Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][N:25]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]1=[O:35].O>CN(C=O)C>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:23][CH2:24][N:25]2[C:26](=[O:35])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]2=[O:34])[CH2:12][CH2:11]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2cccc(Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
1-(2,3-Dichlorophenyl)piperazine hydrochloride (3.16 g, 11.8 mmol) and potassium carbonate (4.08 g, 29.5 mmol) were added to the solution of 2-(2-bromoethyl)isoindoline-1,3-dione (3 g, 11.8 mmol) in DMF (20 ml). The resulting reaction mixture was stirred for overnight at room temperature. After reaction complete, water (40 ml) was added thereto and then normal work-up was taken. The residue thus obtained was purified with normal phase preparative column to afford the title compound (3.87 g, 81% yield) as white solid.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([CH3:14])[N:13]=1>>[CH3:14][C:12]1[N:13]=[C:9]([NH:8][C:5](=[O:7])[CH3:6])[S:10][CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1csc(N)n1
Product: CC(=O)Nc1nc(C)cs1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
To a stirred, cooled (5° C.) solution of acetic anhydride (237 ml, 2.51 mol) is added portionwise 2-amino-4-methyl thiazole (80 g, 0.697 mol). To allow dissolution of the 2-amino-4-methyl thiazole, the reaction mixture is allowed to warm but kept below 35° C. Once a solution forms, the reaction mixture is cooled to 5° C. and stirred overnight. The solvent is removed in vacuo and the solid is dried in a vacuum oven overnight. The resulting solid is triturated with iso-hexane (100 ml) and dried again. Recrystallisation from EtOAc/iso-hexane affords the title product as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10](B(O)O)[CH:9]=[N:8][C:7]=12)[CH3:2].O1CCOCC1.[C:21]([O:25][C@@H:26]([C:32]1[C:47]([CH3:48])=[CH:46][C:35]2[N:36]=[C:37]([C:39]3[CH:44]=[CH:43][N:42]=[C:41](Cl)[CH:40]=3)[S:38][C:34]=2[C:33]=1[C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.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>[C:21]([O:25][C@@H:26]([C:32]1[C:47]([CH3:48])=[CH:46][C:35]2[N:36]=[C:37]([C:39]3[CH:44]=[CH:43][N:42]=[C:41]([C:10]4[CH:9]=[N:8][C:7]5[N:6]([N:5]=[CH:4][C:3]=5[CH2:1][CH3:2])[CH:11]=4)[CH:40]=3)[S:38][C:34]=2[C:33]=1[C:49]1[CH:50]=[CH:51][C:52]([Cl:55])=[CH:53][CH:54]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH3:22])([CH3:23])[CH3:24]
Reactant: CCc1cnn2cc(B(O)O)cnc12
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
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: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cnc5c(CC)cnn5c4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a mixture of the above crude 3-ethylpyrazolo[1,5-a]pyrimidin-6-ylboronic acid in dioxane (˜0.18M, 0.68 mL, 0.123 mmol) was added (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (50 mg, 0.0944 mmol), Pd(PPh3)4 (11 mg, 0.0094 mmol) and 2M potassium carbonate (0.19 mL, 0.378 mmol) was heated in a microwave at 110° C. for 1 h. Reaction mixture was stored overnight at rt, diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 40% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C35H35ClN5O3S: 640.2 (M+H+); Found: 640.3 (M+H+).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[NH:5][CH:4]=[CH:3]1.P(Br)(Br)[Br:15].[OH-].[Na+]>CN(C=O)C>[Br:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc2[nH]ccc(=O)c2c1
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccc2nccc(Br)c2c1
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution of quinolinone (b) (12.0 g, 70.5 mmol) in DMF (60 ml) was treated dropwise with phosphorus tribromide (8.0 ml, 84.6 mmol) over 10 minutes (exothermic). After allowing to stir and cool to room temperature, ice water (100 ml) was added and the mixture was stirred 30 minutes, then basified to pH8 by dropwise addition of 50% NaOH with cooling. The resultant solid was filterd off, washed with water and air dried to afford a tan solid (14.3 g, 87%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]=O)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1.C(O)(=O)C.Cl.[CH3:28][NH:29][CH3:30].C([BH3-])#N.[Na+]>CN(C)C=O>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH2:19][N:29]([CH3:30])[CH3:28])=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1
Reactant: NC(=O)c1nc2n(c1C=O)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN(C)Cc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 10-bromo-9-fluoro-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide (75 mg) in anhydrous N,N-Dimethylformamide was added acetic acid, dimethylamine hydrochloride and 200 mg powdered 4 angstrom molecular sieves. The reaction was stirred for 30 minutes before the addition of sodium cyanoborohydride then continued to stir at room temperature for 18 hours. The reaction mixture was then extracted with dichloromethane and saturated ammonium chloride. The organic layer was dried, filtered and concentrated to afford crude 10-bromo-3-((dimethylamino)methyl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. This crude intermediate was directly reacted with 2-Methyl-3-butyne-ol via General Procedure E to afford 34 mg (41%) of 3-[(dimethylamino)methyl]-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][C@H:11]1[CH2:16][O:15][C@@H:14]([CH3:17])[O:13][C@H:12]1[CH2:18][O:19][C:20](=[O:28])[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:4].[OH-].[Na+]>CO>[C:3]([CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][C@H:11]1[CH2:16][O:15][C@@H:14]([CH3:17])[O:13][C@H:12]1[CH2:18][O:19][C:20](=[O:28])[NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([OH:4])=[O:2]
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1COC(=O)Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1OC[C@H](C/C=C\CCCC(=O)O)[C@H](COC(=O)Nc2ccccc2)O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.2 %

