Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C@@H:10]([OH:30])[CH:11]([N:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]O)=[CH:4][CH:3]=1.O.[C:32]1([CH3:42])[CH:37]=CC(S(O)(=O)=O)=C[CH:33]=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C@@H:10]2[CH:11]([N:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:33][C:32]([CH3:42])([CH3:37])[O:30]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)C(CO)[C@H](O)/C=C/c1ccc(Cl)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)C1CCC(C)(C)O[C@@H]1/C=C/c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 93 %

Procedure:
A mixture of 1,3-diol, 2-hydrazino (7C) (158 mg, 0.35 mmol) and p-toluene sulfonic acid monohydrate (6.8 mg, 0.035 mmol) in 10 mL anhydrous acetone was stirred at rt for 36 h, until the starting material was consumed as indicated by TLC (10:1/CH2Cl2/EtOAc). The reaction mixture was quenched with 5% NaHCO3 and extracted by CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, and removed in vacuo. Purification by flash column chromatography on silica gel afforded the desired product as a white solid (93%).
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][C@@:8]1([CH2:15][NH2:16])[CH2:14][C@@H:13]2[C@H:9]1[CH:10]=[CH:11][CH2:12]2)(C)(C)C>Cl.C(OCC)(=O)C>[NH2:16][CH2:15][C@:8]1([CH2:7][C:6]([OH:17])=[O:5])[CH2:14][C@@H:13]2[C@H:9]1[CH:10]=[CH:11][CH2:12]2
Reactant: CC(C)(C)OC(=O)C[C@@]1(CN)C[C@H]2CC=C[C@H]21
Agent: Cl
Solvent: CCOC(C)=O
Product: NC[C@]1(CC(=O)O)C[C@H]2CC=C[C@H]21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 551 %

Procedure:
A 4 N hydrochloric acid-ethyl acetate solution (200 mL) was added to tert-butyl[(1R,5S,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (17.53 g, 7.4 mmol), and the mixture was stirred at room temperature for 1.5 hours. Then, the solvent was distilled off under reduced pressure. The residue was suspended in dichloromethane. To the suspension, triethylamine was added dropwise, and the resulting powder was collected by filtration, then washed with dichloromethane, and then dried to obtain a white powder A (6.85 g). From the filtrate, the solvent was distilled off under reduced pressure. To the residue, a 4 N hydrochloric acid-ethyl acetate solution (200 mL) was then added again, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was suspended in dichloromethane. To the residue, triethylamine was added dropwise, and the resulting powder was collected by filtration, then washed with dichloromethane, and then dried to obtain a white powder B (2.48 g). This white powder B was combined with the above-obtained white powder A and washed with ethanol and ethyl acetate to obtain the compound of interest as a white powder (7.39 g, 55%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[CH:8]([CH3:10])[CH3:9]>C(Cl)(Cl)Cl.O=[Mn]=O>[CH:8]([C:4]1[N:5]=[CH:6][S:7][C:3]=1[CH:2]=[O:1])([CH3:10])[CH3:9]
Reactant: CC(C)c1ncsc1CO
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CC(C)c1ncsc1C=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 4.65 g (30 mmol) of crude 5-(hydroxymethyl)-4-isopropyl-thiazole in 200 mL of chloroform (CHCl3) was treated with 45 g of MnO2 and stirred at room temperature for 2.5 hours. The suspension was filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel, eluting with 3:1 hexane:EtOAc, to give the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Clc1nc(NCCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3
Reactant: c1nc[nH]n1
Product: c1ncn(-c2nc(NCCc3ccc4c(c3)OCO4)c3c4c(sc3n2)CCCC4)n1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-methylenedioxyphenethylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-methylenedioxyphenethylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30]C)=[O:29])=[C:24]([F:32])[CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[C:24]([F:32])[CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C(=O)O)c(F)c3)c2CC1
Temperature: 0 °C
Yield: 101 %

Procedure:
Heat a stirred solution of 3-tert-butoxycarbonyl-7-chloro-6-(3-fluoro-4-methoxycarbonylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3.56 g, 7.44 mmol) in THF (50 mL) and water (40 mL) overnight at 65° C. in the presence of potassium hydroxide (8.30 g, 148.77 mmol). Cool the mixture to 0° C., add slowly a 1N solution of hydrochloric acid until pH 5. Extract three times with EtOAc, dry over anhydrous Na2SO4 and concentrate in vacuo to provide the desired intermediate as a white solid (3.5 g, 99%).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1CCN2C(=NCCC2)CC1.[CH:24]1([CH2:30]Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C=O)C>[CH:24]1([CH2:30][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: BrCC1CCCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2ccccc2C(=O)N1OCC1CCCCC1
Temperature: 55 °C
Reaction time: 15 h

