Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[CH:22]=[CH:23]/[C:24](O)=[O:25])[CH:17]=3)[O:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:41][O:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][O:44]1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2([CH2:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[CH:22]=[CH:23]/[C:24]([NH:41][O:42][CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][O:44]4)=[O:25])[CH:17]=3)[O:12]2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.7 %

Procedure:
TEA (0.25 ml, 1.8 mmol) was added to a suspension of (E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (430 mg, 1.20 mmol) in DCM (13 ml) and the reaction mixture was stirred at RT for 5 min. The resulting clear solution was cooled down to 0° C., EDC (344 mg, 1.80 mmol) and HOBt (243 mg, 1.80 mmol) were added and the mixture was stirred at 0° C. for 2 h. NH2OTHP (168 mg, 1.43 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was washed with 5% aqueous NaHCO3 solution and brine, the organic layer was dried over Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography on silica gel (eluent: DCM/MeOH 98:2) to give (E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (0.40 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16](Br)=[CH:17][CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])[CH:5]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>COCCOC.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>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(Br)ccc23)c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(-c4ccccc4)ccc23)c1
Temperature: 90 °C

Procedure:
3-(1-Benzyl-6-bromo-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.080 g, 0.17 mmol), phenylboronic acid (0.042 g, 0.34 mmol), NaHCO3 (0.073 g, 0.85 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.012 g, 0.02 mmol) were suspended in DME:H2O (1:1, 3 mL) and the reaction vessel was purged with N2 (g). The reaction was heated to 90° C. and after two hours the mixture was submitted to aqueous workup then purified by silica gel chromatography (0-30% EtOAc in hexanes) to give the title compound.
Reaction SMILES: CCCCCC.[S:7]1[CH:11]=[CH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]1=2.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH:24]=1)[CH:22]=[O:23].[Cl-].[NH4+]>O1CCCC1>[S:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[C:11]1[CH:22]([C:21]1[CH:24]=[C:17]([Br:16])[CH:18]=[CH:19][C:20]=1[O:25][CH3:26])[OH:23]
Reactant: COc1ccc(Br)cc1C=O
Reactant: c1ccc2sccc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(Br)cc1C(O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
1.6 M n-butylithium hexane solution (30.5 mL) was added to a mixture of benzo[b]thiophene (6.6 g, 0.049 mol) and tetrahydrofuran (66 mL) at −78° C. After stirred for 0.5 hours, the reaction mixture was added with a tetrahydrofuran (50 mL) solution of 5-bromo-2-methoxybenzaldehyde (10.0 g, 0.047 mol), further stirred for five minutes and warmed to room temperature. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to obtain pale yellow crystal (1-benzothien-2-yl)(5-bromo-2-methoxyphenyl)methanol (11.3 g, 69%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:17]1[O:27][C:20]2([CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[O:19][CH2:18]1>C1COCC1.CCOCC>[CH3:10][N:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([C:23]2([OH:26])[CH2:24][CH2:25][C:20]3([O:27][CH2:17][CH2:18][O:19]3)[CH2:21][CH2:22]2)=[N:7][CH:6]=1)[CH3:11]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CN(C)Cc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(C2(O)CCC3(CC2)OCCO3)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
1-(6-Bromopyridin-3-yl)-N,N-dimethylmethanamine (1.15 g, 5.4 mmol) was dissolved in 30 mL of THF and 80 mL of anhydrous ether. After the solution was cooled to −78° C., 2.60 mL of n-butyllithium (2.5 M, 6.40 mmol) was slowly dropped through a syringe in 10 min. After being stirred at −78° C. for 30 minutes, 1,4-cyclohexanedione mono-ethylene ketal (1.01 g, 6.4 mmol) was added. The reaction mixture was allowed to warm up to room temperature during two hours and then quenched by addition of 10 mL of water. The mixture was extracted twice using EtOAc. The combined extracts were dried and concentrated. After flash column using 20-40% methanol in EtOAc and 0.5% NH4OH, 0.85 g oil was obtained (54% yield), MS: (M+H)+ 293.2.0.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[NH:11][C:10](=[O:13])[C:9]3=[C:14]([CH3:19])[N:15]=[C:16]([CH2:17][CH3:18])[N:8]3[C:7]=2[N:6]=[C:5](S(C)(=O)=O)[N:4]=1)[CH3:2].[NH2:24][CH2:25][CH:26]([OH:29])[CH2:27][OH:28]>CN1CCCC1=O>[OH:29][CH:26]([CH2:27][OH:28])[CH2:25][NH:24][C:5]1[N:4]=[C:3]([CH2:1][CH3:2])[C:12]2[NH:11][C:10](=[O:13])[C:9]3=[C:14]([CH3:19])[N:15]=[C:16]([CH2:17][CH3:18])[N:8]3[C:7]=2[N:6]=1
Reactant: CCc1nc(S(C)(=O)=O)nc2c1[nH]c(=O)c1c(C)nc(CC)n12
Reactant: NCC(O)CO
Solvent: CN1CCCC1=O
Product: CCc1nc(NCC(O)CO)nc2c1[nH]c(=O)c1c(C)nc(CC)n12