Procedure:
To a solution of (2R,4R,5S)-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-4-phenylcarbamoyloxymethyl-1,3-dioxane (140 mg) in methanol (2 ml) was added 1 ml of 1N aqueous sodium hydroxide and stirred at room temperature for 90 minutes. The reaction mixture was evaporated in vacuo and the residue was neutralized by acetic acid and extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness and the crude product was purified with preparative TLC (ether : dichloromethane=1:1) to give (2R,4R,5S) -5-[(Z)-6-carboxy-2-hexenyl]-2-methyl-4-phenylcarbamoyloxymethyl-1,3-dioxane (115 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([O-])=[C:5]([CH3:10])[CH:4]=1>CC(O)=O.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:10])[CH:4]=1
Reactant: COc1cc[n+]([O-])c(C)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccnc(C)c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-methoxy-2-methylpyridine 1-oxide (20 g, 0.143 mol) in AcOH (200 mL, sdfine, India), was added Fe (16 g, 0.287 mol, sdfine, India) and the reaction mixture was stirred for 2 h at 120° C. The reaction mixture was concentrated and neutralized with sat'd NaHCO3. EtOAc was added to the mixture and it was filtered through Celite® brand filter agent. The organic layer was separated and the aqueous layer was extracted with EtOAc (3×150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the title compound as a brown liquid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (d, J=6 Hz, 1H), 6.68-6.64 (m, 2H), 3.84 (s, 3H), 2.52 (s, 3H). MS (ESI, positive ion) m/z: 124.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([NH:6][C:14](=[O:15])[C:13]([F:20])([F:19])[F:12])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CCOC(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(NC(=O)C(F)(F)F)cc(OC)c1
Yield: 97.4 %