Procedure:
N-hydroxylphthalimide (18.4 mmol, 3.0 g) was dissolved in anhydrous DMF (20 mL) under nitrogen. To the stirring solution, DBU (27.6 mmol, 4.13 mL) was injected followed by cyclohexylmethyl bromide (23.0 mmol, 3.21 mL) and the reaction was warmed to 55° C. After stirring for 15 hours, the reaction was cooled to room temperature and concentrated to a red oil. The reaction was partitioned between ethyl acetate and 1N HCl. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine and dried over magnesium sulfate. The solvent was removed under vacuum, and the crude product was triturated with hexanes providing 3.05 g (64%) of an off-white colored solid. H1-NMR (CDCl3): δ 7.80 (2H,m), 7.73(2H,m), 3.98 (2H,d), 2.03-1.65 (5H,m), 1.31-1.03 (6H,m).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:21].[CH3:25][CH:26](O)[CH2:27][O:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[CH:30]=1>C(Cl)Cl>[CH3:36][C:31]1[CH:30]=[C:29]([CH:34]=[C:33]([CH3:35])[CH:32]=1)[O:28][CH2:27][CH:26]([Br:21])[CH3:25]
Reactant: Cc1cc(C)cc(OCC(C)O)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(C)cc(OCC(C)Br)c1
Yield: 74 %

Procedure:
0.94 Gram (3.6 mmol) of triphenylphosphine and 1.49 g (4.5 mmol) of carbon tetrabromide were added to a solution prepared by dissolving 0.54 g (3 mmol) of 1-methyl-2-(3,5-dimethylphenoxy)ethanol in 10 ml of methylene chloride, and the resultant mixture was stirred at room temperature for 30 minutes. After the reaction, the solid was separated by filtration, and the remaining methylene chloride solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5:1 (v/v)) to give 0.54 g of 1-(3,5-dimethylphenoxy)-2-bromopropane (yield 74.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([O:27][CH2:28][CH2:29][OH:30])[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([O:27][CH2:28][CH2:29][O:30][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(c1ccc(Cl)cc1)C12CCC(OCCO)CC1COc1c(F)ccc(F)c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97 %

Procedure:
A solution of 2-[10a-(4-chloro-benzenesulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-8-yloxy]-ethanol (1.09 g, 2.54 mmol) in CH2Cl2 (25 mL) at 0° C. was treated with Et3N (0.37 mL) and MsCl (0.65 mL), the reaction mixture was slowly warmed to room temperature. After 14 h, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo to afford the title compound (1.24 g, 97%): 1H NMR (CDCl3 400 MHz) δ 7.58 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.07 (m, 1H), 6.40 (m, 1H), 5.23 (dd, J=2.9, 11.7 Hz, 1H), 4.37 (dd, J=3.7, 4.4 Hz, 2H), 4.11 (d, J=11.7 Hz, 1H), 3.72 (m, 2H), 3.58 (m, 1H), 3.13 (s, 1H), 3.01 (m, 1H), 2.40 (m, 2H), 1.87 (m, 2H), 1.56 (ddd, J=1.6, 14.7, 14.7 Hz, 1H), 1.14 (m, 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:18])=[C:11]([NH:14][CH2:15][CH2:16][OH:17])[CH:12]=3)[C:7](=[O:19])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCOCC)C.C(#N)C>C(Cl)(Cl)Cl>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:18])=[C:11]([N:14]4[CH2:15][CH2:16][O:17][CH2:25]4)[CH:12]=3)[C:7](=[O:19])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(NCCO)c(F)cc2c1=O
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CCOCOCC
Product: CCOC(=O)c1cn(C2CC2)c2cc(N3CCOC3)c(F)cc2c1=O
Reaction time: 3 h

