Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:9]1[CH2:20][CH2:19][CH2:18][C@H:10]1[C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[O:8].[NH4+:31].[OH-].[H][H]>CC(N(C)C)=O.[Pd]>[NH2:31][C@H:2]([C:7]([N:9]1[CH2:20][CH2:19][CH2:18][C@H:10]1[C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[O:8])[CH2:3][CH2:4][C:5](=[O:6])[NH2:1]
Reactant: O=C(O)CNC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: [NH4+]
Reactant: [H][H]
Agent: [Pd]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Z-Glp-Pro-Gly-OH (1 eq.) was dissolved under stirring in DMA at 25° C. and NH4OH 25% (6 eq.) was added in such way that the temperature did not rise above 30° C. The mixture was stirred for at least 4 h at 25° C. The solution was concentrated under vacuum till the pH was ≦3. The concentrate was diluted with a NaCl aqueous solution and the pH was adjusted to 2.5 with a solution of KHSO4. The resulting aqueous solution was washed twice with IPE and then extracted three times with n-BuOH at 25° C. The organic layers were combined and washed with water. The resulting organic solution was concentrated under reduced pressure. The concentrated solution was diluted with ethanol and water at 20° C. and Pd/C (0.02 eq.) was added to the peptide solution. The solution was stirred at 20° C. followed by the introduction of hydrogen under pressure (0.3 bar). The solution was stirred for at least 2 hours and the completion of the reaction was checked by HPLC. The solution was filtered to remove the catalyst and, after one washing with demineralised water, the pH of the solution was adjusted to 6.0<pH<6.5 with an aqueous solution of NaHCO3. The free tripeptide was then precipitated by addition of ethanol. The solution was left to mature at 25° C. for 3 hours. The solid was filtered and washed with ethanol. After drying under vacuum, 60% of H-Gln-Pro-Gly-OH was recovered.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:64])[C:49]4[C:50]([O:56][C:57]=3[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[N:51][C:52]([Cl:55])=[CH:53][CH:54]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[ClH:55].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:64])[C:49]4[C:50]([O:56][C:57]=3[C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)=[N:51][C:52]([Cl:55])=[CH:53][CH:54]=4)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4nc(Cl)ccc4c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: Cl
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4nc(Cl)ccc4c3=O)cc2)CCC1

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(7-chloro-4-oxo-2-phenyl-4H-pyrano[2,3-b]pyridin-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as the free base. The residue was dissolved in a mixture of MeOH (1 mL), water (4 mL) and 1 M HCl (0.15 mL) and chromatographed on a 2 g C18 cartridge {gradient 30 to 90% MeOH in water+1 M HCl (60 μL in each 5 mL of eluent)} to give the title compound (3.7 mg, 50%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.61 (d, J=8.3 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.49-7.47 (m, 4H), 7.43-7.30 (m, 5H), 2.81-2.74 (m, 2H), 2.63-2.56 (m, 2H), 2.29-2.19 (m, 1H), 2.02-1.91 (m, 1H). LCMS (Method F): RT=8.90 min, [M+Na]+=418/420.
Reaction SMILES: [ClH:1].Cl.N[C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.N([O-])=O.[Na+].[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[CH2:21]>O.CC(C)=O>[Cl:1][CH:20]([CH2:21][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)[C:19]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CC(=O)COc1ccc(N)cc1
Reactant: C=CC(=O)OCC
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(Cl)Cc1ccc(OCC(C)=O)cc1
Reaction time: 0.33 h

Procedure:
50 ml of 35% w/v aqueous hydrochloric acid were added to a mixture of 20 g of 1-(4-aminophenoxy)propan-2-one hydrochloride [prepared as described in step (a) above], and 400 ml of acetone, and then a solution of 12 g of sodium nitrite in 20 ml of water was added dropwise to the resulting mixture, whilst ice-cooling; the mixture was then stirred at the same temperature for 20 minutes. At the end of this time, 130 g of ethyl acrylate and then 3.2 g of cuprous oxide were added in portions to the mixture, and the resulting mixture was stirred at room temperature for one hour. The reaction mixture was then concentrated by evaporation under reduced pressure, and the concentrate was mixed with water and ethyl acetate. The ethyl acetate layer was separated, washed with water and dried over anhydrous sodium sulfate; the solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 11.3 g of the title compound having an Rf=0.31 (thin layer chromatography on silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: C1(C)C=CC=CC=1.Cl.[NH:9]=[C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[CH:11]1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>O>[C:22]([N:9]=[C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:12]=[CH:11]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N=c1ccn(-c2ccccc2)nc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(N=c1ccn(-c2ccccc2)nc1)c1ccccc1
Yield: 71.6 %