Procedure:
To 3,5-dimethoxyaniline (20 g, 131 mmol) dissolved in anhydrous tetrahydrofuran (90 mL) was added 4-(dimethylamino)pyridine (1.6 g, 13.1 mmol) and ethyl trifluoroacetate (47 mL, 392 mmol). After refluxing 48 hours, the cooled reaction mixture was concentrated and partitioned between ethyl acetate (300 mL) and 2N hydrochloric acid (100 mL). The ethyl acetate layer was washed with water (100 mL), dried using anhydrous sodium sulfate, and concentrated to yield N-(3,5-Dimethoxy-phenyl)-2,2,2-trifluoro-acetamide (31.8 g, 98%) as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[CH2:10][C@H:9]1[C:11](=O)[CH3:12].N1C=CC=CC=1.Cl.[CH3:21][O:22][NH2:23]>CO.O>[CH3:21][O:22][N:23]=[C:11]([C@@H:9]1[CH2:10][C@H:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:12]
Reactant: CC(=O)[C@@H]1C[C@H]1c1ccccc1Cl
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: O
Product: CON=C(C)[C@@H]1C[C@H]1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
To a stirred solution of trans 1-[2-(2-chloro-phenyl)-cyclopropyl]-ethanone (1.0 g; 5.1 mmol) in methanol (10 ml) at ambient temperature was added pyridine (0.85 ml; 10 mmol) and methoxyamine hydrochloride (0.86 g; 10 mmol). The reaction mixture was stirred for 16 hours at ambient temperature then poured in water (50 mL) and extracted with dichloromethane (3×30 ml). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was removed in vacuo to afford 1.1 g (98% of theory) of trans 1-[2-(2-chloro-phenyl)-cyclopropyl]-ethanone O-methyl-oxime as an oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([C:8]1[C:7]([N:24]2[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26][CH2:25]2)=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[C:10]([Cl:17])[CH:9]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)NC1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)NC1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)CC1
Temperature: 65 °C
Yield: 55.2 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.17 g, 0.25 mmol, from Example 47, Step 2), N-piperidin-4-ylacetamide hydrochloride (0.040 g, 0.22 mmol), palladium acetate (1.0 mg, 0.0045 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.2 mg, 0.0067 mmol), and cesium carbonate (0.28 g, 0.85 mmol) in tetrahydrofuran (4 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4, evaporated and purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (42 mg, 54%). LCMS calculated for C18H21ClN3O2 (M+H)+: m/z=346.1; Found: 346.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][NH:29]3)=[N:23][C:22]=2[CH:35]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][N:29]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:11]3[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=3)=[O:9])=[N:23][C:22]=2[CH:35]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Reactant: Cc1ccc(-c2ccnn2C)c(C(=O)O)c1
Product: Cc1ccc(-c2ccnn2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(1-methyl-1H-pyrazol-5-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 478 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[CH:10][C:9]=2[CH2:19][CH:20]2[NH:24][CH2:23][CH2:22][S:21]2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([N:24]1[CH2:23][CH2:22][S:21][CH:20]1[CH2:19][C:9]1[CH:10]=[N:11][N:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:27])[CH3:26]
Reactant: Clc1ccc(-c2c(CC3NCCS3)cnn2-c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCSC1Cc1cnn(-c2ccccc2)c1-c1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
A mixture of 3.56 g of 5-p-chlorophenyl-1-phenyl-4-(thiazolidin-2-yl-methyl)-pyrazole and 55 ml of acetic anhydride is boiled for 3 hours. 55 ml of pyridine is then added and the mixture is heated for a further 5 hours at 50° and subjected to the customary working up. 4-(3-Acetylthiazolidin-2-yl-methyl)-5-p-chlorophenyl-1-phenylpyrazole is obtained; m.p. 121°-122°.
Reaction SMILES: Cl.C([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][N:20]=2)[N:15]=[CH:14][C:13]=1[NH:22][C:23](=O)[CH2:24][CH2:25][CH3:26])(=O)C.[OH-].[Na+]>C(O)C>[CH2:24]([C:23]1[N:11]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][OH:5])[C:12]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1)[CH2:25][CH3:26]
Reactant: CCCC(=O)Nc1cnc2cccnc2c1NCCOCCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc2cnc3cccnc3c2n1CCOCCO
Temperature: 60 °C
Yield: 89 %

Procedure:
Modifying the procedure described in Part E of Examples 127-135, 2-(2-{[3-(butyrylamino)[1,5]naphthyridin-4-yl]amino}ethoxy)ethyl acetate hydrochloride (approximately 24.5 mmol) was treated with 2 M NaOH (37 mL, 73.5 mmol) in ethanol. After the solution was heated at 60° C. overnight, more 2 M NaOH was added (1 equivalent) and the mixture was heated at 70° C. for 8 hours. After the work-up described in Part E of Examples 127-135, 6.55 g of 2-[2-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethoxy]ethanol was isolated as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:18][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: NC1CC1
Reactant: O=C1CCN(c2ncc(Cl)cn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1-(5-Chloropyrimidin-2-yl)piperidin-4-one (1.5 g) is dissolved in anhydrous dichloromethane (25 mL) and cyclopropylamine (0.42 g) is added followed by glacial acetic acid (0.80 mL). Sodium triacetoxyborohydride (1.8 g) is then added in one portion under nitrogen and the resulting mixture stirred at r.t. for 17 h. The mixture is diluted with dichloroemthane (25 mL) and extracted with 3 M HCl (75 mL and 50 mL). The combined HCI layers are cooled on ice and 4 M NaOH (100 mL) is added in portions until the mixture is strongly basic (pH ˜14). The mixture is then extracted with dichloroemthane (150 mL and 100 mL) and the combined dichloromethane layers are dried over Na2SO4, filtered and concentrated to yield the title compound. LC (method 21): tR=2.57 min; Mass spectrum (APCI): m/z=253 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([C:26]([F:29])([F:28])[F:27])=[C:23]([F:25])[F:24])[CH:19]=[CH:18][C:17]=2[O:30][CH3:31])[C@@H:9]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O)(C)(C)C.[ClH:38].Cl.CC(C1C=CC(OC)=C(C=1)CN[C@H]1CCCN[C@H]1C1C=CC=CC=1)(C)C#CC(F)(F)F>>[ClH:38].[ClH:38].[F:25][C:23]([F:24])=[C:22]([C:20]1[CH:19]=[CH:18][C:17]([O:30][CH3:31])=[C:16]([CH:21]=1)[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]([F:27])([F:29])[F:28]
Reactant: COc1ccc(C(=C(F)F)C(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: COc1ccc(C(C)(C)C#CC(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: Cl
Product: COc1ccc(C(=C(F)F)C(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 80 in the same manner of Compound 60.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8]1.[F:19][C:20]1[CH:21]=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[F:26]>>[F:19][C:20]1[CH:21]=[C:22]([S:27]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([C@H:9]3[CH2:10][CH2:11][CH:7]([N:3]4[CH2:4][CH2:5][CH2:6][C@@H:2]4[CH3:1])[CH2:8]3)=[CH:13][CH:14]=2)(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Product: C[C@H]1CCCN1C1CC[C@H](c2ccc(NS(=O)(=O)c3ccc(F)c(F)c3)cc2)C1