Procedure:
A mixture of 0.67 g of ethyl 1-cyclopropyl-6-fluoro-7-(2-hydroxyethylamino)-1,4-dihydro-4-oxoquinoline-3-carboxylate, 0.08 g of p-toluenesulfonic acid, 2.08 g of diethoxymethane and 20 ml of acetonitrile was stirred for 3 hours under reflux. After the reaction mixture was allowed to cool down, 100 ml of chloroform was added to the reaction mixture. The resultant mixture was successively washed with 5% aq. sodium carbonate solution and saturated saline, dried over anhydrous magnesium sulfate and then concentrated.
Reaction SMILES: [CH2:1]([N:4]([CH2:23][CH2:24][CH3:25])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[O:18][CH:19]=[C:20]([CH3:22])[N:21]=2)[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:6])[CH2:2][CH3:3]>CO.[OH-].[K+].O>[CH2:23]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[O:18][CH:19]=[C:20]([CH3:22])[N:21]=2)[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:6])[CH2:24][CH3:25]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2nc(C)co2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2nc(C)co2)c1
Yield: 97.9 %

Procedure:
A solution of methyl 3-[(dipropylamino)carbonyl]-5-(4-methyl-1,3-oxazol-2-yl)benzoate (118 mg, 0.34 mmol) in methanol (1 mL) and potassium hydroxide (1 mL of a 1.0 M solution in water, 1 mmol) was stirred at room temperature for 45 min. The solvent was removed under reduced pressure, the residue was dissolved in water, extracted with ethyl acetate, the aqueous layer was acidified to pH 4 with 1 N hydrochloric acid, extracted with chloroform (3×100 mL), and the combined organics were concentrated under reduced pressure to afford 3-[(dipropylamino)carbonyl]-5-(4-methyl-1,3-oxazol-2-yl)benzoic acid (110 mg): 1H NMR (300 MHz, CD3OD) δ 8.66 (d, J=1 Hz, 1H), 8.17 (d, J=1 Hz, 1H), 8.07 (d, J=1 Hz, 1H), 7.75 (d, J=1 Hz, 1H), 3.51 (t, J=7 Hz, 2H), 3.25 (t, J=7 Hz, 2H), 2.23 (s, 3H), 1.74 (d, J=7 Hz, 2H), 1.60 (d, J=7 Hz, 2H), 1.01 (t, J=7 Hz, 3H), 0.76 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]2[C:18]3[N:19]=[C:20]([CH3:26])[N:21]([CH2:22][O:23][CH2:24][CH3:25])[C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:40][CH2:41][CH2:42][Cl:43].C(OCC)(=O)C>O1CCCC1.C(OCC)C.O>[C:28]1([CH2:27][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[C:18]3[N:19]=[C:20]([CH2:26][CH2:40][CH2:41][CH2:42][Cl:43])[N:21]([CH2:22][O:23][CH2:24][CH3:25])[C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOCn1c(C)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Reactant: ClCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOCn1c(CCCCCl)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.9 %

