Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[O:27]=[S:28]1(=[O:47])[CH2:32][CH2:31][CH:30]([N:33]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:35]=[N:34]2)[CH2:29]1.C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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.O>[O:47]=[S:28]1(=[O:27])[CH2:32][CH2:31][CH:30]([N:33]2[CH:37]=[C:36]([C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]5[CH:17]=[C:16]([N:18]6[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]6)[N:15]=[C:14]([NH2:25])[N:13]=5)[CH2:9]4)=[CH:4][CH:3]=3)[CH:35]=[N:34]2)[CH2:29]1
Reactant: CC1(C)OB(c2cnn(C3CCS(=O)(=O)C3)c2)OC1(C)C
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
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: C1COCCO1
Solvent: CO
Solvent: O
Product: CC1Cc2ccc(-c3cnn(C4CCS(=O)(=O)C4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(1,1-dioxidotetrahydro-3-thienyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (12.0 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol) and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling, it was diluted with methanol. The solid was filtered off. The filtrate was purified with RP-HPLC (pH=10) to afford the desired product (2.8 mg). LCMS (M+H)+: m/z=523.3.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:17]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:16]=2)(O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>Cl.C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[C:17]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)CCCN(Cc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C1=C(c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)CN(Cc2ccccc2)CC1
Yield: 52.6 %

Procedure:
A mixture of 1.5 g of the product of Step A in 15 ml of 2N hydrochloric acid was refluxed for 6 hours and after cooling, the mixture was diluted with methylene chloride. The mixture was made alkaline with sodium hydroxide addition and the methylene chloride phase was recovered by decanting, was dried and evaporated to dryness. The residue was chromatographed over silica gel and elution with a 90-5-5 cyclohexane-chloroform-triethylamine mixture yielded 0.76 g of N-benzyl-3-(3',4'-dibenzyloxyphenyl)-1,2,5,6-tetrahydropyridine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:20]([N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])[CH2:19][CH2:18][N:17]=1>>[O:11]=[C:9]1[N:17]2[CH2:18][CH2:19][CH:20]([N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])[C:16]2=[N:15][C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:8]1
Reactant: NC1=NCCC1N1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)CC(=O)c1ccncc1
Product: O=C1c2ccccc2C(=O)N1C1CCn2c1nc(-c1ccncc1)cc2=O

Procedure:
By analogy with the method described in example 1 (step 1.3), using ethyl 3-(4-pyridinyl)-3-oxopropionate (prepared by analogy to the method described in patent DE 2705582) and using 2-(2-amino-4,5-dihydro-3H-pyrrol-3-yl)-isoindole-1,3-dione, the compound was obtained as a white powder.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:43](=[NH:45])[NH2:44])[CH:39]=2)[CH:34]=1)(=O)=O.C(OCC)C>N1C=CC=CC=1>[CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([O:12][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([C:43](=[NH:44])[NH2:45])[CH:39]=3)[CH:34]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCCC1CCCCC1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: N=C(N)c1ccc2cc(OC(=O)CCCC3CCCCC3)ccc2c1
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
