Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[CH3:14][O:15][NH2:16]>CO.O>[CH3:14][O:15][N:16]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=2[Cl:11])[CH2:5][CH2:6]1
Reactant: O=C1CCc2cc(Cl)cc(Cl)c21
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: O
Product: CON=C1CCc2cc(Cl)cc(Cl)c21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 5,7-dichloro-1-indanone (0.34 mmol) in 2 mL MeOH was added O-methylhydroxylamine HCl (0.34 mmol). The reaction mixture was stirred at RT for 17 h and then heated to 50° C. for 24 h. The mixture was cooled to RT, diluted with water and extracted 3 times with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].[Cl:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19][N+:20]2[C:25]([O-:26])=[C:24](I)[C:23](=[O:28])[N:22]3[CH:29]=[CH:30][CH:31]=[CH:32][C:21]=23)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C1(P([Pd](Cl)(Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl.CO>[Cl:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19][N+:20]2[C:25]([O-:26])=[C:24]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[C:23](=[O:28])[N:22]3[CH:29]=[CH:30][CH:31]=[CH:32][C:21]=23)=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=c1c(I)c([O-])[n+](Cc2ccc(Cl)nc2)c2ccccn12
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2c([O-])[n+](Cc3ccc(Cl)nc3)c3ccccn3c2=O)cc1
Temperature: 100 °C

Procedure:
To a mixture of 53 mg (0.36 mmol) (4-cyanophenyl)boronic acid, 100 mg (0.24 mmol) 1-[(6-chloro-3-pyridyl)methyl]-3-iodo-4-oxo-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Synthesis described in WO 2009/099929), 35 mg (0.05 mmol) bis(triphenylphosphino)-palladium dichloride and 17 mg (0.05 mmol) caesium carbonate was added 160 ml of dioxane. The mixture was heated to 100° C. for 18 hours. Silica was added and the product was obtained by column chromatographie (dichloromethane/methanol) (24 mg).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[CH3:14][O:15][NH2:16].[OH-:17].[Na+]>CCO>[CH3:14][O:15][NH:16][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[O:17])[N:11]=1
Reactant: [OH-]
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CON
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CONc1nc(=O)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a suspension of 2,4-dichloroquinazoline (995 mg, 5.0 mmol) in dry EtOH (100 mL), were added methoxyamine hydrochloride (569 mg, 5.5 mmol) and NaOH (227 mg, 5.5 mmol) in one portion at 0° C. The reaction mixture was stirred at 0° C. for 1 hour, then placed in a refrigerator at 4° C. for 72 h. Upon completion, the reaction was concentrated, and the residue was dissolved in EtOAc and washed with saturated NaHCO3 (1×) and brine (1×). The organic phase was dried over MgSO4, filtered and concentrated. The crude product was purified by preparative HPLC (10-90% CH3CN in H2O) to provide 4-(methoxyamino)quinazolin-2(1H)-one (556 mg, 36%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 3.68 (s, 3H), 7.02 (t, J=7.4 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.52 (ddd, J=8.1, 7.0, 1.5 Hz, 1H), 7.77 (dd, J=7.8, 1.4 Hz, 1H), 10.13 (br s, 1H), 10.89 (br s, 1H). MS 192.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:19])[O:16][C:15](=[O:17])[CH2:14][C:13](=[O:18])[O:12]1.[CH:20](OCC)(OCC)OCC>C(O)C>[CH3:10][C:11]1([CH3:19])[O:16][C:15](=[O:17])[C:14](=[CH:20][NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[C:13](=[O:18])[O:12]1
Reactant: CCOC(OCC)OCC
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: N#Cc1ccc(N)cc1
Solvent: CCO
Product: CC1(C)OC(=O)C(=CNc2ccc(C#N)cc2)C(=O)O1
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 4-aminobenzonitrile (12.5 g, 0.106 mol), 2,2-dimethyl-[1,3]dioxane-4,6-dione (Meldrum's acid) (18.3 g, 0.127 mol) and triethyl orthoformate (16 ml) in ethanol (100 ml) was refluxed for 3 hours. After cooling to room temperature the product was filtered, washed with cold ethanol and air dried to afford an off-white solid (27.9 g, 97%).
Reaction SMILES: [Cl:1][C@@H:2]1[CH2:15][C@@H:14]([O:16]C2CCCCO2)[C@H:13](/[CH:23]=[CH:24]/[C@@H:25]([O:34]C2CCCCO2)[C:26]([CH3:33])([CH3:32])[CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]>C(O)(=O)C.O.O1CCCC1>[Cl:1][C@@H:2]1[CH2:15][C@@H:14]([OH:16])[C@H:13](/[CH:23]=[CH:24]/[C@@H:25]([OH:34])[C:26]([CH3:33])([CH3:32])[CH2:27][CH:28]=[C:29]([CH3:30])[CH3:31])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CC(C)=CCC(C)(C)[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@H](Cl)C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)=CCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@H](Cl)C[C@H]1O
Yield: 51.4 %