Procedure:
80 ml of toluene were added to a solution of 10.0 g (48.2 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride in 80 ml of water. First 6.8 g (48.4 millimoles) of benzoyl chloride and then, in the course of 15 minutes, 4.0 g (100 millimoles) of NaOH in 20 ml of water were added to the two-phase system at room temperature, whilst stirring, the mixture was stirred for a further hour at room temperature and the product was then filtered off under suction. The solid obtained was washed with water, dried and recrystallized from ethanol. 9.5 g (72% of theory) of 4-benzoylimino-1,4-dihydro-1-phenylpyridazine were isolated as yellow crystals of melting point 175°-176° C.
Reaction SMILES: [N:1]1[C:10]2C(=[CH:6][CH:7]=[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]3=2)C=C[CH:2]=1.CI.C[O:18]C1C=NC2C(C=1)=CC=C1C=CC=CC=21.[CH2:33]([Li])[CH2:34][CH2:35][CH3:36].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH3:2][N:1]1[C:10]2[C:36](=[CH:6][CH:7]=[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]3=2)[CH:35]=[CH:34][CH:33]1[OH:18]
Reactant: COc1cnc2c(ccc3ccccc32)c1
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)ccc1cccnc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1c2c(ccc3ccccc23)C=CC1O
Reaction time: 1 h

Procedure:
Compound 13 was alkylated with MeI according to a general amino group alkylation procedure as follows. The 3-methoxybenzoquinoline derivative (100 mg) 13 was suspended in 5 mL of dry THF and cooled to −5° C. (ice/NaCl). 1.1 equivalents of n-butyl lithium (1 M) was added dropwise, and the reaction was stirred for 1 hour. 3 equivalents of the MeI alkylating agent was added slowly and the reaction was allowed to stir at room temperature for 2 hours. Aqueous work-up using NH4Cl and EtOAc gave a crude alkylated 3-methoxybenzoquinoline intermediate 14. Intermediate 14 was then purified by normal phase flash chromatography employing EtOAc:hexane (1:19) as the mobile phase (1HNMR: CD3Cl d 8.1 (broad d, 1 H, J=8.1 Hz), 7.68(dd, 1 H, J=8.1, 1.8 Hz), 7.34 (m, 2 H), 6.8 (s, 1 H), 3.92 (s, 3 H), 3.21 (m, 2 H), 2.94 (s, 3 H), 2.77 (t, 2 H, J=6.6 Hz), 1.92 (m, 2 H)). Subsequent methoxy group deprotection by the general boron tribromide procedure described above in Example 1 resulted in the N-methyl-hydroxybenzoquinoline derivative 15.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:10]2=[O:16])[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[C:24]([F:25])=[CH:23][C:22]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH:34][CH3:35])=[O:33])=[CH:28][CH:27]=2)=[C:21]([CH3:36])[CH:20]=1.C(O)(C(F)(F)F)=O>CC(O)C>[Cl:17][C:5]1[C:6]([NH:8][CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:10]2=[O:16])=[N:7][C:2]([NH:18][C:19]2[C:24]([F:25])=[CH:23][C:22]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([NH:34][CH3:35])=[O:33])=[CH:30][CH:31]=3)=[C:21]([CH3:36])[CH:20]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccc(-c2cc(F)c(N)cc2C)cc1
Reactant: O=C1NCCCCC1Nc1nc(Cl)ncc1Cl
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1ccc(-c2cc(F)c(Nc3ncc(Cl)c(NC4CCCCNC4=O)n3)cc2C)cc1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A mixture of 3-(2,5-dichloropyrimidin-4-ylamino)azepan-2-one (Intermediate 16, 28 mg, 0.10 mmol), 4′-Amino-5′-fluoro-N,2′-dimethylbiphenyl-4-carboxamide (Intermediate 17, 31 mg, 0.12 mmol, 1.2 equiv.) and TFA (37 μL, 57 mg, 0.50 mmol, 5 equiv.) in 2-propanol (3 mL) is stirred in a sealed tube at 100° C. for 48 h. The resulting solution is concentrated and then purified by preparative RP-HPLC to afford (±)-4′-(5-chloro-4-(2-oxoazepan-3-ylamino)pyrimidin-2-ylamino)-5′-fluoro-N,2′-dimethylbiphenyl-4-carboxamide; ESMS m/z 497.2 (M+H+).
Reaction SMILES: C(O)=O.C(O[CH:7](OCC)[CH2:8][CH:9]([O:14][CH3:15])[CH2:10][CH2:11][CH:12]=[CH2:13])C.C([O-])(=O)C.[Na+].Cl.[NH2:25][OH:26]>C(O)C>[CH3:15][O:14][CH:9]([CH2:10][CH2:11][CH:12]=[CH2:13])[CH2:8][CH:7]=[N:25][OH:26]
Reactant: C=CCCC(CC(OCC)OCC)OC
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Solvent: CCO
Product: C=CCCC(CC=NO)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 80% formic acid solution (30 mL) was added to 7,7-diethoxy-5-methoxyhept-1-ene obtained in Preparation Example 57-(2) (2.98 g), and the mixture was stirred at room temperature for 10 minutes. After further adding a 75% ethanol solution (64 mL), sodium acetate (3.75 g) and hydroxylamine hydrochloride (1.92 g) were added, followed by further stirring for one hour and 20 minutes. The solvent was concentrated to about 40 mL under reduced pressure, followed by extraction with ethyl acetate. The resulting organic layer was sequentially washed with a saturated sodium bicarbonate solution (three times), water and brine. The resulting organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (1.95 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=[O:2].C1(C)C=CC(S([CH2:21][N+:22]#[C-:23])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[O:2]1[C:1]([C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=2)[C:6]([OH:8])=[O:7])=[CH:23][N:22]=[CH:21]1
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(O)c1cccc(-c2cnco2)c1
Yield: 76.8 %

