Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][C:40]=2[CH3:41])[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][C:40]=2[CH3:41])[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccncc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: Cc1ccncc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K30) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (276 mg, 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([O-])=[C:5](C)[C:4]=1[N+:11]([O-:13])=[O:12].[C:14](=[O:17])([O-])[O-:15].[K+].[K+].[Mn]([O-])(=O)(=O)=O.[K+]>C(OC(=O)C)(=O)C.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:14]([OH:15])=[O:17])[C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: COc1cc[n+]([O-])c(C)c1[N+](=O)[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: COc1ccnc(C(=O)O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Methoxy-2-methyl-3-nitropyridine-N-oxide (mixture with the positional isomer, 10.97 g, 48.5 mmol) was stirred in acetic anhydride (100 mL) at 80° C. for 8 hours. The reaction solution was concentrated under reduced pressure, and in methanol (100 mL), potassium carbonate (33 g, 0.243 mol) was added to the resulting residue at room temperature and stirred at that temperature for 2 hours. The solvent was evaporated off under reduced pressure, and the resulting residue was diluted with ethyl acetate, and washed with water. The resulting organic layer was dried with magnesium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was suspended in water (100 mL), and potassium permanganate (23 g, 0.145 mol) was added thereto at room temperature. The reaction solution was stirred at 90° C. for 16 hours, then potassium permanganate (20 g, 0.126 mol) was added thereto and stirred at 90° C. for 3 hours. The reaction solution was cooled to room temperature, methanol was added thereto, and stirred at room temperature for 2 hours. The reaction liquid was filtered, concentrated, and 2 N hydrochloric acid was added to the resulting residue, and the solution was controlled to have a pH of 2. The reaction solution was stirred at 0° C. for 1 hour, then the resulting milky white solid was taken out through filtration and dried to obtain the intended compound (1.35 g, 3 steps, 14%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([O:47]CC2C=CC=CC=2)[C@@H:15]([N:32](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([O:24]CC3C=CC=CC=3)[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:55][CH2:56][C:57]([F:60])([F:59])[F:58])[C@@H:9]1[CH3:61])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(C)(C)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:47])[C@@H:15]([NH2:32])[CH2:16][C:17]2[CH:18]=[C:19]([OH:24])[CH:20]=[C:21]([F:23])[CH:22]=2)[CH2:12][O:11][C@@H:10]([O:55][CH2:56][C:57]([F:60])([F:58])[F:59])[C@@H:9]1[CH3:61])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1[C@H](OCC(F)(F)F)OC[C@H]([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(OCc3ccccc3)c2)N(Cc2ccccc2)Cc2ccccc2)N1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: C[C@H]1[C@H](OCC(F)(F)F)OC[C@H]([C@@H](O)[C@@H](N)Cc2cc(O)cc(F)c2)N1C(=O)OC(C)(C)C
Yield: 115.6 %

Procedure:
Add 20% palladium hydroxide on carbon (200 mg) to a solution of (2S,3S,5R)-5-[(1S,2S)-1-benzyloxy-3-(3-benzyloxy-5-fluoro-phenyl)-2-dibenzylamino-propyl]-3-methyl-2-(2,2,2-trifluoro-ethoxy)-morpholine-4-carboxylic acid tert-butyl ester (116 mg, 0.138 mmol) in tert-butanol (10 mL). Heat to 45° C. and hydrogenate at 50 psi hydrogen gas for 18 hours. Filter and evaporate to give the desired compound (77 mg). MS(ESI): m/z=483 [M+H]+.
Reaction SMILES: [CH2:1]([C@@:4]1([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].Br[C:36]1[S:37][CH:38]=[CH:39][N:40]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].C1COCC1>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C@@:4]1([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:36]3[S:37][CH:38]=[CH:39][N:40]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: Brc1nccs1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3nccs3)cc2)C(=O)O1
Temperature: 140 °C
Yield: 33 %