To a solution of 3.0 g of 4-cyclohexylbutyric acid in 50 ml of anhydrous pyridine, while being cooled in ice and stirred, was added 4.4 g of DCC. After 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture, and the mixture was stirred for 24 hours at room temeprature. The precipitate which was formed upon addition of ethyl ether was collected by filtration, admixed with dimethylformamide. Ethyl ether was added to the filtrate, and the precipitate was collected by filtration. On recrystallization from a dimethylformamide ethyl ether mixture there were obtained 3.2 g of a white powder of 6-amidino-2-naphthyl 4-cyclohexylbutyrate methanesulfonate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:35]=[CH:34][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:17](=[O:33])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.[CH3:36][C:37]([CH3:39])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][CH:27]3[CH2:28][CH2:29][N:30]([CH:37]([CH3:39])[CH3:36])[CH2:31][CH2:32]3)[C:17](=[O:33])[CH2:16]2)=[O:14])=[CH:34][CH:35]=1
Reactant: O=C(c1ccc(Cl)cc1)N1CC(=O)N(CC2CCNCC2)c2ccccc2C1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N1CCC(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.08 mmol of 4-(4-chlorobenzoyl)-1-(4-piperidinylmethyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on trifluoroacetate obtained in Example 140 and 7 mg (0.12 mmol) of acetone were dissolved in 3 ml of dichloromethane. 12 mg (0.20 mmol) of acetic acid was added to the obtained solution. After stirring at room temperature for 30 minutes. 53 mg (0.25 mmol) of sodium triacetoxyborohydride was added to the obtained mixture, and they were stirred at room temperature overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([OH:25])[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:32]12[O:38][CH:37]1[CH2:36][CH2:35][N:34]([C:39]([O:41][CH2:42][C:43]1[CH:52]=[CH:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:44]=1)=[O:40])[CH2:33]2.[NH4+].[Cl-]>CC(N(C)C)=O.C(Cl)(Cl)Cl>[OH:38][C@H:32]1[C@H:37]([O:25][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[N:16]=[C:15]([C:12]2[N:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]4=[N:14][CH:13]=2)[CH:24]=[CH:23]3)[CH2:36][CH2:35][N:34]([C:39]([O:41][CH2:42][C:43]2[CH:52]=[CH:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:44]=2)=[O:40])[CH2:33]1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O)c4n3)cnc2c1
Reactant: O=C(OCc1ccc2ccccc2c1)N1CCC2OC2C1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)N(C)C
Product: COCCOc1ccn2c(-c3ccc4cccc(O[C@@H]5CCN(C(=O)OCc6ccc7ccccc7c6)C[C@H]5O)c4n3)cnc2c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 58.1 %

Procedure:
2-(7-(2-Methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-ol (0.10 g, 0.309 mmol) was slurried in DMA (1.0 mL) and treated with Cs2CO3 (0.201 g, 0.618 mmol). After 10 minutes, naphthalen-2-ylmethyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (0.100 g, 0.355 mmol) was added. The reaction was warmed to 90° C. and stirred for 40 hours. The reaction mixture was cooled to ambient temperature then added dropwise into saturated NH4Cl (5 mL). Chloroform (25 mL) was added and the layers were separated. The aqueous layer was washed with CHCl3 and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient from 1 to 20% (6% NH4OH in MeOH)/ethyl acetate to provide the desired product (111 mg). MS ESI (+) m/z 619.2 (M+1) detected.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]1OC(C)(C)[O:7][C@@H:6]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH2:5]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=O)[CH:28]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:29]([C:39](=O)[CH:40]([CH3:42])[CH3:41])[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:31])=[CH:23][CH:22]=1.O1CCCC1.[Cl-].[NH4+]>CCCCCCC.C1(C)C=CC=CC=1.O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:1]([CH2:2][CH2:3][C@@H:4]3[CH2:5][C@@H:6]([OH:7])[CH2:12][C:13](=[O:14])[O:15]3)[C:39]([CH:40]([CH3:42])[CH3:41])=[C:29]([C:30]([NH:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:31])[C:28]=2[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[CH:25][CH:26]=1
Reactant: CC(C)C(=O)C(C(=O)Nc1ccccc1)C(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@@H](O)CC(=O)O1
Reaction time: 15 h

Procedure:
