solvent was removed from the reaction mixture in vacuo and the reaction mixture was added dropwise to the cold diethyl ether. The resulting precipitate (4) was filtered, dried and the Boc group was deprotected (acidolytic removal) to yield the desired dipeptide ester of acyclovir Val-Val-ACV (5).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])OC(C)(C)C)[CH2:4][CH2:3]1.[C:16](OC(=O)C)(=O)C.[ClH:23].O1CCOCC1>C(Cl)Cl>[ClH:23].[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[CH3:16])[CH2:4][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)N[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl trans-4-aminocyclohexylcarbamate (500 mg, 2.333 mmol) in DCM (20 mL) was added acetic anhydride (0.231 mL, 2.450 mmol). The solution was stirred overnight at RT. After 16 hours, 4 M HCl in dioxane (2.333 mL, 9.33 mmol) was added, and the reaction was stirred at RT for 3 days. The resulting white solid was collected by vacuum filtration and dried in vacuo to generate N-(trans-4-aminocyclohexyl)acetamide hydrochloride as a white powder (0.49 g, 109% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:15]=O.[Na].[BH4-].[Na+]>CO>[CH3:15][NH:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:8][CH3:9])[O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: C=O
Reactant: COP(=O)(Cc1ccc(N)cc1)OC
Agent: [BH4-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CNc1ccc(CP(=O)(OC)OC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 12.7 %

Procedure:
Dimethyl 4-aminobenzylphosphonate (21.5 g) and then paraformaldehyde (80%, 5.3 g) were added at room temperature to a solution of sodium metboxide in methanol (prepared from 27 g of sodium and 250 ml of methanol). After this mixture was stirred at room temperature for 15 hours, sodium borohydride (3.8 g) was added, and the mixture was heated for 1.5 hours while refluxing. The reaction mixture was concentrated under reduced pressure and then the residue was treated with 1NKOH (500 ml) and extracted with chloroform. The chloroform layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-chloroform-methanol (25:25:1, v/v) to yield dimethyl 4-methylaminobenzylphosphonate (2.9 g, 13%) as an oily subsatance. NMR(δ ppm in CDCl3): 2.55(1H,broad s), 2.82(3H,s), 3.07(2H,d,J=21 Hz), 3.63(3H,s), 3.69(3H,s), 6.57(2H,dd,J=9&1 Hz), 7.11(2H,dd,J=9&3 Hz)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N+:9]([O-])[C:10]3[C:15]([C:16]=2[N+:17]([O-:19])=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.N1C=CC=CC=1.C(OC(=O)C)(=[O:29])C>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8](=[O:29])[NH:9][C:10]3[C:15]([C:16]=2[N+:17]([O-:19])=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1c(N2CCOCC2)c[n+]([O-])c2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=c1[nH]c2ccccc2c([N+](=O)[O-])c1N1CCOCC1

Procedure:
The 3-morpholino-4-nitroquinoline-N-oxide (4 g, 0.015 mol) obtained in Example 5-(b) was dissolved in acetic anhydride (20 ml) and pyridine (20 ml) and the solution was heated on an oil bath at 80° C. for 3 hours. Excess acetic anhydride and pyridine were distilled off from the whole reaction mixture in vacuum and the residue was washed with ether to obtain 3-morpholino-4-nitro-2-quinolone in an amount of 3.5 g (yield, 88%),
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([OH:16])[C@@H:11]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CS(O[CH2:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([N:39]2[C:43]([CH3:44])=[N:42][N:41]=[N:40]2)[CH:30]=1)(=O)=O.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([O:16][CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[C:31]([N:39]3[C:43]([CH3:44])=[N:42][N:41]=[N:40]3)[CH:30]=2)[C@@H:11]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@@H]1c1ccccc1
Reactant: Cc1nnnn1-c1cc(COS(C)(=O)=O)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nnnn1-c1cc(CO[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 24 mg, 0.6 mmol) was added to a stirred, cooled (0° C.) solution of [2S,3S]-1-tert-butoxycarbonyl-2-phenylpiperidin-3-ol (138 mg, 0.5 mmol) in N,N-dimethylformamide (2 ml). The mixture was stirred at room temperature for 30 minutes, cooled in ice and 1-(methanesulfonyloxymethyl)-3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)benzene (168 mg, 0.5 mmol) in N,N-dimethylformamide (2 ml) was added. The mixture was stirred at room temperature for 66 hours, saturated aqueous sodium hydrogen carbonate (20 ml) and water (10 ml) were added and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic fractions were washed with saturated aqueous sodium hydrogen carbonate (4×20 ml) and brine (20 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by MPLC on silica gel, eluting with ethyl acetate/hexane (40:60 increasing to 60:40) to give [2S,3S]-1-tert-butoxycarbonyl-2-phenyl-3-[3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine as a pale yellow oil (133 mg, 51%), 1H (CDCl3) δ 7.69 (1H, s), 7.65 (1H, s), 7.52 (3H, m), 7.31-7.19 (3H, m), 5.68 (1H, br s), 4.77 (2H, s), 3.92 (2H, m), 2.78 (1H, m), 2.58 (3H, s), 2.00 (2H, m), 1.66 (2H, m), and 1.45 (9H, s). m/z 518 (M+H+).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]4[CH2:30][CH2:29][N:28]([CH2:31][CH3:32])[CH2:27][CH2:26]4)=[CH:21][N:20]=3)[C:15](=[O:33])[N:14]([CH3:34])[N:13]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:35]1[N:44]=[CH:43][C:42]2[C:37](=[C:38]([F:49])[CH:39]=[C:40]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH:41]=2)[C:36]1=[O:50])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:45]([C:40]1[CH:41]=[C:42]2[C:37](=[C:38]([F:49])[CH:39]=1)[C:36](=[O:50])[N:35]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[N:20]=[CH:21][C:22]([CH:25]5[CH2:30][CH2:29][N:28]([CH2:31][CH3:32])[CH2:27][CH2:26]5)=[CH:23][CH:24]=4)[C:15](=[O:33])[N:14]([CH3:34])[N:13]=3)[C:6]=1[CH2:5][OH:4])[N:44]=[CH:43]2)([CH3:46])([CH3:47])[CH3:48]
Reactant: CCN1CCC(c2ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4COC(C)=O)nn(C)c3=O)nc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCN1CCC(c2ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)nn(C)c3=O)nc2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(1-ethylpiperidin-4-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate (147 mg, 216 μmol, Eq: 1.00) in MeOH (15 ml) was added potassium carbonate (59.8 mg, 432 μmol, Eq: 2.0). The reaction mixture stirred at 40° C. for 1 h. The solution was cooled to room temperature. Concentrated in vacuo. The residue was taken up in DCM/water and the layers were separated. The aqueous layer was extracted once with DCM. The organic layers were combined, and then dried over Na2SO4. Concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 25% to 75% (60:10:1 DCM:MeOH:NH4OH)/DCM gradient) to give 6-tert-butyl-2-{3-[5-(1′-ethyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one (108 mg, 78%). LC/MS-ESI observed [M+H]+ 638. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16 (br. s., 2H) 1.43 (s, 9H) 1.84 (br. s., 4H) 2.06 (br. s., 2H) 2.51 (br. s., 3H) 3.11 (br. s., 2H) 3.69-4.09 (m and overlapping singlet, 4H) 4.42 (d, J=6.80 Hz, 2H) 6.91 (d, J=8.69 Hz, 1H) 7.37-7.77 (m, 6H) 8.11-8.36 (m, 3H) 8.60 (s, 1H)