Procedure:
1.04 g of (5Z,13E)-(8R,9R,11R,12R,15R)-9-chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,16,19-trimethyl-5,13,18-prostatrienoic acid was stirred under argon at room temperature for 19 hours with 21 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10). The mixture was then evaporated under vacuum and the residue purified by column chromatography on silica gel with hexane/0-100% ethyl acetate as the eluent, thus obtaining 380 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH:10]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])[CH3:11].CC(C)([O-])C.[K+].N1C=CC=NC=1>O1CCCC1>[CH:10]([O:13][C:14]([N:16]1[CH2:17][CH2:18][CH:19]([O:22][C:2]2[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=2)[CH2:20][CH2:21]1)=[O:15])([CH3:12])[CH3:11]
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: c1cncnc1
Product: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: -12.5 °C
Yield: 96.3 %

Procedure:
4,6-Dichloro-5-methylpyrimidine (1) (2.4235 Kg, 1.000 equivalents) and 4-hydroxypiperidine-1-carboxylic acid isopropyl ester (2) (2.8182 Kg, 1.012 equivalents) were dissolved in tetrahydrofuran (THF, 25.0028 Kg), and the resulting solution was cooled to −15 to −10° C. To the cold solution, potassium-tert-butoxide in tetrahydrofuran (1 M, 12.6051 Kg, 0.9399 equivalents) was added at a rate sufficiently slow to maintain the reaction mixture below 0° C. with reactor jacket cooling. The reaction mixture was then stirred at about −5° C. for about 2 hours before an additional portion of potassium-tert-butoxide in tetrahydrofuran (1 M, 0.5692 Kg, 0.0424 equivalents) was added to achieve >97% conversion of the pyrimidine after an additional hour of stirring at about −5° C. Most of the solvent was then removed by distillation at 30-65° C., ≦80 torr. Addition of water (19.9681 Kg) to the evaporation residue precipitated the product. Distillative removal of THF was then completed at 30-65° C., ≦80 torr, and the resulting stirred slurry was cooled to 0° C. for an hour. The solids were then collected by suction filtration, washed with water (8.011 Kg, 4° C.), and vacuum dried to constant weight at 50° C., ≦40 torr to provide product (3) (4.491 Kg, 96.3% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[C:35](Cl)[N:34]=[N:33][C:32]=2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:27][C:26]=1[O:42][CH3:43])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:35]2[N:34]=[N:33][C:32]([CH2:38][CH2:39][CH2:40][CH3:41])=[C:31]([C:28]3[CH:29]=[CH:30][C:25]([O:24][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:26]([O:42][CH3:43])[CH:27]=3)[CH:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OCc2ccccc2)c(OC)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (3.0 mmol, 604 mg) in THF (10 mL) at 0° C., NaH (60% dispersion in mineral oil, 4.0 mmol, 160 mg) was added and stirring continued for 10 min at room temperature, then 4-(4-benzyloxy-3-methoxy-phenyl)-3-butyl-6-chloro-pyridazine (2.0 mmol, 766 mg) was added. The resulting mixture was stirred at 50° C. for 1 hour, poured into ice-water and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The product was purified by column chromatography using 50% ethyl acetate in hexanes to give 4-[5-(4-benzyloxy-3-methoxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester, which was dissolved in dichloromethane (2.0 mL), added 4.0 M HCl in dioxane (2.0 mL) and stirred at room temperature for 1 hour. Solvents were evaporated in vacuo to give 4-(4-benzyloxy-3-methoxy-phenyl)-3-butyl-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (635 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([Cl:27])[C:24]([S:28](=[O:31])(=[O:30])[NH2:29])=[CH:23][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH2:11][CH2:10]1)=[O:5].[C:32](Cl)(Cl)=[O:33]>C(O)(=O)C.C1(C)C=CC=CC=1>[ClH:27].[Cl:27][C:25]1[CH:26]=[C:2]2[C:3]([C:4](=[O:5])[N:6]([CH2:7][CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[O:21][CH3:22])[CH2:11][CH2:10]3)[C:32](=[O:33])[NH:1]2)=[CH:23][C:24]=1[S:28](=[O:30])(=[O:31])[NH2:29]
Reactant: COc1ccccc1N1CCN(CCNC(=O)c2cc(S(N)(=O)=O)c(Cl)cc2N)CC1
Reactant: O=C(Cl)Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3cc(Cl)c(S(N)(=O)=O)cc3c2=O)CC1
Product: Cl
Temperature: 25 °C
Yield: 26.7 %