Procedure:
(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (20 mg, 0.043 mmol), 2-bromothiazole (14 mg, 2 equiv), 2M aq Na2SO4 solution (0.5 mL) and Pd(PPh3)2Cl2 were mixed with THF (0.6 mL) and heated in a microwave oven for 2 h at 140° C. LC-MS found reaction completed. The mixture was diluted with EtOAc (8 mL), washed with water (2 mL), 1% aq HCl (2 mL) and brine (1.5 mL). After concentration, the residue was purified by preparative HPLC to afford (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(thiazol-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (6.0 mg, 33%). LC-MS (3 min) tR=1.86 min, m/z=423 (M+1).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C@H:5]1[CH2:9][N:8]([CH2:10][C:11](=[O:22])[NH:12][C:13]2[S:14][C:15]3[CH2:16][CH2:17][CH2:18][NH:19][C:20]=3[N:21]=2)[CH2:7][C@@H:6]1[NH:23][C:24]([C:26]1[S:27][C:28]([Cl:31])=[CH:29][CH:30]=1)=[O:25].Br[CH2:33][CH:34]1[CH2:36][CH2:35]1>>[CH:34]1([CH2:33][CH:18]2[CH2:17][CH2:16][C:15]3[S:14][C:13]([NH:12][C:11]([CH2:10][N:8]4[CH2:9][C@H:5]([O:4][CH3:3])[C@@H:6]([NH:23][C:24]([C:26]5[S:27][C:28]([Cl:31])=[CH:29][CH:30]=5)=[O:25])[CH2:7]4)=[O:22])=[N:21][C:20]=3[NH:19]2)[CH2:36][CH2:35]1
Reactant: BrCC1CC1
Reactant: CO[C@H]1CN(CC(=O)Nc2nc3c(s2)CCCN3)C[C@@H]1NC(=O)c1ccc(Cl)s1
Agent: Cl
Product: CO[C@H]1CN(CC(=O)Nc2nc3c(s2)CCC(CC2CC2)N3)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
In analogy to example 94.3 5-chloro-thiophene-2-carboxylic acid {(3S,4S)-4-methoxy-1-[(4,5,6,7-tetrahydro-thiazolo[5,4]pyridin-2-ylcarbamoyl)-methyl]-pyrrolidin-3-yl}-amide dihydrochloride (example 94.2) was reacted with 1-(bromomethyl)cyclopropane to give 5-chloro-thiophene-2-carboxylic acid {(3S,4S)-1-[(5-cyclopropylmethyl-4,5,6,7-tetrahydro-thiazolo[5,4]pyridin-2-ylcarbamoyl)-methyl]-4-methoxy-pyrrolidin-3-yl}-amide. Yellow solid. MS 510.5 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH:5]([CH:8]=O)[CH2:4][CH2:3]1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH:5]([CH2:8][NH:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(C=O)CC1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)CCC(CNCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4,4-dimethylcyclohexanecarbaldehyde (6.6 g, 0.047 mol), benzylamine (5.0 g, 0.047 mol) and acetic acid (1 mL) in methanol (60 mL) was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (10.0 g, 0.047 mol) was added in one portion and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated in vacuo and partitioned between dichloromethane and water. The organic phase was washed with brine, silica gel was added and the mixture was concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2/MeOH), affording [(4,4-dimethyl cyclohexyl)methyl](phenylmethyl)amine as a white solid. (M+H) 232, 1.76 min. (LC/MS method B).
Reaction SMILES: [Na].[F:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:18][C:19]([OH:21])=O)[N:13]([CH3:17])[C:14](=[O:16])[CH:15]=2)[CH2:5]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26]>>[F:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:18][C:19]([NH:26][C:25]3[CH:27]=[CH:28][C:29]([F:30])=[C:23]([Cl:22])[CH:24]=3)=[O:21])[N:13]([CH3:17])[C:14](=[O:16])[CH:15]=2)[CH2:5]1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cn1c(CC(=O)O)nc(N2CCOC(CF)C2)cc1=O
Agent: [Na]
Product: Cn1c(CC(=O)Nc2ccc(F)c(Cl)c2)nc(N2CCOC(CF)C2)cc1=O

Procedure:
The product is prepared by following the procedure described in step 3b of example 1b, but using 250 mg of the sodium salt of [4-(2-fluoromethylmorpholin-4-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid and 237 mg of 3-chloro-4-fluoroaniline. 97 mg of 2-[4-(2-fluoromethylmorpholin-4-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]-N-(3-chloro-4-fluorophenyl)acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([NH:16][CH2:17][CH:18]=[O:19])[CH:14]=[CH2:15]>C1C=CC=CC=1>[CH2:13]([N:16]([CH2:17][CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]=1)=[O:12])[CH:14]=[CH2:15]
Reactant: CC(C)(C)c1nnc(N=C=O)s1
Reactant: C=CCNCC=O
Solvent: c1ccccc1
Product: C=CCN(CC=O)C(=O)Nc1nnc(C(C)(C)C)s1