A solution of (4R-cis)-1,1-dimethylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate, 2.56 g (9.36 mol), and (±)-4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N,β-diphenylbenzenebutaneamide mixture of R-(R*,R*)], [R-(R*,S*)], [S-(R*,R*)]and [S-(R*,S*)]isomers, 3.00 g (7.20 mol), in 60 mL of heptane:toluene (9:1) is heated at reflux for 24 hours. The solution is cooled and poured into 300 mL of tetrahydrofuran and 150 mL of saturated ammonium chloride in water. The layers are separated and the organic layer is added to 15 mL of 10% hydrochloric acid solution and the solution is stirred for 15 hours. To this solution is added sodium hydroxide (3.6 g) and the mixture is stirred for 30 hours. The reaction is stopped by adding 150 mL of water, 90 mL of hexane, and separating the layers. The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 150 mL of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution and the solution is allowed to stand 18 hours. The solution is concentrated in vacuo and the concentrate is redissolved in 50 mL of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred two hours, concentrated in vacuo, and dissolved in 3.0 mL of toluene. (2R-trans)-5-(4-fluorophenyl)-2(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1H-pyrrole-3carboxamide (2.92 g) is isolated in two crops.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[N:5][N:4]=1)[CH3:2].[CH:16]([Cl:19])([Cl:18])[Cl:17].[OH-].[K+]>CN(C=O)C.CO>[Cl:17][C:16]([Cl:19])([Cl:18])[CH:12]([C:11]1[CH:14]=[CH:15][C:8]([C:6]2[O:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=2)=[CH:9][CH:10]=1)[OH:13]
Reactant: ClC(Cl)Cl
Reactant: CCc1nnc(-c2ccc(C=O)cc2)o1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CCc1nnc(-c2ccc(C(O)C(Cl)(Cl)Cl)cc2)o1
Temperature: -10 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 4-(5-ethyl-1,3,4-oxadiazol-2-yl)benzaldehyde (1.6 g, 7.9 mmol) in anhydr DMF (7 mL) was added CHCl3 (2.13 g, 17.8 mmol). After cooling to −10° C., a solution of KOH (0.31 g, 5.5 mmol) in anhydr MeOH (1.5 mL) was added dropwise over 20 min. After stirring at −10° C. for 1 hr, the reaction mixture was quenched with 1 M HCl. The solid formed was collected on a Buchner, washed with H2O and dried under vacuum to give 2,2,2-trichloro-1-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)ethanol as a white solid (2.0 g, 80% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10](=O)[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH:12]=3)=[CH:4][C:3]=1[O:29][CH3:30].[NH2:31][CH2:32][C:33]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>>[C:36]([NH:35][C:33](=[O:34])[CH2:32][N:31]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:29][CH3:30])[CH:4]=2)=[CH:17][C:16]2[C:11](=[CH:12][C:13]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[C:10]1=[O:9])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)NC(=O)CN
Reactant: COc1ccc(COc2ccc3cc(-c4ccc(F)c(OC)c4)oc(=O)c3c2)cc1
Product: COc1ccc(COc2ccc3cc(-c4ccc(F)c(OC)c4)n(CC(=O)NC(C)(C)C)c(=O)c3c2)cc1
Temperature: 120 °C
Yield: 92 %

Procedure:
A neat mixture of 3-(4-fluoro-3-methoxyphenyl)-7-(4-methoxybenzyloxy)isochromen-1-one (100 mg, 0.25 mmol) and 2-amino-N-tert-butyl acetamide (INTERMEDIATE I.2) (32 mg, 2.46 mmol) was heated at 120° C. for 3 h. The reaction mixture was cooled and partitioned between ethyl acetate and sat. NH4Cl (aq.). The organic layer was washed with brine (1×20 mL), dried (MgSO4) and concentrated in vacuo to afford N-tert-butyl-2-(3-(4-fluoro-3-methoxyphenyl)-7-(4-methoxybenzyloxy)-1-oxo-1H-isoquinolin-2-yl)acetamide (120 mg, 0.23 mmol, 94%) which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:5]=[CH:6][CH:7]=1.[Si](OCC)(OCC)(OCC)OCC.[CH:29]([C:32]1[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]([CH3:41])[CH3:40])[C:33]=1[NH2:34])([CH3:31])[CH3:30].OS(O)(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:34][C:33]2[C:35]([CH:39]([CH3:40])[CH3:41])=[CH:36][CH:37]=[CH:38][C:32]=2[CH:29]([CH3:31])[CH3:30])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(c1ccccc1)c1cccc(Br)c1
Agent: CCO[Si](OCC)(OCC)OCC
Agent: O=S(=O)(O)O
Product: CC(C)c1cccc(C(C)C)c1N=C(c1ccccc1)c1cccc(Br)c1
