Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[C:5]([CH3:36])([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35])[CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20]CC2C=CC=CC=2)=[CH:16][CH:15]=1)OC(=O)C(F)(F)F)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:37])[C:5]([CH3:36])([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35])[CH2:6][C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Oc1ccccc1C)C(OC(=O)C(F)(F)F)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1C
Reaction time: 96 h
Yield: 106.8 %

Procedure:
3-(4-Benzyloxy-phenyl)-2-methyl-2-o-tolyloxy-3-(2,2,2-trifluoro-acetoxy)-propionic acid ethyl ester (7.4 g, 14.3 mmol) was dissolved in ethyl acetate (300 mL), treated with 5% palladium on carbon (7.4 g), and stirred under an atmosphere of hydrogen for 96 h. The suspension was filtered through celite and concentrated in vacuo to provide the titled compound (4.8 g, 100%) as an opaque yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:19][CH2:20][CH2:21]Cl)[S:10](=[O:18])(=[O:17])[C:11]3[C:12]=2[C:13]=1[CH:14]=[CH:15][CH:16]=3)(=[O:3])[CH3:2].[C:23]1([C:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH:34]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:19][CH2:20][CH2:21][N:32]3[CH2:31][CH:30]=[C:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:34][CH2:33]3)[S:10](=[O:18])(=[O:17])[C:11]3[C:12]=2[C:13]=1[CH:14]=[CH:15][CH:16]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c3c(cccc13)S(=O)(=O)N2CCCCl
Reactant: C1=C(c2ccccc2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)Nc1ccc2c3c(cccc13)S(=O)(=O)N2CCCN1CC=C(c2ccccc2)CC1
Temperature: 20 °C
Yield: 32.1 %

Procedure:
5-Acetylamino-2-(3-chloropropyl)naphto[1,8-cd]isothiazole 1,1-dioxide (0.8 g), 4-phenyl-1,2,3,6-tetrahydropyridine (0.4 g), potassium carbonate (4 g) and acetonitrile (25 cc) are heated at boiling point for 20 hours. The reaction mixture is cooled to a temperature of about 20° C. The solution is filtered and then concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is purified by chromatography on a silica column with a mixture of ethyl acetate and methylene chloride (70-30 vol) as eluant, then recrystallized from boiling ethanol (20 cc). 5Acetylamino-2-[3-(4-phenyl 1,2,3,6-tetrahydro-1-pyridyl)-propyl]naphtho[1,8-cd]isothiazole 1,1-dioxide (0.35 g) is obtained, m.p. 178° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]=1.[NH2:12][C@H:13]([C:15]1[N:20]=[C:19]2[CH:21]=[CH:22][N:23]([CH3:24])[C:18]2=[CH:17][C:16]=1[N:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]1)[CH3:14].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:12][C@H:13]([C:15]2[N:20]=[C:19]3[CH:21]=[CH:22][N:23]([CH3:24])[C:18]3=[CH:17][C:16]=2[N:25]2[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:27][CH2:26]2)[CH3:14])[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCCN(C(=O)OC(C)(C)C)CC2)c1C#N
Temperature: 90 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a 25 mL pear flask were added 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (70.7 mg, 0.419 mmol) and tert-butyl (S)-4-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-1,4-diazepane-1-carboxylate (87 mg, 0.23 mmol) in DMSO (1.2 mL). Triethylamine (162 μL, 1.17 mmol) was added to the mixture which was then heated to 90° C. After 1 hour, UPLC indicated the reaction was complete. The reaction mixture was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The residue was purified by liquid chromatography (SiO2, 25-100% EtOAc/heptanes gradient) to give the title compound as a foam (81 mg, 69%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35-1.52 (m, 12H), 1.91 (s, 2H), 2.24 (s, 3H), 2.95-3.19 (m, 4H), 3.57 (d, J=5.56 Hz, 4H), 3.80 (br s, 1H), 5.90-6.01 (m, 1H), 6.49 (d, J=3.28 Hz, 1H), 6.95 (br s, 4H), 7.55 (d, J=3.03 Hz, 1H), 7.81 (d, J=6.82 Hz, 1H); ESI-MS m/z [M+H]+ calc'd for C26H35N9O2, 506. found 506.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[O:6][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:11]
Reactant: CCOC(=O)CBr
Reactant: CN(C(=O)c1ccccc1O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccccc1C(=O)N(C)c1ccccc1
Yield: 97.9 %