Procedure:
A mixture of 7-chloro-6-sulfamoylisatoic anhydride (7.45 g) and 1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine (6.64 g) was dissolved in methanol (100 ml), and the resulting mixture was heated under reflux for 3 hours under a nitrogen stream. After completion of the reaction, the solvent was distilled off under vacuum and the residue was recrystallized from methanol-acetone and dried to give 2-amino-4-chloro-5-sulfamoyl-N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]benzamide. A solution of this benzamide derivative (1.32 g) in acetic acid (20 ml) was added dropwise to a solution of phosgene (2.33 g) in toluene (10 ml) under stirring at room temperature. Then, the mixture was refluxed for one hour and cooled to room temperature. The resulting crystal was filtered and suspended in a mixture of methanol (10 ml) and water (10 ml), and after passing hydrogen chloride gas into the suspension for about 5 minutes, the solvent was distilled off under vacuum to provide a crystalline residue. It was recrystallized from water-methanol-ether to give colorless needles crystal of 7-chloro-6-sulfamoyl-3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H,3H)quinazolinedione hydrochloride (200 mg) having a m.p. of 266°-268° C. (with decomposition).
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)=[O:24])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(C(F)(F)F)c2)o1
Product: Cc1nc(C(=O)Nc2cnn(Cc3nc(C(C)(F)F)cs3)n2)c(-c2cccc(C(F)(F)F)c2)o1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[CH3:11][CH2:12][N:13](C(C)C)[CH:14](C)[CH3:15].[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=O.C(NCC)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([N:13]([CH2:14][CH3:15])[CH2:12][CH3:11])=[O:25]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCNCC
Product: CCN(CC)C(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 129.8 %

Procedure:
HOBT (2.72 g, 10.08 mmol), DIPEA (3.52 mL, 20.16 mmol), 2-bromo benzoic acid (4.08 g, 10.08 mmol), and diethyl amine (2.08 mL, 10.08 mmol) were dissolved in DCM (100 mL) and stirred at r.t. for about 30 minutes. EDCI (3.86 g, 10.08 mmol) was added, and the mixture was stirred at r.t. for about 16 hours. The reaction was concentrated to an oil, and the oil was purified via column chromatography to give 2-bromo-N,N-diethyl-benzamide (3.35 g, 68%) as a yellow oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:25])=[C:20]([CH:24]=2)[C:21]([OH:23])=O)[CH:11]=[CH:12][CH:13]=1.CN(C)C=O.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:34][C:33]=1[CH3:44]>ClCCl.C(N(CC)CC)C>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:25])=[C:20]([C:21]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:34][C:33]=3[CH3:44])=[O:23])[CH:24]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cc1ccc(N)c(C)c1
Reactant: Cc1ccc(OCc2cccc(Cl)c2)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(NC(=O)c2cc(OCc3cccc(Cl)c3)ccc2C)c(C)c1
Temperature: 20 °C
Reaction time: 1.25 h