Procedure:
The title compound was synthesized essentially in the same manner as Example 28 by employing 4-[(S)-3-((S)-2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 14) and 3,4-difluorobenzene sulfonyl chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:25]([O:27]CC)=[O:26])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([O:22][CH2:23][CH3:24])[N:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:25]([OH:27])=[O:26])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([O:22][CH2:23][CH3:24])[N:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2nc(OCC)ccc2cc1NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)O)nc2n1
Temperature: 65 °C
Yield: 25 %

Procedure:
A solution containing ethyl 3-{[(benzyloxy)carbonyl]amino}-7-ethoxy-1,8-naphthyridine-2-carboxylate (47 mg, 0.12 mmol) and lithium hydroxide monohydrate (25 mg, 0.59 mmol) in THF (2.0 mL) and water (1.0 mL) was heated at 65° C. in a sealed vial for 2 h. A precipitate was filtered off and washed with EtOAc to afford the sub-title compound (11 mg). The filtrate was diluted with water (1 mL) and the solution was extracted with EtOAc (2×5 mL). The combined organic extract were washed with brine (3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give additional sub-title compound (30 mg). The crude product was used directly in the subsequent reaction. LCMS (ESI) calc. for C19H18N3O5 [M+H]+: m/z=368.1. found: 368.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[CH:4][CH:3]=1.[ClH:20].O1CCOCC1>>[ClH:20].[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]2[CH2:12][NH:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(Sc2ccc(F)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1ccc(SC2CNC2)cc1

Procedure:
To tert-butyl 3-[(4-fluorophenyl)thio]azetidine-1-carboxylate (139 mg, 0.49 mmol) synthesized in Reference Synthesis Example 64, 4 M hydrogen chloride/1,4-dioxane solution (1.0 mL) was added and the resultant solution was stirred at 0° C. for 30 minutes and at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product (119 mg) of the title compound.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1)[NH2:2].Cl.CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1>C(O)C.C(OCC)C>[O:12]1[CH2:11][CH2:10][N:9]([C:6]2[N:5]=[N:4][C:3]([NH:1][N:2]3[CH:18]=[CH:22][CH:21]=[CH:20]3)=[CH:8][CH:7]=2)[CH2:14][CH2:13]1
Reactant: NNc1ccc(N2CCOCC2)nn1
Reactant: COC1CCC(OC)O1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: c1ccn(Nc2ccc(N3CCOCC3)nn2)c1
Temperature: 60 °C
Yield: 2 %

Procedure:
To 5.85 g (30 m mol) of 3-hydrazino-6-morpholino-pyridazine in 130 ml of ethanol, ethyl ether (45 ml) saturated with hydrogen chloride is added. The suspension of pale yellow precipitate which forms is additioned with 12 g (90 m mol) of 2,5-dimethoxytetrahydrofuran and the mixture is refluxed (60° C.) for 6 hours. The solvent is removed under vacuum and the residue is dissolved in water, brought to pH 8 by addition of a sodium carbonate solution and extracted with four portions (each of 100 ml) of dichloromethane. The organic extracts are pooled together, washed with water (50 ml) and anhydrified over sodium sulfate. Evaporation of the solvent yields an oil which is purified through column chromatography (silicagel, 500 g) using as the eluent a mixture of dichloromethane and ethyl acetate wherein the ratio of ethyl acetate is gradually increased from 20% to 100%. Evaporation of the more polar fraction yields 0.15 g (2%) of the product of the title which melts at 228° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C>CN(C)C=O.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([O:10][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
(2S,4S)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (CAS Reg. No. 227935-38-8)(300 mg, 1.2 mmol) and 60% sodium hydride mineral oil dispersion (61 mg, 1.5 mmol) were dissolved in anhydrous dimethylformamide (9 ml) at 0° C. under a nitrogen atmosphere. After 10 mins stirring benzylbromide (0.153 ml, 1.3 mmol) in CH2Cl2 (1 ml) was added drop wise and the reaction mixture stirred to room temperature for 1 hour. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate (25 ml), washed with water (2×25 ml), dried (magnesium sulphate), filtered and evaporated under reduced pressure. The residue was purified using flash chromatography eluting with a solvent gradient 4:1 heptane:ethyl acetate, yielding the title compound (167 mg, 42% yield) as an oil.