Procedure:
A mixture of 5-t-butyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-allylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-allyl-3-(5-t-butyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: ClC1C=CC(C([O:8][C:9]2[CH:18]3[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:12][C:11](=[O:19])[CH:10]=2)=O)=C([N+]([O-])=O)C=1.[Cl:25][C:26]1[CH:45]=[CH:44][C:29]([C:30](OC2CC3C(CCCC3)C(=O)C=2)=[O:31])=[C:28]([N+:46]([O-:48])=[O:47])[CH:27]=1.C(N(CC)CC)C.CC(C)(O)C#N>C(#N)C>[Cl:25][C:26]1[CH:45]=[CH:44][C:29]([C:30]([CH:10]2[C:11](=[O:19])[CH2:12][CH:13]3[CH:18]([CH2:17][CH2:16][CH2:15][CH2:14]3)[C:9]2=[O:8])=[O:31])=[C:28]([N+:46]([O-:48])=[O:47])[CH:27]=1
Reactant: O=C(OC1=CC(=O)C2CCCCC2C1)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=C1C=C(OC(=O)c2ccc(Cl)cc2[N+](=O)[O-])C2CCCCC2C1
Agent: CC(C)(O)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CC2CCCCC2C(=O)C1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(4-chloro-2-nitrobenzoyloxy)-4a,5,6,7, 8,8a-hexahydro-3(4H)-naphthalenone and 3-(4-chloro-2-nitrobenzoyloxy)-4a,5,6,7,8,8a-hexahydro-l(4H)-naphthalenone (17.75 g, 50.6 mmol) in 100 ml of acetonitrile is added triethylamine (14.1 ml). Acetone cyanohydrin (2.5 ml) is added and the mixture is stirred overnight at RT. The solvent is removed under vacuum and the residue is dissolved in ether. The solution is washed with 2N HCl, separated and the organic layer is dried. The crude product is purified by chromatography to give 2-(4-chloro-2-nitrobenzoyl)-4a,5,6,7, 8,8a-hexahydro-1,3-(2H,4H)-naphthalenedione, a pure white crystalline solid (compound 1), m.p. 112°.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[I:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([CH3:23])=[C:17](/[CH:19]=[CH:20]/[C:21]#[N:22])[N:18]=2)[CH:15]=1>CN(C=O)C>[I:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([CH3:23])=[C:17]([CH:19]3[CH2:4][CH:20]3[C:21]#[N:22])[N:18]=2)[CH:15]=1
Reactant: Cc1c(/C=C/C#N)nc2ccc(I)cn12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C2CC2C#N)nc2ccc(I)cn12
Reaction time: 3 h
Yield: 6.4 %

Procedure:
To a stirred suspension of NaH (60% in oil, 270 mg) in DMF (5 ml) was added trimethylsulfoxonium iodide (1.37 g) at room temperature, and the mixture was stirred for 3 h. A solution of (2E)-3-(6-iodo-3-methylimidazo[1,2-a]pyridin-2-yl)prop-2-enenitrile (600 mg) in DMF (1 ml) was added, and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (hexane/EtOAc) followed by preparative HPLC to afford the title compound (40 mg) as an off-white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][NH2:15].[BH4-].[Na+]>CO.ClCCl>[C:4]([O:3][C:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:15][CH3:14])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CNC1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 1-N-BOC-3-pyrrolidinone (3.0 g) in methanol (30 ml) was added a solution of freshly prepared methylamine (0.75 g) in methanol (3.1 ml). The reaction mixture was stirred for 1 hour and then sodium borohydride (0.61 g) was added. After stirring for 4 hours the reaction mixture was then diluted with dichloromethane, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo to give 3-methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester (3.18 g).
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:28]C)[C:8]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1P(C1CCCCC1)C1CCCCC1.[OH-:30].[K+]>>[CH3:6][CH2:7]/[CH:8]=[CH:3]/[CH:4]=[CH:5]/[CH:14]=[CH:13]/[CH:12]=[CH:11]/[CH2:10][CH2:9][CH2:8][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:28])=[O:30]
Reactant: [OH-]
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [K+]
Product: CC/C=C/C=C/C=C/C=C/CCCCCCCC(=O)O