Procedure:
Oxalyl chloride (15.1 ml, 173 mmol) was added over approx 1 minute to a stirred suspension of 5-{[(3-chlorophenyl)methyl]oxy}-2-methylbenzoic acid (31.8 g, 115 mmol) in dichloromethane (1.14 L) at 20° C. under argon. This was followed by the addition of N,N dimethylformamide (2 ml, 25.8 mmol) over 3 minutes with accompanying gas evolution but no noticeable temperature rise. Within approx 15 minutes the suspension dissolved and turned a darker brown. The mixture was stirred under argon at 20° C. for a total of 75 minutes. After 75 minutes the reaction mixture was evaporated in vacuo to a cream solid which was dried under vacuum at room temperature for 1 h. The solid was then redissolved in dichloromethane (900 ml) and to the stirred solution at 20° C. under argon was simultaneously added a solution of ethyl (4-amino-3-methylphenyl)acetate (24.4 g, 126 mmol) in dichloromethane (240 ml) and triethylamine (24 ml) over 10-15 minutes. The temperature rise in the reaction was from 20° C. to 30° C. over this time and thereafter slowly cooled to ambient. The brown solution was stirred under argon at room temperature for 14 h. After 14 h stirring the brown solution was washed with water (2×1 L). The combined aqueous washes were re-extracted with dichloromethane (500 ml) and all the organic extracts were combined, dried (MgSO4) and evaporated in vacuo to a brown oily solid which was dried at room temperature, under vacuum for 0.5 hours (wt=51.7 g). This material was dissolved in dichloromethane (200 ml) and the solution column chromatographed on Biotage 75 L system eluting with an ethyl acetate/iso-hexane gradient mixture and collecting 400 ml fractions as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.CON(C)[C:26](=[O:28])[CH3:27].[NH4+].[Cl-]>C1COCC1>[CH:9]([O:8][C:5]1[N:6]=[CH:7][C:2]([C:26](=[O:28])[CH3:27])=[CH:3][CH:4]=1)([CH3:11])[CH3:10]
Reactant: CON(C)C(C)=O
Reactant: CC(C)Oc1ccc(Br)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OC(C)C)nc1
Temperature: -66 °C
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
A round-bottomed flask was charged with 5-bromo-2-iso-propoxypyridine (IM1) (5.00 g, 23.1 mmol) in THF (100) under N2 and cooled in an acetone/dry-ice bath to −66° C. (internal temperature). A solution of 2.5 M n-butyllithium in hexane (10.1 mL, 25.3 mmol) was added drop wise over 10 minutes at keeping the internal temperature below −55° C. The mixture was stirred at −65° C. for 15 minutes. N-methoxy-N-methylacetamide (3.07 mL, 28.9 mmol) dissolved in THF (10 mL) was then added drop wise over 10 minutes while keeping the internal temperature below −65° C. After stirring for 1 h the mixture was allowed to reach room temperature. The mixture was poured into saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and evaporated to dryness. Flash chromatography (silica, heptanes/EtOAc 4:1) gave the title compound as a colorless oil (3.20 g, 77%) sufficiently pure for the next step.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:16]=2)[N:11]=1.C(#N)C>O>[O:20]([C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc2ccc(Oc3ccccc3)nc2n1
Reactant: O=C(O)c1ccoc1
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccc2ccc(Oc3ccccc3)nc2n1)c1ccoc1
Temperature: 4 °C
Yield: 64.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3-furancarboxylic acid (7.5 g), N,N'-carbonyldiimidazole (10.9 g) and 2-amino-7-phenoxy-1,8-naphthyridine (11.9 g). The product produced by precipitation in water (13 g; m.p. approximately 90° C.) is dissolved in boiling acetonitrile (80 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-Phenoxy-1,8-naphthyridin-2-yl)-3-furancarboxamide (10.7 g) is produced, m.p. 102° C.
Reaction SMILES: CS(O)(=O)=O.[CH2:6]([O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:14])=[NH:13])[CH2:7][CH3:8].[OH-:19].[Na+].[OH2:21]>>[OH:19][C:16]1[N:14]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[O:9][CH2:6][CH2:7][CH3:8])[N:13]=[C:11]([C:10]([OH:9])=[O:21])[CH:15]=1
Reactant: O
Reactant: CCCOc1ccccc1C(=N)N
Reactant: [OH-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Product: CCCOc1ccccc1-c1nc(O)cc(C(=O)O)n1