Procedure:
Prepared by the treatment of the product of Example 41b with 10 eq. of 3-amino-1,2-propanediol in N-methylpyrrolidinone at 100° C. for 18 hours. The mixture was poured on water to precipitate the product. The solids were filtered, washed with water, and then acetonitrile, to provide the title compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[N:13]=[CH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22](O)=[O:23])=[CH:17][C:16]=4[CH3:25])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:57]([NH2:64])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>CC(N(C)C)=O>[CH2:57]([NH:64][C:22]([C:18]1[CH:19]=[C:20]2[C:15](=[C:16]([CH3:25])[CH:17]=1)[CH:14]=[N:13][C:12]([NH:11][CH:8]1[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]1)=[CH:21]2)=[O:23])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: Cc1cc(C(=O)O)cc2cc(NC3CCC4(CC3)OCCO4)ncc12
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)NCc2ccccc2)cc2cc(NC3CCC4(CC3)OCCO4)ncc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
3-(1,4-Dioxa-spiro[4.5]dec-8-ylamino)-8-methyl-isoquinoline-6-carboxylic acid (100.0 mg, 0.29 mmol) in 5 ml DMA was treated with a HATU (240.0 mg, 0.63 mmol) and triethylamine (192.0 mg, 1.89 mmol) for 1 hour at room temperature. After 1 hour, benzylamine (74.5 mg, 0.69 mmol) was added and the mixture was heated to 50° C. for 2 hours. The reaction was completed by LC/MS monitoring. The solvent DMA was evaporated under vacuum, and the crude was dissolved in CH2Cl2 and washed with NaHCO3 aqueous (10%) to remove the by-products from HATU. The crude residue was purified by a silica gel column to give 119.0 mg (94.4%). 1H NMR (400 MHz, CHLOROFORM-d) ppm 1.59-1.75 (m, 2H), 1.78-1.95 (m, 4H), 2.01-2.12 (m, 2H), 2.64 (s, 3H), 3.39-3.55 (m, J=4.28 Hz, 1H), 3.91-4.04 (m, 4H), 4.69 (d, J=5.54 Hz, 2H, 6.62 (s, 1H), 6.94 (s, 1H), 7.34-7.46 (m, 5H), 7.87 (s, 1H), 8.85 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[CH:23]([CH3:25])[CH3:24].[CH2:26]([N:28]1[C:33](=[O:34])[N:32]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:31](=[O:42])[C:30]([C:43](O)=[O:44])=[N:29]1)[CH3:27]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:43]([C:30]2[C:31](=[O:42])[N:32]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:33](=[O:34])[N:28]([CH2:26][CH3:27])[N:29]=2)=[O:44])=[CH:18][C:17]=1[CH:23]([CH3:25])[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C(C)C)c2cc1OC
Reactant: CCn1nc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: CCn1nc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C(C)C)c2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-dimethoxy-quinolin-4-yloxy)-3-isopropyl-phenylamine and 2-ethyl-4-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid using the procedure for example 1. mp=155-156° C.; LCMS m/z=600 (M+1); 1H NMR (CDCl3) δ: 10.78 (s, 1H), 8.47 (d, 1H, J=5.5 Hz). 7.72 (s, 1H), 7.66 (d, 1H, J=8 Hz), 7.59 (s, 1H), 7.43 (s, 1H), 7.31-7.24 (m, 3H), 7.07 (d, 1H, J=9 Hz), 6.35 (d, 1H, J=6 Hz), 4.34 (q, 2H, J=7.3 Hz), 4.05 (s, 6H), 3.11 (m, 1H), 1.58 (t, 3H, J=6 Hz), 1.19 (d, 6H, J=7 Hz).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])[CH3:3].C[O-].[Na+].[CH:16]12[O:21][CH:17]1[CH2:18][CH2:19][CH2:20]2.Cl>CO.[Cl-].[Na+].O.O>[CH3:1][C:2]([C:7]1[CH:8]=[C:9]([S:11][C@@H:20]2[CH2:19][CH2:18][CH2:17][C@H:16]2[OH:21])[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[OH:12])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(S)ccc1O
Reactant: C1CC2OC2C1
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(S[C@@H]2CCC[C@H]2O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2.6-bis (1,1-Dimethylethyl-4- mercaptophenol (11.5 g, 0.048 mole) was added to a solution of sodium methoxide [prepared from sodium (2.2 g, 0.097 mole)] in methanol (75 ml). After several minutes, cyclopentene oxide (3.86 g, 0.046 mole) was added, and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into water (100 ml) containing saturated brine (50 ml) and 1 N hydrochloric acid (80 ml) . The mixture was extracted twice with 100 ml of diethyl ether. The combined diethyl ether extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil with a rotary evaporator. The product was purified by silica gel chromatography to give the product as a white solid which was recrystallized from hexane (DSC.m.p. 90° C.). The structure was supported by NMR and elemental analysis.
Reaction SMILES: [CH3:1][CH:2]([CH:4](O)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[CH3:3]>ClCCl>[CH3:1][C:2]1([CH3:3])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: Cc1ccc(CCC(O)C(C)C)cc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(C)(C)CCC2
Temperature: 60 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A solution of 2-methyl-5-(p-tolyl)-3-pentanol (74 g, 0.385 mol) in dichloromethane (100 mL) was mixed with polyphosphoric acid (570 g) and the reaction mixture was heated to 60° C. and stirred overnight. After cooling, ice/water was slowly added and the aqueous extracted with dichloromethane. The organic layer was successively washed with water, aq NaHCO4, water and brine, dried (Mg2SO4), filtered and evaporated to give 67 g of 1,1,7-trimethyl-1,2,3,4-tetrahydronaphthalene and used without further purification in the next step (step f). 1H NMR (300 MHz; CDCl3): 1.34 (s, 6 H), 1.69 (m, 2 H), 1.83 (m, 2 H), 2.37 (s, 3 H), 2.78 (m, 2 H), 6.99 (m, 2 H), 7.19 (s, 1 H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])[CH:19]=3)[NH:14][C:13]([CH3:30])([CH3:29])[CH:12]=2)[CH:5]=[C:6](Cl)[CH:7]=1.BrCC1C2C(=CC=C(C3C=CC=CC=3OC)C=2)NC(C)(C)C=1.C(=O)([O-])[O-].[K+].[K+].ClC1C=C(C=C(Cl)C=1)N>>[CH3:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:30])([CH3:29])[CH:12]=[C:11]2[CH2:10][NH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CNc1cc(Cl)cc(Cl)c1)=CC(C)(C)N2
Agent: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: Nc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2
Yield: 71.2 %