Temperature: 170 °C
Reaction time: 50 h
Yield: 84 %

Procedure:
In 25 mL Claisens flask in an argon atmosphere, a mixture of 5.22 g (20.0 mmol) of 16, 5.00 g (24.0 mmol) of Si(OEt)4, and 3.90 g (22.0 mmol) of 2,6-diisopropylaniline was heated to 170° C., and then 0.13 mL of 96% H2SO4 was added. This mixture was stirred at this temperature for 50 hr, and the formed ethanol was slowly distilled off. Later, 300 mL of cold water was added, and the product was extracted with 2×70 mL of diethyl ether. The combined extract was dried over K2CO3 and then evaporated to dryness. The product was isolated by flash-chromatography on silica gel 60 (40-63 um, eluent: from hexanes to hexanes-diethyl ether, 100:1, vol.). This procedure gave 7.06 g (84%) of the title product 17.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])(=[O:17])[CH:14]([CH3:16])[CH3:15].Cl[Si:25]([CH3:28])([CH3:27])[CH3:26]>O1CCCC1.CCCCCC>[CH3:23][N:21]([CH3:22])[CH2:20][CH2:19][O:18][C:13]([O:17][Si:25]([CH3:28])([CH3:27])[CH3:26])=[C:14]([CH3:16])[CH3:15]
Reactant: CC(C)C(=O)OCCN(C)C
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC(C)=C(OCCN(C)C)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
To a solution of 31.78 g (44 mL, 0.314 mol) of diisopropylamine (Aldrich gold label) in 300 mL of tetrahydrofuran at -5° to 0° C. was added over a period of about 30 min. 0.314 mol of 1.6N n-butyl lithium in hexane (196 mL). After 30 min at 0° C., the solution was cooled to -78° C. and 50 g (0.314 mol) of 2-dimethylaminoethyl isobutyrate, prepared as above, was added keeping the temperature below -70° C. Then 34.11 g (39.9 mL, 0.314 mol) of chlorotrimethylsilane was added below -70° C. After warming to room temperature, the mixture was concentrated on a rotary evaporator, and the residue was treated with hexane and filtered under argon. The filtrate was concentrated on a rotary evaporator and distilled in a spinning band column to give 45.4 g of 1-(2-dimethylaminoethoxy)-1-trimethylsiloxy-2-methyl-1-propene, b.p. 39°-42.5° C. (0.5 mm). 1H-NMR (360 MHz, benzene-d6): 0.22 (s, 9 H, SiMe), 1.67 (s, 3 H, =CCH3), 1.77 (s, 3 H, =CCH3), 2.12 (s, 6 H, NCH3), 2.46 (t, J=6 Hz, 2 H, CH2N), 3.85 (t, J=6 Hz, 2 H, CH2O). Anal Calcd for C11H25O2SiN: C 57.09, H 10.89, N 6.05, Si 12.14. Found: C 57.27, H 11.11, N 6.17, Si 11.37. IR (neat): 1705 cm-1 (C=C), no C=O absorption.
Reaction SMILES: [N+:1]([C:4]1[C:5]2[CH2:18][CH:17]([C:19](O)=[O:20])[CH2:16][C:6]=2[C:7]2[NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[CH3:41][NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH3:41][N:42]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:19]([CH:17]1[CH2:16][C:6]2[C:7]3[NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11][C:12]=3[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=2[CH2:18]1)=[O:20]
Reactant: O=C(O)C1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Reactant: CNc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C(=O)C1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1)c1ccccc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A solution of 6-nitro-2,3,-dioxo-2,3,4,7,8,9-hexahydro-1H-cyclopenta[f]quinoxaline-8-carboxylic acid (1 mmol, example 78) in anhydrous DMF was treated with carbonyldiimidazole (2 mmol) and triethylamine (1 mL) and then heated at 70° C. for 45 min. After cooling to room temperature methylphenylamine (1.2 mL) was added and the mixture stirred at 50° C. for 6 h. The solvent was removed in vacuo, and the residue triturated with acetone. The solid was collected by filtration, washed with diethyl ether and dried in vacuo. Calc'd for C19H16N4O5.1.2 H2O: C, 56.77; H, 4.61; N, 13.93; found: C, 56.22; H, 4.13; N, 14.62. MS M+1 (381).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:6]([SH:15])[CH:5]=1.F[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:18]=1[C:27]([F:30])([F:29])[F:28]>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:6]([S:15][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][C:18]=2[C:27]([F:28])([F:30])[F:29])[CH:5]=1