Procedure:
A solution of 2-propoxybenzamidine methanesulfonate (2.9 g), 10% sodium hydroxide (4 ml) and ethyl 4-oxalacetate (1.6 g ) in water (8 ml) was stirred at ambient temperature for 42 hours. The reaction mixture was evaporated to dryness to yield a crude product which was washed with dilute hydrochloric acid and water to yield the title compound, 0.82 g, m.p. 179.5-181.5° C. A sample (0.4 g) was recrystallized from ethanol to yield the pure title compound, 0.24 g, m.p. 184-5° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.CN(C)[CH:9]=[CH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)=O>C(O)(=O)C>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([C:11]2[N:3]3[N:4]=[CH:5][N:6]=[C:2]3[N:1]=[CH:9][CH:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1nc[nH]n1
Reactant: COc1cccc(C(=O)C=CN(C)C)c1
Solvent: CC(=O)O
Product: COc1cccc(-c2ccnc3ncnn23)c1

Procedure:
A mixture of 2.54 g. of 3-amino-1,2,4-triazole and 6.15 g. of 3-dimethylamino-3'-methoxyacrylophenone in 25 ml. of glacial acetic acid is refluxed for 6 hours. The resulting mixture is worked up as described in Example 54 to give the product of the Example, m.p. 163°-165° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Li]CCCC.C(NC(C)C)(C)C.[NH:21]([C:28]1[N:29]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:30]2[C:35]([C:36](=[O:38])[CH:37]=1)=[C:34]([CH3:39])[CH:33]=[CH:32][N:31]=2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1C[O:49]CC1>>[NH:21]([C:28]1[N:29]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:30]2[C:35]([C:36](=[O:38])[CH:37]=1)=[C:34]([CH2:39][OH:49])[CH:33]=[CH:32][N:31]=2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C1CCOC1
Reactant: Cc1ccnc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nccc(CO)c12
Temperature: 78 °C
Yield: 53 %

Procedure:
A solution of LDA (38.2 mmol, freshly prepared from n-BuLi and diisopropylamine) in THF (53 mL) was added to a cooled (˜78° C.) and stirred suspension of 2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (2.50 g, 7.64 mmol) in THF (100 mL). The resulting mixture was stirred for 1 h, and then oxygen gas was bubbled, through a fritted glass tube, into the bottom of the reaction vessel. The mixture was stirred overnight, with continued bubbling of oxygen with slow warming to room temperature. The reaction was quenched with water and 1 M HCl (5 mL), and then extracted with CH2Cl2. The organic phase was dried over Na2SO4 and concentrated in vacuo to afford an orange solid which was recrystalized from EtOAc to obtain 2-anilino-5-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (1.38 g, 53%): LCMS RT: 2.01 min, MH+: 344.3, Rf=0.22 (95:5 CH2Cl2:MeOH).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[C:38]([F:46])=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH:47]([C:50]1[S:54][C:53]([C:55](O)=[O:56])=[CH:52][CH:51]=1)([CH3:49])[CH3:48].C(N(CC)CC)C>CN(C=O)C>[F:46][C:38]1[C:39]([CH2:43][CH2:44][OH:45])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:33]1[CH2:34][CH2:35][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:55]([C:53]3[S:54][C:50]([CH:47]([CH3:49])[CH3:48])=[CH:51][CH:52]=3)=[O:56])[CH2:29]2)[CH2:31][CH2:32]1
Reactant: CC(C)c1ccc(C(=O)O)s1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.2 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.13 g), 5-isopropylthiophene-2-carboxylic acid (0.07 g) and triethylamine (0.23 mL) in DMF (7 mL) at 0° C. The resulting yellow solution was allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL), the organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added, and the solvent evaporated to give the subtitled compound as a clear gum. Yield 0.23 g.