Procedure:
To a mixture of 3-formylbenzoic acid (500 mg) and p-toluenesulfonylmethyl isocyanide (715 mg) in methanol (20 mL) was added potassium carbonate (1.38 g) and the mixture was heated under reflux for 2 hours. After evaporation of solvent, the residue was partitioned between ethyl acetate and water. The aqueous layer was separated and acidified with 1N hydrochloric acid. The resulting precipitates were collected and washed with water, methanol and ether to give 3-(1,3-oxazol-5-yl)benzoic acid as a colorless amorphous powder (484 mg).
Reaction SMILES: Cl[C:2]1[C:19](=[O:20])[CH:18]=[CH:17][C@@:16]2([CH3:21])[C:3]=1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22].[NH4+:23].[OH-]>O1CCOCC1>[NH2:23][C:2]1[C:19](=[O:20])[CH:18]=[CH:17][C@@:16]2([CH3:21])[C:3]=1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22]
Reactant: [NH4+]
Reactant: C[C@]12C=CC(=O)C(Cl)=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@]12C=CC(=O)C(N)=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 75 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
A mixture of 4-chloroandrosta-1,4-diene-3,17-dione (957 mg, 3 mmole), dioxane (30 ml) and 30% NH4OH aqueous solution (60 ml) is stirred at 75° C. in a pressure vessel during 18 hours. After cooling to room temperature, the reaction mixture is worked up as described in the Example 1. There are obtained 242 mg (0.81 mmole, 27% yield) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].Cl[CH:20](C)CC(C1C=CC=CC=1)=O.[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C.CCN(CC)CC>C(Cl)Cl>[C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[CH:10]\[CH2:11][CH3:20])([CH3:7])[CH3:6])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(Cl)CC(=O)c1ccccc1
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Yield: 74 %