Procedure:
(3,5-Dichlorophenyl)-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]amine 2 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 32 mg of potassium carbonate, and 20 mg of 3,5-dichloroaniline reacted to give 1.2 mg of the title compound as a foam.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.S(=O)(=O)(O)O.[CH3:22]O>C(OCC)C>[CH3:22][O:15][C:14]([C:3]1[C:2]([OH:1])=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=2)[CH:4]=1)=[O:16]
Reactant: COc1ccc2cc(O)c(C(=O)O)cc2c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COC(=O)c1cc2cc(OC)ccc2cc1O

Procedure:
To a solution of 3-hydroxy-7-methoxy-naphthalene-2-carboxylic acid (2.5 g, 11.45 mmol) in 50 mL methanol was added 0.3 mL of concentrated sulfuric acid. The resulting mixture was heated at reflux for 18 hours, then cooled and diluted with diethyl ether. The organic phase was washed with water and saturated aqueous sodium bicarbonate, dried (Na2SO4), filtered and concentrated under reduced pressure to give 2.51 g of 3-hydroxy-7-methoxy-naphthalene-2-carboxylic acid methyl ester, MP=129-131° C.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:25])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[C:10]([Cl:20])=[CH:9][C:8]=2[C:21]([F:24])([F:23])[F:22])(=[O:3])[CH3:2].[CH2:26]([NH2:29])[C:27]#[CH:28]>>[C:1]([C:4]1[C:5](=[O:25])[NH:6][C:7]2[C:12]([C:13]=1[NH:29][CH2:26][C:27]#[CH:28])=[CH:11][C:10]([Cl:20])=[CH:9][C:8]=2[C:21]([F:24])([F:23])[F:22])(=[O:3])[CH3:2]
Reactant: C#CCN
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)c(Cl)cc(C(F)(F)F)c2[nH]c1=O
Product: C#CCNc1c(C(C)=O)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)cc12
Yield: 82.9 %