Procedure:
A solution of N-methyl-N-phenylsalicylamide (13.5 g.), ethyl bromoacetate (10 g.) and anhydrous potassium carbonate (8.4 g.) in N,N-dimethylformamide (90 ml.) was stirred at room temperature for 7 hours. The resultant mixture was added to water and extracted with diethyl ether, and the extract was washed with 10% aqueous solution of sodium hydroxide and water in turn, dried over magnesium sulfate and then evaporated under reduced pressure to give oily ethyl 2-[2-(N-methyl-N-phenylcarbamoyl)phenoxy]acetate (18.23 g.).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[S:12][C:11]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:10][N:5]2[C:6](=[O:9])[C:7]=1[CH3:8].[F-:21].[K+].S1(CCCC1)(=O)=O>O>[F:21][C:2]1[N:3]=[C:4]2[S:12][C:11]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:10][N:5]2[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: [F-]
Reactant: CCCCCCCSc1nn2c(=O)c(C)c(Cl)nc2s1
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CCCCCCCSc1nn2c(=O)c(C)c(F)nc2s1
Yield: 63 %

Procedure:
A solution of 8.6 g of the thus obtained 7-chloro-2-heptylthio-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one, 3.0 g of spray dry potassium fluoride and 32 ml of sulfolane was heated at 205°~225° C. in a stream of nitrogen for 1 and half hours. After cooling, water was added to the mixture, and the mixture was extracted with toluene. The toluene layer was collected and washed with water. The toluene phase was dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by column chromatography on a silica gel with an ethyl acetate/n-hexane (1:3) mixture as an eluent. After the solvent was distilled off, 5.2 g of 7-fluoro-2-heptylthio-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained.
Reaction SMILES: [CH3:1][C:2]([S:12]([CH2:15][C@@H:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17]([OH:19])=[O:18])(=[O:14])=[O:13])([C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])[CH3:3].[H][H]>CO.[Rh]>[CH3:3][C:2]([S:12]([CH2:15][C@@H:16]([CH2:20][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[C:17]([OH:19])=[O:18])(=[O:13])=[O:14])([C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])[CH3:1]
Reactant: CC(C)(C(=O)N1CCOCC1)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: [H][H]
Agent: [Rh]
Solvent: CO
Product: CC(C)(C(=O)N1CCOCC1)S(=O)(=O)C[C@@H](CC1CCCCC1)C(=O)O