Procedure:
Compound 9s was synthesized by a procedure similar to that described for 9a using 3-chlorobutyrophenone (8j, 3.1 g, 0.0169 mol), TBDMSOTf (4.3 mL, 18.6 mmol), and Et3N (3.8 mL) in CH2Cl2 (30 mL). After purification, 3.7 g (74%) of the title product was isolated as colorless oil: 1H NMR (CDCl3) δ 7.48-7.44 (m, 1H), 7.38-7.32 (m, 1H), 7.31-7.29 (m, 2H), 5.16 (t, 1H, J=7.1 Hz), 2.30-2.19 (m, 2H), 1.09-1.03 (m, 3H), 1.01 (s, 9H), −0.04 (s, 6H); 13C NMR (CDCl3) δ 147.5, 141.7, 133.9, 129.2, 127.3, 125.9, 123.8, 114.9, 25.8, 19.5, 14.1, 0.0, −4.1. C16H25ClOSi.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:42](=[O:48])[O:43][C:44](Cl)(Cl)Cl)Cl.[CH3:50][O:51][C:52]1[CH:53]=[C:54]([CH:57]=[CH:58][C:59]=1[O:60][CH3:61])CO>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:42](=[O:48])[O:43][CH2:44][C:57]1[CH:54]=[CH:53][C:52]([O:51][CH3:50])=[C:59]([O:60][CH3:61])[CH:58]=1
Reactant: COc1ccc(CO)cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)Nc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2Cl)cc1OC
Temperature: 25 °C
Yield: 44 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (76 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (105 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3,4-dimethoxybenzyl alcohol (58 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (53 mg, yield 42%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[CH2:10][CH:9]=[CH:8][NH:7]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([N:7]1[CH2:8][CH:9]=[CH:10][NH:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: C1=CNNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC=CN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
114.5 g of methanesulphonic acid chloride were added dropwise to 70 g of pyrazoline and 101 g of triethylamine in 300 ml of methylene chloride at room temperature. The mixture was subsequently stirred at room temperature for 3 hours and was filtered. The filtrate was washed with water, dried over sodium sulphate and concentrated. 114 g (77% of theory) of methanesulphonylpyrazoline of melting point 62° C. were obtained.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[CH:25]=[CH:24][C:11]2[C:12]([CH:21]([CH3:23])[CH3:22])=[N:13][C:14]3[CH:15]=[CH:16][NH:17][C:18](=O)[C:19]=3[C:10]=2[CH:9]=1)=O)(=[O:3])[CH3:2].O=P(Cl)(Cl)[Cl:28].[OH-].[Na+]>C(#N)C>[Cl:28][C:18]1[N:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[C:10]1[CH:9]=[C:8]([C:6]3[O:3][C:1]([CH3:2])=[N:4][N:5]=3)[CH:25]=[CH:24][C:11]=1[C:12]([CH:21]([CH3:22])[CH3:23])=[N:13]2
Reactant: CC(=O)NNC(=O)c1ccc2c(C(C)C)nc3cc[nH]c(=O)c3c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1nnc(-c2ccc3c(C(C)C)nc4ccnc(Cl)c4c3c2)o1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of N′-acetyl-6-isopropyl-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridine-9-carbohydrazide (30 mg, 0.089 mmol) in ACN (1.0 mL) was added POCl3 (1.0 ml). The resulting suspension was stirred at 100° C. in a sealed vial for 3 hr. The solution was diluted with additional acetonitrile (10 mL), and then added to cooled 6N NaOH (20 mL). The resulting mixture was extracted with EtOAc (1×25 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to afford crude 1-chloro-6-isopropyl-9-(5-methyl-1,3,4-oxadiazol-2-yl)benzo[c]-1,6-naphthyridine that was used directly without further purification. LRMS (ESI) calc'd for (C18H15ClN4O) [M+H]+, 339.1; found 339.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1>CC(O)C>[N:1]1([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4ccccc43)c2cc1OC
Yield: 94 %