Procedure:
3-Acetyl-6-chloro-4-methylsulfoxy-8-trifluoromethyl-2-quinolinone (351 mg, 1 mmol) and propargylamine (55 mg, 1 mmol) were used and the reaction was carried out as in the above process of example 1 to obtain the desired product (284 mg, yield: 83%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([O:24][CH3:25])[C:11](=[O:23])[N:12]([CH3:22])[C:13]=3[C:17]([O:19]CC)=[O:18])[C:8]2=[O:26])=[CH:4][CH:3]=1.[Li+].[OH-].Cl>CO.O.C1COCC1>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([O:24][CH3:25])[C:11](=[O:23])[N:12]([CH3:22])[C:13]=3[C:17]([OH:19])=[O:18])[C:8]2=[O:26])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c2c(c(OC)c(=O)n1C)C(=O)N(Cc1ccc(F)cc1)CC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1c2c(c(C(=O)O)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Reaction time: 2 h

Procedure:
To a solution of ethyl 6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (1.15 g, 2.96 mmol) in 1:1:1 MeOH/H2O/THF (15 mL) was added LiOH (0.37 g, 8.88 mmol) and the solution was stirred for 2 hours. A solution of 1 N HCl (8.9 mL) was added, the solution was concentrated and CHCl3 and 10% KHSO4 were added. The layers were separated and the aqueous was extracted repeatedly. The combined organic layers were filtered and the solid collected. The remaining organic was dried over Na2SO4, filtered, combined with the collected solid and evaporated to give the crude product.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][N:17]=[CH:18][C:11]=2[N:10]([CH2:19][C:20](=[O:33])[NH:21][C:22]2[CH:27]=[C:26]([Cl:28])[C:25]([O:29][CH3:30])=[CH:24][C:23]=2[O:31][CH3:32])[C:9]1=[O:34])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:28][C:26]1[C:25]([O:29][CH3:30])=[CH:24][C:23]([O:31][CH3:32])=[C:22]([NH:21][C:20]([CH2:19][N:10]2[C:11]3[CH:18]=[N:17][CH:16]=[CH:15][C:12]=3[C:13](=[O:14])[N:8]([CH2:7][C:6]([OH:35])=[O:5])[C:9]2=[O:34])=[O:33])[CH:27]=1
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)OC(C)(C)C)c(=O)c3ccncc32)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)O)c(=O)c3ccncc32)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a vial containing a solution of {1-[(5-Chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-pyrido[3,4-d]pyrimidin-3-yl}-acetic acid tert-butyl ester (Intermediate V) (15 mg, 0.029 mmol) in DCM (1 ml), TFA (1 ml) is added. The mixture is stirred at RT overnight. The reaction mixture is then transferred to a 10 ml round bottomed flask, diluted with a minimal amount of DCM and concentrated in vacuo. This process is repeated once with DCM, twice with EtOAc, and once with MeOH, the solvent being concentrated in vacuo each time, finally giving the title, [M+H]+ 448.93.
Reaction SMILES: [N:1]([C@@H:4]1[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:12]([O:18][C:19](=[O:21])[CH3:20])[C@H:11]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:10][C@@H:5]1[O:6][C:7](=[O:9])[CH3:8])=[N+]=[N-].[CH3:27][C:28](OC(C)=O)=[O:29]>[Pd]>[C:28]([NH:1][C@@H:4]1[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:12]([O:18][C:19](=[O:21])[CH3:20])[C@H:11]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:10][C@@H:5]1[O:6][C:7](=[O:9])[CH3:8])(=[O:29])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)OC[C@@H]1O[C@H](OC(C)=O)[C@H](N=[N+]=[N-])[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Pd]
Product: CC(=O)N[C@H]1[C@@H](OC(C)=O)O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 10 h
Yield: 83 %