Procedure:
A solution of 610mg (1.59mmol) (S)-α-[[[1-methyl-1-(morpholinocarbonyl)ethyl]sulfonyl]methyl]hydrocinnamic acid in 20 ml of methanol was hydrogenated in the presence of 60 mg of rhodium on aluminium oxide at 500 for 4 hours at a pressure of 106Pa of hydrogen. Subsequently, the catalyst was filtered off and rinsed with methanol. The methanolic solution was evaporated under reduced pressure, whereby 580 mg of (S)-α-[[[1-methyl-1-(morpholinocarbonyl)ethyl]sulfonyl]methyl]cyclohexanepropionic acid, MS: 346 (M-C3H7)+ were obtained as a colourless crystalline solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C@H:8]2[CH2:9][C@@H:3]1[CH2:4][CH2:5][C:6]2=[CH2:7].B.S1CC[O:15]CC1.[OH-].[Na+].OO>C(O)C.CCCCC>[CH3:1][C:2]1([CH3:10])[C@H:8]2[CH2:9][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:7][OH:15]
Reactant: C1CSCCO1
Reactant: C=C1CC[C@H]2C[C@@H]1C2(C)C
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: CCCCC
Product: CC1(C)[C@H]2CC[C@@H](CO)[C@@H]1C2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
Hydroboration was carried out by adding (-)-B-pinene (11.9 ml, 75 mmol, 95.5% optical purity) dropwise to a well-stirred mixture of borane-1,4-thioxane (3.13 ml, 25 mmol) and pentane (18.3 ml) at room temperature (under nitrogen). The solution was allowed to stand for 15 min. to complete the hydroboration. Then ethanol (15 ml) was added, followed by 3 M sodium hydroxide (25.0 ml, 75 mmol). The reaction mixture was then immersed in a cooling bath and 30% aqueous hydrogen peroxide (9.4 ml, 75 mmol) was added dropwise over 15 min. at such a rate that the temperature did not rise over 35° C. (gentle reflux). The reaction mixture was then heated under reflux for 1 hour and then poured into ice-water (300 ml). The mixture was extracted with ether (70 ml). The ether layer was washed thoroughly with water (3×200 ml), followed by saturated brine solution (50 ml). The organic layer was dried over anhydrous potassium carbonate, filtered, and concentrated. Distillation under vacuum provided pure (-)-cis-myrtanol: 9.0 g, a yield of 79%; b.p. 68°-69° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([OH:11])[CH:3]=1.[S-:12][C:13]#[N:14].[K+].BrBr>O.CN(C)C=O.N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:9][CH2:10]2)[N:5]=[C:4]([OH:11])[C:3]=1[S:12][C:13]#[N:14]
Reactant: N#C[S-]
Reactant: Nc1cc(O)nc(C2CC2)n1
Agent: BrBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: N#CSc1c(N)nc(C2CC2)nc1O
Temperature: 40 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a mixed solution of the compound (0.30 g) obtained in Step 1, potassium thiocyanate (0.77 g) and N,N-dimethylformamide (6.0 ml) was added pyridine (0.29 ml) at 90° C. After allowing to cool to 40° C., a mixed solution of bromine (0.15 ml) and N,N-dimethylformamide (1.0 ml) was added, and the mixture was stirred at room temperature for 1 hr. Under ice-cooling, water (12 ml) was added to the reaction solution, and the precipitated solid was collected by filtration, washed with water and dried to give the title compound (0.40 g).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]4[N:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:31]([C:33]1[O:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32]>C1COCC1.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>[CH3:24][O:23][C:21]([C:18]1[CH:19]=[N:20][C:15]([N:13]2[CH2:12][CH2:11][C:6]3[NH:7][C:8]4[CH:9]=[CH:10][C:2]([C:36]5[O:37][C:33]([CH:31]=[O:32])=[CH:34][CH:35]=5)=[CH:3][C:4]=4[C:5]=3[CH2:14]2)=[N:16][CH:17]=1)=[O:22]
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(Br)cc4c3C2)nc1
Reactant: O=Cc1ccc(B(O)O)o1
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: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5ccc(C=O)o5)cc4c3C2)nc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 46.6 %

Procedure:
To a solution of Example 33 (0.25 g, 0.64 mmol) in THF:H20 (4:1) were added Cs2CO3 (1.689 g, 5.16 mmol) and 5-formyl-2-furanboronic acid (0.180 g, 1.29 mmol). The reaction mixture was thoroughly degassed and freshly prepared tetrakis(triphenylphosphine)palladium(0) (0.186 g, 0.16 mmol) was added under nitrogen atmosphere at room temperature. The reaction mixture temperature was raised to 80° C. and continued stirring for 12 hr. The progress of the reaction was monitored by TLC analysis and upon completion of the reaction the THF was removed under reduced pressure. The mixture was partitioned between ethyl acetate (100 mL) and water (15 mL). The organic layer was separated, dried over Na2SO4 filtered and the solvent was removed under reduced pressure to give crude residue, which was purified by column chromatography using silica gel to give methyl-2-{8-[5-(formyl)-2-furyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (0.12 g, 46.2%)
Reaction SMILES: [Na].Cl.[Cl:3][CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[N:7]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:6]1.[CH2:29]=O>CO.C1COCC1>[Cl:3][CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]([CH3:29])[CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[CH:11][CH:12]=2)[N:7]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:6]1
Reactant: CS(=O)(=O)N1CC(CCl)c2ccc(NCc3ccc([N+](=O)[O-])cc3)cc21
Reactant: C=O
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1ccc([N+](=O)[O-])cc1)c1ccc2c(c1)N(S(C)(=O)=O)CC2CCl
Yield: 73 %