Procedure:
The machine was equipped with a deprotection tube (empty, but used for sparging the MIDA boronate solution) and a reaction tube charged with the Pd-mixture (60 mg), the SPhos-mixture (60 mg), KOH (75 mg, 1.7 mmol) and halide 3 (11 mg, 0.037 mmol).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([OH:23])[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[C:6](=[O:24])[C:5]([C:25](O)=[O:26])=[CH:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:61]1([CH2:66][CH2:67][NH2:68])[CH2:65][CH2:64][CH2:63][CH2:62]1>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([OH:23])[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[C:6](=[O:24])[C:5]([C:25]([NH:68][CH2:67][CH2:66][N:61]2[CH2:65][CH2:64][CH2:63][CH2:62]2)=[O:26])=[CH:4]1)[CH3:2]
Reactant: NCCN1CCCC1
Reactant: CCn1cc(C(=O)O)c(=O)c2c(O)c(OCc3ccc(OC)cc3)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)NCCN2CCCC2)c(=O)c2c(O)c(OCc3ccc(OC)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To a solution of 1-ethyl-5-hydroxy-6-((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (1.4 g, 3.79 mmol) in N,N-Dimethylformamide (DMF) (30 mL) was added HATU (1.729 g, 4.55 mmol) and DIPEA (1.655 mL, 9.48 mmol), the resulting mixture was stirred at r.t. for 30 min. Then 2-(pyrrolidin-1-yl)ethanamine (0.656 mL, 4.17 mmol) was added and the resulting mixture was stirred at r.t. for 3 h. The reaction mixture was concentrated and the residue was dissolved in DCM and washed with water, sat. NaHCO3 (aq.) and brine. The organic layer was separated and concentrated, the residue was purified by normal phase silica gel chromatography (CombiFlash), eluting with MeOH/DCM (0-20%) to afford 1-ethyl-5-hydroxy-6-((4-methoxybenzyl)oxy)-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide (1 g, 2.148 mmol, 56.7% yield) as a yellow solid. LCMS: (M+H)+: 466.3.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH3:17])[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:24]([O-])([N+]([O-])=O)=[O:25]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:24]=[O:25])[C:5]([N:7]([CH3:17])[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 70.2 %

Procedure:
2.7 g of 1-(2-chloroethyl)-3-methyl-3-D-ribofuranosylurea are dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.1 g of 1-(2-chloroethyl)-1-nitroso-3-methyl-3-ribofuranosylurea are thereby obtained as a yellow powder.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.Cl.Cl[CH2:14][C:15]1[C:16]([C:21]2[N:25]([CH:26]([CH3:28])[CH3:27])[N:24]=[CH:23][CH:22]=2)=[N:17][CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:26]([N:25]1[C:21]([C:16]2[C:15]([CH2:14][O:1][C:2]3[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:22][CH:23]=[N:24]1)([CH3:28])[CH3:27]
Reactant: CC(C)n1nccc1-c1ncccc1CCl
Reactant: COc1cc(C=O)c(O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(OCc2cccnc2-c2ccnn2C(C)C)cn1
Temperature: 70 °C
Yield: 64.9 %

Procedure:
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (395 mg, 2.58 mmol, 1 eq.), 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (700 mg, 2.58 mmol, 1 eq.), and K2CO3 (1.4 g, 10.32 mmol, 4 eq.) in DMF (10.0 mL) was heated at 70° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (590 mg, 65%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 8.76 (dd, J=4.7, 1.6 Hz, 1H), 8.04 (dd, J=7.9, 1.6 Hz, 1H), 7.90 (s, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.44 (dd, J=7.9, 4.8 Hz, 1H), 7.10 (s, 1H), 6.37 (d, J=1.8 Hz, 1H), 5.14 (s, 2H), 4.65 (sep, J=6.6 Hz, 1H), 3.91 (s, 3H), 1.49 (d, J=6.6 Hz, 6H); MS (ESI) m/z 353.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:34])[CH2:16][C:17](=[O:33])[N:18]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>C1C=CC=CC=1>[CH2:12]([O:14][C:15](=[O:34])[CH2:16][C:17](=[O:33])[N:18]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[CH:28][CH:27]=1)[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH3:13]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CC(=O)N(CCC(=O)OC)Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)CC(=O)N(CCC(=O)OC)Cc1ccc(NC(=O)OCc2ccccc2)cc1
Yield: 94.2 %