Procedure:
Under a nitrogen atmosphere, a solution of N,N-bis(phenylmethyl)-1-ethoxymethyl-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.12 g, 2.56 mmole) in tetrahydrofuran (20 mL) was cooled to -78° C. Butyllithium (1.03 mL of 2.5M in hexanes, 2.56 mmole) was added and the reaction mixture was stirred for 5 minutes. 1-Bromo-3-chloropropane (2.7 mL, 25 mmole) was added and the reaction mixture was allowed to warm to ambient temperature. When the reaction was complete, as indicated by thin layer chromatography (silica gel, 30% ethyl acetate in hexanes v/v), the reaction mixture was diluted with diethyl ether and water. The ether layer was separated, dried over magnesium sulfate and then concentrated under vacuum. The resulting residue was purified by column chromatography (silica gel eluting with 10-20% ethyl acetate in hexanes v/v) to provide 0.76 g of N,N-bis(phenylmethyl)-2-(4-chlorobutyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:5][CH:4]=1.N1C=CC=CC=1.[OH-].[Na+].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>O>[O:20]=[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:21])[N:11]1[CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:22]=[CH:23][C:3]([NH:2][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:4][CH:5]=1
Reactant: Nc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 7.0 g sample of 2-[3-(4-aminophenoxy)-propyl]-1H-isoindole-1,3(2H)-dione monohydrochloride (Example 95) is added to 100 ml of pyridine, 2.2 ml of 10N NaOH and 2.5 g methanesulfonyl chloride. The mixture is stirred at room temperature for 6 hours and 1 hour on a steam bath. The reaction mixture is poured into 900 ml of cold water and stored at 0° C. for 18 hours. The precipitate is collected, washed with 200 ml of water and dried to give 6.5 g of solid. A 1.0 g sample is crystallized from 100 ml of boiling ethanol after treatment with activated carbon to give 0.6 g of solid, m.p. 176°-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[C:14]([CH3:21])=[CH:15][C:16]([F:20])=[C:17]([CH:19]=3)[NH2:18])[C:8]([CH3:12])=[N:9]2)=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].Cl[C:28]([O:30][C:31]([CH3:33])=[CH2:32])=[O:29]>CCOC(C)=O>[CH2:32]=[C:31]([O:30][C:28](=[O:29])[NH:18][C:17]1[CH:19]=[C:13]([C:7]2[C:8]([CH3:12])=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][N:3]=[C:2]([Cl:1])[CH:11]=3)[C:14]([CH3:21])=[CH:15][C:16]=1[F:20])[CH3:33]
Reactant: Cc1cc(F)c(N)cc1-c1cc2cnc(Cl)cc2nc1C
Reactant: C=C(C)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(Cl)cc3nc2C)c(C)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Treat a solution of 5-(7-chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluoro-4-methylaniline (0.5 g, 1.657 mmol) in EtOAc (10 mL) with satd. NaHCO3 (10 mL) followed by isopropenyl chloroformate (0.199 mL, 1.823 mmol) and stir the bi-phasic mixture at RT overnight. Separate the layers, extract the aqueous with EtOAc (2×), dry the combined organics over MgSO4 and concentrate to dryness to the title compound (646 mg, 101%). MS (ESI) m/z: 386.1 (M+H+).
Reaction SMILES: CN(/[CH:4]=[C:5]1\[C:6](=O)[C:7]2[CH:16]=[CH:15][CH:14]=[N:13][C:8]=2[NH:9][C:10](=[O:12])[CH2:11]\1)C.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:28][C:29]([NH2:31])=[NH:30])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:28][C:29]2[N:31]=[CH:4][C:5]3[CH2:11][C:10](=[O:12])[NH:9][C:8]4[N:13]=[CH:14][CH:15]=[CH:16][C:7]=4[C:6]=3[N:30]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(NC(=N)N)cc1OC
Reactant: CN(C)/C=C1/CC(=O)Nc2ncccc2C1=O
Product: COc1ccc(Nc2ncc3c(n2)-c2cccnc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to method H (NaHCO3 used in place of K2CO3) (Z)-6-dimethylaminomethylene-6,7-dihydro-9H-pyrido[2,3-b]azepine-5,8-dione (v-h) and 1-(3,4-dimethoxyphenyl)guanidine were converted to I-1 (85%): MS Rt═1.3 min. m/z 364 (M+H).
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][NH:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][N:15]1[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CCOC(=O)c1cccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1N1CCc2ccccc2C1

Procedure:
4.0 g (19.4 mmol) of ethyl 2-chloronicotinate, together with 3.2 g (19.4 mmol) of 1,2,3,4-tetrahydroisoquinoline hydrochloride and 5.36 g of potassium carbonate were heated at 110° C. for 3 h in 50 ml of DMF while stirring. Water was then added and the whole was extracted with ether; the ether phase was then washed with ammonium chloride, dried and evaporated. The crude product was purified chromatographically (silica gel/heptane-ethyl acetate 20-1), giving a yield of 4.8 g (87%).
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].B1([CH:24]2[CH2:26][CH2:25]2)OC(=O)CN(C)CC(=O)O1.P(C1CCCCC1)(C1CCCCC1)C1CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:24]1([C:2]2[C:8]([F:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=2[NH2:4])[CH2:26][CH2:25]1
Reactant: Nc1cc([N+](=O)[O-])cc(F)c1Br
Reactant: CN1CC(=O)OB(C2CC2)OC(=O)C1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1cc([N+](=O)[O-])cc(F)c1C1CC1
Temperature: 100 °C
Yield: 89.8 %

Procedure:
A mixture of 2-bromo-3-fluoro-5-nitroaniline (1.6 g, 6.81 mmol, 1 equiv), cyclopropylboronic acid MIDA ester (Aldrich; 4.0 g, 20.43 mmol, 3 equiv), Pd(OAc)2 (238 mg, 1.06 mmol, 0.15 equiv), Cy3P (578 mg, 2.06 mmol, 0.3 equiv) and Cs2CO3 (13.26 g, 40.8 mmol, 6 equiv) in toluene (70 mL) and H2O (14 mL) was de-gassed with N2 for 5 minutes. The mixture was then heated at 100° C. (oil bath temperature) overnight. After allowing to cool to room temperature, the mixture was diluted with EtOAc (100 mL) and H2O (50 mL) and the mixture filtered through Celite. The filter cake was washed with EtOAc (2×50 mL) and the filtrate partitioned. The organic layer was evaporated under vacuum to leave a crude residue which was purified by column chromatography on silica gel using EtOAc/hexanes (1:4) as eluent to give the product (1.2 g, 90%) as a dark yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][C:26]#[N:27]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][C:26]#[N:27])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: N#CCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 31.5 %