Procedure:
Sodium cyanoborohydnide (40 mg, 0.64 mmol) then 2N HCl (0.5 mL) were added to a solution of 30 (96 mg, 0.24 mmol) and formaldehyde (0.18 mL of a 40% w/v aq. solution, 2.4 mmol) in MeOH (15 mL) and THF (5 mL) and the mixture stirred at 20° C. for 45 min. The solvent was evaporated, the residue was diluted with water and extracted with CH2Cl2 (×2), and the extracts dried (Na2SO4) and evaporated. Dry column chromatography (eluting with 1:2 EtOAc:petroleum ether) gave 3-(chloromethyl)-1-(methanesulfonyl)-6-[N-methyl-N-(4-nitrobenzyl)amino]indoline (31) (73 mg, 73%), mp (benzene-petroleum ether) 138-139 C. 1H NMR (CDCl3) a 8.18 (d, J=8.8 Hz, 2 H, ArH o to NO2), 7.39 (d, J=8.8 Hz, 2 H, ArH m to NO2), 7.05 (d, J=8.4 Hz, 1 H, H-4), 6.82 (d, J=2.4 Hz, 1 H, H-7), 6.3 5 (dd, J=8.4 2.4 Hz, 1 H, H-5), 4.63 (s, 2 H, NCH2Ar), 4.04 (dd, J=10.8, 8.8 Hz, 1 H, CHHN), 3.93 (dd, J=10.8, 4.7 Hz, 1 H, CHHN), 3.71 (dd, J=10.4, 4.1 Hz, 1 H, CHHCl), 3.68-3.61 (m, 1 H, H-3), 3.55 (dd, J=10.4, 7.8 Hz, 1 H, CHHCl), 3.11 (s, 3 H, NCH3), 2.81 (s, 3 H, NSO2CH3). 13C NMR a 150.3, 147.1, 146.5, 143.5, 118.9 (C-6,8,9,1,4), 127.4, 123.9 (C-2 and 6, 3 and 5), 125.5, 107.7, 97.9 (C-4,5,7), 56.5, 54.7 (C-2, NCH2Ar), 46.9 (CH2Cl), 41.8 (C-3), 39.5 (NCH3), 34.5 (SO2CH3). Anal. Calculated for C18H20ClN3O4S): C, 52.8; H, 4.9; N, 10.3; Cl, 8.7. Found: C, 52.6; H 5.1; N, 10.1; Cl, 8.9%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]([CH3:26])([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].O>CN(C=O)C.CCOCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][C:17]([CH3:26])([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:4][CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)CSc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To a slurry of 4-hydroxythiophenol (259.4 g, 2.06 mol) and potassium carbonate (284.2 g, 2.06 mol) in 500 mL of DMF at 0° C. was added tert-butyl 3-chloropivaloate (373.8 g, 1.94 mol) dropwise over 2 hours. After stirring to room temperature overnight, the reaction was heated to 110° C. for 3 hours. The reaction was allowed to cool for room temperature and water and ether were added. The layers were separated and the organic layer washed with water and 5% NaOH, dried over MgSO4 and concentrated. The resulting oil was recrystallized from 1:3 CH2Cl2 /pet. ether to afford 328.0 g (60%) of the desired product. mp 100°-100.5° C.; 1H NMR (CDCl3) δ1.22 (s,6H), 1.44 (s,9H), 3.07 (s,2H), 5.42 (br s,1H,--OH), 6.77 (d,2H,J=8.7 Hz); 13C NMR (CDCl3) δ 24.62, 27.73, 44.58, 46.86, 81.00, 116.2, 127.7, 133.5, 155.4, 176.7; IR (KBr, film) 3362, 2971, 1720, 1693, 1600, 1583, 1495, 1472, 1366, 1320, 1223, 1150(s), 835, 817 cm-1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([CH2:30][CH2:31][OH:32])=[CH:28][CH:27]=1>C(OCCO)C>[OH:32][CH2:31][CH2:30][C:29]1[CH:33]=[CH:34][C:26]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[CH:27][CH:28]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc(CCO)cc3)c2cc1OC
Yield: 93.8 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 12 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 178.3 mg (1.3 mmol) of 4-aminophenethyl alcohol to give 327.8 mg (93.9%) of the product as an off white yellow solid, m.p. 208-210° C., mass (electrospray, m/e): M+H 349.9.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:17])[CH:6]=[C:7]([C:13]([O:15]C)=[O:14])[NH:8]2)[CH3:2].[OH-].[Na+]>>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:17])[CH:6]=[C:7]([C:13]([OH:15])=[O:14])[NH:8]2)[CH3:2]
Reactant: CCc1cccc2[nH]c(C(=O)OC)cc(=O)c12
Agent: [Na+]
Agent: [OH-]
Product: CCc1cccc2[nH]c(C(=O)O)cc(=O)c12
Yield: 59.3 %