Reactant: O=C(O)CCc1ccc(Cl)cc1S
Reactant: CS(=O)(=O)c1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Sc2cc(Cl)ccc2CCC(=O)O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% wt. disp. oil, 0.063 g) was added to a solution of the product from step (iii) (0.180 g) in dry DMF (10 ml) and stirred at RT for 1 h before adding the product from example 44 step (i) (0.188 g). The mixture was heated at 80° C. for 1 h, then partitioned between 2M hydrochloric acid/ethyl acetate. The organics were dried, concentrated under reduced pressure to give an oil. The residue was purified by reverse phase HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[NH2:5].C1C(=O)N([Br:20])C(=O)C1>C(Cl)Cl>[Br:20][C:6]1[CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[C:2]([F:1])=[CH:3][C:4]=1[NH2:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(C(F)(F)F)c(F)c1
Solvent: ClCCl
Product: Nc1cc(F)c(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirring mixture of 3-fluoro-4-(trifluoromethyl)aniline (1.5 g) in DCM (12 mL) at room temperature was added dropwise a solution of NBS (1.5 g) in DCM (24 mL) over 15 min. The reaction mixture was stirred at rt for 1.5 h. The product mixture was concentrated under reduced pressure to one half of its original volumn. The white solid was filtered off and the crude product mixture was further purified via column chromatography. Retention time (min)=2.490, method [1], MS(ESI) 257.9 (M+H).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)[CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([O:16]C)=[O:15])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+]>C1COCC1.O>[C:1]1([CH:7]([C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)[CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CN1CCC(C(c2ccccc2)c2cccc(C)c2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C(c2ccccc2)C2CCN(CC(=O)O)C2)c1
Reaction time: 4 h
Yield: 50.2 %

Procedure:
To a solution of methyl 2-(3-(phenyl(m-tolyl)methyl)pyrrolidin-1-yl)acetate (1.5 g, 4.64 mmol) in THF at 0° C. was added a solution of lithium hydroxide (0.58 g, 13.8 mmol) in water and the reaction mixture was stirred for 4 h. The reaction mixture was concentrated under reduced pressure. To the residue was added water, the pH of the aqueous layer was adjusted to 3 using dil.HCl and extracted with 30% methanol in chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 0.72 g of the title compound.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Cl:14][C:15]1[CH:35]=[N:34][C:18]2[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)C(=O)[O:21][C:22](=O)[C:17]=2[CH:16]=1.Cl>CC(N(C)C)=O>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:19]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:18]2[C:17]([C:22]=1[OH:21])=[CH:16][C:15]([Cl:14])=[CH:35][N:34]=2)=[O:4])[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc(Cn2c(=O)oc(=O)c3cc(Cl)cnc32)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2cc(Cl)cnc2n(Cc2ccc(OC)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
Diethyl malonate (6.02 mL, 71.38 mmol) was added slowly to a suspension of NaH (60% in mineral oil, 3.13 g, 78.24 mmol) in dimethylacetamide (200 mL) and stirred at room temperature for 0.5 h under argon atmosphere. 6-Chloro-1-(4-methoxy-benzyl)-1H-pyrido-[2,3-d]-[1,3]-oxazine-2,4-dione (73) (21.5 g, 71.31 mmol) was added to the solution and heated at 110° C. for 4 h (TLC control). The solution was cooled and poured into ice water. The pH of the solution was adjusted to 3 by cold 10% HCl. The solids formed were filtered, washed by excess water, and dried in a vacuum oven to yield 14.0 g (99%) of 6-chloro-4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (75) as white solids. MP: 198° C.; 1H-NMR (DMSO-d6): δ 1.28 (t, J=7.2 Hz, 3H), 3.68 (s, 3H), 4.30 (q, J=7.2 Hz, 2H), 5.43 (s, 2H), 6.81 (m, Hz, 2H), 7.20 (m, 2H), 8.43 (d, J=2.8 Hz, 1H), 8.74 (d, J=2.8 Hz, 1H); EIMS: 389 (M+1).