Procedure:
Utilizing a procedure analogous to that described in Example 2, this product was prepared in 94% yield from indoline (2 eq.) and 4-chloro-6,7-dimethoxyquinazoline (1.0 eq) in i-PrOH. (M.P. 162°-163° C.; LC-MS: 308 (MH+); anal. RP18-HPLC RT: 4.11 min.).
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[C:12](=[O:13])[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]4[CH:25]=[C:24]([NH:26][C:27]5[CH:31]=[C:30]([CH:32]6[CH2:34][CH2:33]6)[NH:29][N:28]=5)[C:23](=[O:35])[N:22](COCC[Si](C)(C)C)[N:21]=4)[C:15]=3[CH3:44])[CH2:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)S(O)(=O)=O>ClCCl.FC(F)(F)C(O)=O>[C:1]([C:5]1[S:6][C:7]2[C:12](=[O:13])[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]4[CH:25]=[C:24]([NH:26][C:27]5[CH:31]=[C:30]([CH:32]6[CH2:34][CH2:33]6)[NH:29][N:28]=5)[C:23](=[O:35])[NH:22][N:21]=4)[C:15]=3[CH3:44])[CH2:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(-c2cc(Nc3cc(C4CC4)[nH]n3)c(=O)n(COCC[Si](C)(C)C)n2)cccc1N1Cc2nc(C(C)(C)C)sc2C1=O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2cc(Nc3cc(C4CC4)[nH]n3)c(=O)[nH]n2)cccc1N1Cc2nc(C(C)(C)C)sc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a mixture of 2-tert-butyl-5-(3-(5-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-3-yl)-2-methylphenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one 111b in dichloromethane (5 mL) and trifluoro-acetic acid (5 mL) was added anisole (0.11 mL, 1.0 mmol) and trifluoromethanesulfonic acid (0.054 mL, 0.61 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated. The residue was purified by reverse phase HPLC: C-18 column eluted with 20 to 60% acetonitrile in water with 1% ammonium hydroxide to afford 2-tert-butyl-5-(3-(5-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)-2-methylphenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one 111 (50 mg, 50%). M+1 502.2. 1H NMR (400 MHz, DMSO) δ 12.94 (s, 1H), 12.02 (s, 1H), 9.06 (s, 1H), 7.82 (s, 1H), 7.50 (dd, J=5.8, 3.5, 1H), 7.38 (dd, J=8.0, 5.6, 2H), 5.87 (d, J=2.0, 1H), 4.96 (s, 2H), 2.13 (s, 3H), 1.84 (td, J=8.4, 4.2, 1H), 1.47 (s, 9H), 0.98-0.82 (m, 2H), 0.71-0.59 (m, 2H).
Reaction SMILES: [Na].[O:2]1CCO[CH2:4][CH2:3]1.CS[C:10](SC)=[C:11]([C:14](=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[C:12]#[N:13].[CH2:28]([OH:30])[CH3:29]>>[CH2:3]([O:2][C:10]([O:30][CH2:28][CH3:29])=[C:11]([C:14](=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[C:12]#[N:13])[CH3:4]
Reactant: CSC(SC)=C(C#N)C(=O)c1cccc(C(F)(F)F)c1
Reactant: CCO
Reactant: C1COCCO1
Agent: [Na]
Product: CCOC(OCC)=C(C#N)C(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium (0.126 g, 5.5 mmol) was dissolved in 15 mL of ethanol and 20 mL of dioxane was added followed by 1.59 g (5.0 mmol) of 3,3-bis-methylthio-2-(3-trifluoromethylbenzoyl)-acrylonitrile and the reaction mixture was refluxed for 4 hours and let stir overnight at room temperature. This compound was relatively unstable to aqueous conditions and was not isolated as such. Instead, an aliquot of the mixture was stripped and the product was identified by 300 MHz proton NMR: NMR (DMSO-d6): 1.14 (6H, tJ=7), 3.45 (4H, q, J=7), 7.44-8.16 (4H, m).
Reaction SMILES: C([O:3][C:4](=[O:32])/[C:5](/[O:29][CH2:30][CH3:31])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[CH3:28])C>C1COCC1.CO.O>[CH2:30]([O:29]/[C:5](=[CH:6]\[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[CH3:28])/[C:4]([OH:32])=[O:3])[CH3:31]
Reactant: CCOC(=O)/C(=C/c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1C)OCC
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1C)C(=O)O
Reaction time: 48 h
Yield: 90.9 %

Procedure:
To a solution of 0.40 g of 2Z-ethoxy-3-{2-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-acrylic acid ethyl ester in 10 ml of THF, 5 ml of MeOH and 5 ml of water was added at 22° C. 0.116 g of LiOHxH2O and stirring was continued for 2 d. The yellow solution was evaporated, the residue dissolved in 20 ml of water and the pH was adjusted to 5 using ca. 2.6 ml of 1 N aqueous HCl. The suspension was filtered, the residue washed with water and dried to give 0.34 g (91%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][NH2:16].[H][H]>[Pt]=O.C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:16][CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Reactant: CN
Agent: O=[Pt]
Solvent: CCO
Product: CNC1CCN(Cc2ccccc2)CC1

Procedure:
A solution of 1-benzyl-4-piperidone in 40 ml. of absolute ethanol was added to a solution of 8.5 g. of methylamine in 40 ml. of ethanol. The resulting solution was added to a suspension of 0.5 g. of platinum oxide in 30 ml. of ethanol which had been pretreated with 50 psi of hydrogen for 1 hour. This suspension was reduced at 50 psi of hydrogen until one equivalent of hydrogen was consumed and then filtered. The filtrate was concentrated in vacuo to give 1-benzyl-4-methylaminopiperidine.