Procedure:
A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (11 g, 50 mmol), K2CO3 (8.5 g, 74 mmol) and 3-bromopropionitrile (8.2 g, 1.2 eq) in acetonitrile (300 ml) was heated at reflux for 24 hours. The mixture was cooled and the insolubles were filtered. The solvent was removed on a rotary evaporator and the crude product was purified by flash chromatography over a silica gel column (SiO2, 120 g). The product thus purified weighed 8.94 g. Recrystallization from ethanol yielded the nitrile as white crystals 4.3 g, m.p. 100-101° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].[O-]CC.[Na+].[C:16](OCC)(=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].[Na].Cl>C(O)C>[CH3:1][N:2]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:9](=[O:11])[CH:10]=[C:16]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CNc1ccccc1C(C)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2ccccc2n1C
Yield: 69.2 %

Procedure:
149 mgs (1 mMol) of 1-(2'-methylaminophenyl)ethanone was heated under reflux with 4 mMol of sodium ethoxide and 4 mMol of diethyl oxalate in 7 ml of ethanol for 11/2 hr. The reaction mixture, which contained the sodium salt of ethyl (2-N-methylaminobenzoyl)pyruvic acid was poured into dilute hydrochloric acid and extracted with chloroform. Evaporation to dryness and boiling the residue in diethyl ether afforded, after storing at 0°-5°, 160 mgs (70%) of the title product, mp 114°-5°.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:17])/[CH2:4][CH2:5][C:6]1[C:7]([CH3:16])=[N:8][C:9]2[NH:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1.[CH2:18]1[CH2:22][C:21]2([CH2:29][C:27](=O)[O:26][C:24](=[O:25])[CH2:23]2)[CH2:20][CH2:19]1>O1CCOCC1>[CH3:16][C:7]1[C:6]([CH2:5][CH2:4][C:3]2[N:17]=[C:27]([CH2:29][C:21]3([CH2:23][C:24]([OH:26])=[O:25])[CH2:22][CH2:18][CH2:19][CH2:20]3)[O:1][N:2]=2)=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]=2[N:8]=1
Reactant: O=C1CC2(CCCC2)CC(=O)O1
Reactant: Cc1nc2c(cc1CC/C(N)=N/O)CCCN2
Solvent: C1COCCO1
Product: Cc1nc2c(cc1CCc1noc(CC3(CC(=O)O)CCCC3)n1)CCCN2
Temperature: 100 °C

Procedure:
A stirred mixture of the product of EXAMPLE 7, STEP 3 (100 mg), 3,3-tetramethyleneglutaric anhydride (80 mg, Aldrich) and 1,4-dioxane (2 mL, Aldrich) was heated to 100° C. for 16 hrs. The resulting mixture was purified by HPLC to provide the title compound as a gum. 1H (CD3OD) δ 1.66 (8H, m); (1.93, 2H, p); 2.40 (3H, s); 2.42 (2H, s); 2.77 (2H, t); 2.97 (2H, t); 3.00 (2H, t); 3.14 (2H, s); 3.46 (2H, t); 7.51 (1H, s).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=[O:7])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH:18](I)([CH3:20])[CH3:19]>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH:18]([CH3:20])[CH3:19])[CH:6]=[O:7])[CH3:2]
Reactant: CCc1cc(C=O)ccc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(C=O)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of the 3-ethyl-4-hydroxy-benzaldehyde (7.8 g, 51.9 mmol) obtained in Example 179.1, K2CO3 (10.8 g, 78 mmol) and isopropyl iodide (7.86 ml, 78 mmol) was heated in DMF (65 ml) for 3 h. to 80° C. and subsequently stirred for 12 h. at room temperature. The mixture was poured into ice-cold 0.5M HCl and extracted with diethyl ether. The organic phase was washed with NaCl solution, dried, filtered and concentrated. The residue was purified by chromatography (SiO2, hexane/EtOAc 4:1). 3-Ethyl-4-isopropoxy-benzaldehyde was obtained as an orange oil (6.12 g, 61%); MS: 192 ([M]+).