Procedure:
A solution of benzyloxycarbonyl chloride (539 mg) in benzene (1.5 ml) is added dropwise to a mixture of ethyl[N-(p-aminobenzyl)-N-(methoxycarbonylethyl)carbamoyl]acetate (810 mg), potassium carbonate (595 mg), benzene (10 ml) and water (10 ml) at a temperature of 8° C. under stirring. The mixture is stirred at the same temperature for 30 minutes. The mixture is extracted with ethyl acetate, and the extract is washed with water, dried and then distilled to remove the solvent. The residue is purified by silica gel column chromatography (solvent, ethyl acetate:benzene=3:7) to give ethyl[N-(p-(N-benzyloxycarbonylamino)benzyl)-N-(methoxycarbonylethyl)carbamoyl]acetate (1.08 g, 94.2%) as colorless oil.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[NH:20][C:19](=[O:21])[C@H:18]([CH:22]([CH3:24])[CH3:23])[NH:17][C:16](=[O:25])[C@@H:15]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH2:14][C:13]2=[CH:37][CH:38]=[C:10]([CH:11]=[CH:12]2)[O:9][CH2:8][CH2:7][CH2:6]1)=O.CC(C[AlH]CC(C)C)C.CCOC(C)=O>C(Cl)Cl>[F:36][C:33]1[CH:34]=[CH:35][C:30]([S:27]([NH:26][C@H:15]2[CH2:14][C:13]3=[CH:12][CH:11]=[C:10]([CH:38]=[CH:37]3)[O:9][CH2:8][CH2:7][CH2:6][C@@H:5]([CH:3]=[O:2])[NH:20][C:19](=[O:21])[C@H:18]([CH:22]([CH3:23])[CH3:24])[NH:17][C:16]2=[O:25])(=[O:28])=[O:29])=[CH:31][CH:32]=1
Reactant: COC(=O)[C@@H]1CCCOc2ccc(cc2)C[C@H](NS(=O)(=O)c2ccc(F)cc2)C(=O)N[C@@H](C(C)C)C(=O)N1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]1NC(=O)[C@@H](NS(=O)(=O)c2ccc(F)cc2)Cc2ccc(cc2)OCCC[C@@H](C=O)NC1=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Ester 68 (39 mg) was dissolved in DCM (6 mL) under an atmosphere of argon. The reaction was cooled to −78° C. To the resultant solution DIBAL (0.39 mL) was added dropwise. This was stirred for 2 h before being allowed to warm to rt overnight. The reaction mixture was partitioned between EtOAc and 1M hydrochloric acid. The aqueous phase was extracted again with EtOAc and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification was achieved using flash chromatography, eluting with a gradient of 1/1 EtOAc/(50/70) petroleum ether to EtOAc to yield a light brown solid, 15 mg, 40%. Rf=0.25 (1/1 EtOAc/(50/70) petroleum ether).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.O[Li].O.Cl>C1COCC1.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:21][CH:22]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(C#Cc2ccc(O)cc2)cc1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc(C#Cc2ccc(O)cc2)cc1
Reaction time: 2 h

Procedure:
Ethyl 2-(4-((4-hydroxyphenyl)ethynyl)phenoxy)acetate (39.9 mg, 0.135 mmol) was dissolved in THF (1.5 mL) and LiOH.H2O (17.0 mg, 0.405 mmol) in water (1 mL) was added. The mixture was stirred for 2 h. and 14% HCl (0.2 mL) was added until pH<1. Water (10 mL) was added, and the mixture was extracted with EtOAc (3×10 mL). The combined EtOAc phases was washed with brine (10 mL), dried over MgSO4, and concentrated under reduced pressure. The product was white/yellow and solid (35.7 mg, 97%) Rf=0.01 (EtOAc:hexanes 1:1 v/v). 1H-NMR (DMSO-d6):□ 4.71 (s, 2H, OCH2); 6.78 (d, 2H, J=8.7 Hz, Ph); 6.93 (d, 2H, J=8.7 Hz, Ph); 7.33 (d, 2H, J=8.1 Hz, Ph); 7.43 (d, 2H, J=8.4 Hz, Ph); 9.87 (s, 1H, OH); 13.00 (s, 1H, COOH). 13C-NMR (DMSO-d6):□ 64.5 (OCH2); 87.2 (CC); 88.6 (CC); 112.8, 114.8, 115.4, 115.7, 132.5, 132.8, 157.6, 157.8 (Ph); 170.0 (COO). MALDI-MS: m/z calculated for C16H12O3 [M]+ 268.0730. found 268.0739.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S(=O)(=O)(O)O.[CH3:19][CH2:20]O>>[CH2:19]([O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=1)[CH3:20]
Reactant: COc1ccc(CC(=O)O)cc1O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(OC)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-hydroxy-4-methoxyphenylacetic acid (5.0 g, 23.8 mmol) in EtOH (100 mL) was added sulfuric acid (1 mL), and the reaction was stirred overnight at room temperature. Once no starting material was seen by analytical tlc, the mixture was concentrated to give the desired product.