Procedure:
Treatment of methyl 5-ethyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (0.61 g) with sodium hydroxide (0.42 g), as described in Example 1c, gave 5-ethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (0.34 g), m.p. 272°-273° C., δ (360 MHz, NAOD) 1.22 (3H, t, CH3), 3.41 (2H, q, CH2), 6.65 (1H, s. 3-H), 7.18 (1H, d, 6-H), 7.54 (1H, t, 7-H), 7.68 (1H, d, 8-H), 11.94 (1H, s, NH), (Found: C, 65.97; H, 4.86; N, 6.72%, C12H11NO3 requires C, 66.35; H, 5.10; N, 6.45%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21](=[O:24])[CH2:22][CH3:23])=[CH:18][CH:19]=2)[CH2:14][CH2:13][C:12]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:27](OCCC(C)C)=[O:28]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21](=[O:24])[C:22](=[N:27][OH:28])[CH3:23])=[CH:18][CH:19]=2)[CH2:14][CH2:13][C:12]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)c1ccc2c(c1)CCC(=O)N2CCOCc1ccccc1
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: ClCCl
Product: CC(=NO)C(=O)c1ccc2c(c1)CCC(=O)N2CCOCc1ccccc1
Reaction time: 1 h
Yield: 26.1 %

Procedure:
1-(2-Benzyloxyethyl)-2-oxo-6-propionyl-1,2,3,4-tetrahydroquinoline (32.4 g) was dissolved in methylene chloride (97 ml) and the solution was saturated with hydrogen chloride. To the stirred solution was added dropwise iso-amyl nitrite (13.5 g) over 0.5 hour. After stirring for 1 hour, the reaction mixture was evaporated in vacuo and the oily residue was dissolved in diethyl ether and extracted with 10% aqueous solution of sodium hydroxide. The extract was washed with diethyl ether, acidified with diluted hydrochloric acid, and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was triturated with benzene to give 1-(2-benzyloxyethyl)-6-(2-hydroxyiminopropionyl)-2-oxo-1,2,3,4-tetrahydroquinoline (9.19 g).
Reaction SMILES: O=[CH:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[O:12])[CH2:6][CH2:5]1.[Cl:23][C:24]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:25]=1[O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:23][C:24]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:25]=1[O:26][CH:27]1[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][C@H:4]2[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[O:12])[CH2:6][CH2:5]2)[CH2:31][CH2:32]1
Reactant: O=CC[C@H]1CC[C@H](NC(=O)c2ccnc3ccccc23)CC1
Reactant: Clc1cccc(OC2CCNCC2)c1Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(Oc3cccc(Cl)c3Cl)CC2)CC1)c1ccnc2ccccc12