Procedure:
A solution of Compound 9 (0.60 g, 1.62 mmol) in Ac2O (20 mL) was hydrogenated over 70 mg of 10 percent palladium on charcoal under atmospheric pressure. After 10 hours, the solution was filtered and the filtrate was concentrated in vacuo. By flash column chromatography with EtOAc-toluene (2.5:1), 0.52 g of Compound 10 was obtained in 83 percent yield. 1H NMR (CDCl3) δ6.03 (1H, d, J1-2=1.5 Hz, H-1), 5.34 (1H, dd, J3-4=10.0 Hz, J3-2=5.0 Hz, H-3), 5.18 (1H, t, J4-5=J4-3=10.0 Hz, H-4), 4.65 (1H, ddd, J5-4=10.0 Hz, J5-6a=5.0 Hz, J5-6b=2.0 Hz, H-5), 4.29 (1H, dd, J6a-6b12.5 Hz, J6a-5b=5 Hz, H-6a), 4.06 (1H, dd, J2-3=5.0 Hz, J2-1=1.5 Hz, H-2), 4.05 (1H, dd, J6b-6a=12.5 Hz, J6b-5=2.0 Hz, H-6b), 2.18 (3H, s, acetyl), 2.10 (3H, s, acetyl), 2.07 (3H, s, acetyl), 2.07 (3H, s, acetyl), 2.01 (3H, s, acetyl). 13C NMR (CDCl3) δ170.4, 170.1, 170.0, 169.6, 168.0, 91.7, 73.4, 70.1, 65.5, 62.1, 49.3, 23.2, 20.8, 20.7, 20.7, 20.6. HRMS (FAB) calcd for C16H23NO10Na (M+Na+) 412.1220, found 412.1224.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]=[C:9]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:19][CH:20]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C:21](OC)=[O:22])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:41]([O:43][CH:44]([O:49][CH2:50][CH3:51])[CH2:45][CH2:46][CH2:47][NH2:48])[CH3:42]>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]=[C:9]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:18])[NH:19][CH:20]([O:25][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:27])[CH3:28])[C:21](=[O:22])[NH:48][CH2:47][CH2:46][CH2:45][CH:44]([O:43][CH2:41][CH3:42])[O:49][CH2:50][CH3:51])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(NC(=O)CCCCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: CCOC(CCCN)OCC
Solvent: c1ccccc1
Product: CCOC(CCCNC(=O)C(NC(=O)CCCCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)OCC
Temperature: 38 °C
Reaction time: 51 h
Yield: 63.3 %

Procedure:
1.80 g (3.06 mmol) of methyl 7-[2,3-bis(t-butoxycarbonyl)-guanidino]heptanoyl-α-t-butyldimethylsilyloxyglycinate and 0.542 g (3.36 mmol) of 4-aminobutyraldehyde diethyl acetal were dissolved in 5.6 ml of benzene and stirred at 38° C. for 51 hours. Then the solvent was distilled off under reduced pressure and the oily substance thus obtained was subjected to column chromatography with the use of Silica gel 60 (mfd by Merck Co. & Inc.). By eluting with chloroform/ethyl acetate (3:2, v/v), 1.39 g of the aimed compound was obtained in the form of an oily product (yield 63.3%).
Reaction SMILES: [Cl-].[CH2:2]1[CH2:12][CH2:11][N:10]2[C:5](=N[CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3]1.[C:13]1(C)[C:14](C)=CC=C[CH:18]=1>>[CH2:11]([N:10]1[CH2:9][CH2:8][CH2:7][CH2:4][CH2:5]1)[C:12]1[CH:2]=[CH:3][CH:14]=[CH:13][CH:18]=1
Reactant: Cc1ccccc1C
Reactant: C1CCC2=NCCCN2CC1
Agent: [Cl-]
Product: c1ccc(CN2CCCCC2)cc1
Temperature: 100 °C
Yield: 60 %

Procedure:
Chloride 12 (23.0 g, 1.0 equiv) was combined with DBU (20.4 g, 2 equiv) in 400 mL xylene and stirred at 100° C. until TLC examination indicated complete reaction (ca. 5 h). The reaction was concentrated to dryness in vacuo. The residue was dissolved in methylene chloride and extracted with water (1×). The organic solvent was removed in vacuo and the residue was flash chromatographed in 10% ethyl acetate/methylene chloride to afford 11.8 g (60%) of 11 as an oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:16]([CH2:24][C:25](=[O:29])C=CC)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]([CH2:14][CH3:15])=[CH:12]C)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC[C@@H]1C=C(C)C(=O)CN1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][C@@H:10]1[C:11]([CH2:14][CH3:15])=[CH:12][C:25](=[O:29])[CH2:24][N:16]1[C:17]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC=CC(=O)CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C(=CC)CC
Agent: CC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC1=O
Product: CCC1=CC(=O)CN(C(=O)OC(C)(C)C)[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 86 °C
Yield: 54.2 %

Procedure:
The title compound was prepared from (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-ethylpent-3-en-2-yl(2-oxopent-3-enyl)carbamate (Intermediate 206, 10.95 g, 25.72 mmol) according to the procedure described for Intermediate 7, except the reaction was heated at 86° C. for 6 days. Silica gel chromatography (0-10% ethyl acetate/hexanes) afforded the title compound (5.15 g, 54.1%) as a light yellow oil.