Procedure:
The title compound was prepared analogously to example 71 using quinoline-4-carboxylic acid trans-[4-(2-oxo-ethyl)-cyclohexyl]-amide and 4-(2,3-dichloro-phenoxy)-piperidine as starting materials.
Reaction SMILES: C(OC([N:8]([C:26]1[CH:30]=[C:29]([CH3:31])[N:28](C(OC(C)(C)C)=O)[N:27]=1)[C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19](O)=[O:20])=[CH:16][CH:17]=2)[C:12](=[O:22])[N:11]([CH:23]([CH3:25])[CH3:24])[N:10]=1)=O)(C)(C)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:23]([N:11]1[N:10]=[C:9]([NH:8][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)[C:18]2[C:13](=[CH:14][C:15]([C:19]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:20])=[CH:16][CH:17]=2)[C:12]1=[O:22])([CH3:25])[CH3:24]
Reactant: C1COCCN1
Reactant: Cc1cc(N(C(=O)OC(C)(C)C)c2nn(C(C)C)c(=O)c3cc(C(=O)O)ccc23)nn1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nn(C(C)C)c(=O)c3cc(C(=O)N4CCOCC4)ccc23)n[nH]1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
1-[tert-Butoxycarbonyl-(1-tert-butoxycarbonyl-5-methyl-1H-pyrazol-3-yl)-amino]-3-isopropyl-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (13 mg, 0.025 mmol) was dissolved in DMF (2 ml). To this was added morpholine (6.4 mg, 0.075 mmol) and the reaction mixture was cooled to 0° C., 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (15 mg, 0.03 mmol) and TEA (0.014 ml, 0.1 mmol) were added consecutively and the reaction mixture stirred at RT for 24 hours. After this time, the reaction mixture was partitioned between EtOAc (10 ml) and water (10 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum. The resulting residue (13.0 mg, 0.02 mmol) was dissolved in a 20% TFA/DCM solution (2 ml) and the reaction mixture was stirred for 48 hours. After this time, the reaction mixture was concentrated and the resulting residue was triturated with diethyl ether to give the corresponding 2-Isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(morpholine-4-carbonyl)-2H-phthalazin-1-one (Example M-2). 1H-NMR: (400 MHz, D6-DMSO) 9.40 (1H, s), 8.50 (1H, d), 8.23 (1H, s), 7.91 (1H, d), 6.36 (1H, s), 5.28-5.21 (1H, m), 4.12-3.30 (8H, obscured) 2.26 (3H, s), 1.33 (6H, d) MS (ESI+)=(M+H)+ 397.21.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:9]=[C:8]([CH3:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[N:6]=1.[NH:19]1[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:27])[CH3:26])[CH2:20]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C)C=O>[Cl:18][C:13]1[CH:12]=[C:11]([N:7]2[C:8]([CH3:10])=[CH:9][C:5]([O:4][CH2:3][CH2:2][N:19]3[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:27])[CH3:26])[CH2:20]3)=[N:6]2)[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: Cc1cc(OCCCl)nn1-c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)NC1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)NC1CCN(CCOc2cc(C)n(-c3ccc(Cl)c(Cl)c3)n2)C1
Yield: 29.5 %

Procedure:
3-(2-chloroethoxy)-1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole (0.5 g, 1.64 mmol), N-(pyrrolidin-3-yl)acetamide (0.23 g, 1.8 mmol), K2CO3 (0.68 g, 4.9 mmol) and NaI (245 mg, 1.64 mmol) in dry dimethylformamide (10 ml) was warmed overnight at 85° C., and then an additionally 16 hrs at 95° C., in a dry nitrogen atmosphere. Solvents were evaporated in vacuo and the crude residue partitioned in water/ethyl acetate. The combined organic extracts were washed with water, dried on Na2SO4 and concentrated in vacuo to obtain a yellow crude oil, which was purified by column chromatography on silica gel (eluent: ethyl acetate 100% and ethyl acetate/MeOH 9/1) yielding 192 mg of N-(1-(2-(1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)pyrrolidin-3-yl)acetamide as an oil.