Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=[O:14])[CH:8]=2)[C:3]=1[C:16]([NH2:18])=[O:17].[H][H]>CO.[Pt]=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][OH:14])[CH:8]=2)[C:3]=1[C:16]([NH2:18])=[O:17]
Reactant: NC(=O)c1c(-c2cccc([N+](=O)[O-])c2)nsc1N
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: NC(=O)c1c(-c2cccc(NO)c2)nsc1N
Reaction time: 67 h
Yield: 67.3 %

Procedure:
A mixture of 5-amino-3-(3-nitrophenyl)isothiazole-4-carboxamide (50 mg, 0.19 mmol) and platinum oxide (20 mg, 0.088 mmol) in 5 mL MeOH was hydrogenated under 60 PSI hydrogen. After 5 hours an additional catalytic amount of platinum oxide was added and the reaction continued for 67 hours. The reaction mixture was filtered using Celite and the filter bed rinsed with 40% MeOH/CHCl3. The filtrate was evaporated to give 32 mg of yellow solid. Then 22 mg of this material was chromatographed eluting with CHCl3/MeOH to give the title compound as a pale yellow solid (10.2 mg).
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:19]1[CH:33]=[CH:32][C:22]([CH2:23]P(=O)(OCC)OCC)=[CH:21][CH:20]=1.[C:34]1([N:40]([C:47]2[CH:54]=[CH:53][C:50]([CH:51]=O)=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CC(C)([O-])C.[K+]>C1COCC1>[C:34]1([N:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:47]2[CH:54]=[CH:53][C:50](/[CH:51]=[CH:23]/[C:22]3[CH:32]=[CH:33][C:19]([C:2]4[CH:3]=[CH:4][C:5]5[C:6]6[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=6)[C:12]6[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=6)[C:18]=5[CH:1]=4)=[CH:20][CH:21]=3)=[CH:49][CH:48]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOP(=O)(Cc1ccc(-c2ccc3c4ccccc4c4ccccc4c3c2)cc1)OCC
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C(=C/c1ccc(N(c2ccccc2)c2ccccc2)cc1)\c1ccc(-c2ccc3c4ccccc4c4ccccc4c3c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
Compound E (1.0 g, 2.20 mmol) or E1 and 4-(N,N-diphenylamino)benzaldehyde (0.72 g, 2.64 mmol) and dry THF (20 ml) were charged in two necked-bottle in an ice bath, potassium-tert-butoxide (0.49 g, 4.4 mmol) in dry THF (20 ml) was added under nitrogen. The reaction mixture was stirred for 15 min at 0° C., followed by 1 h at room temperature. The solution mixture was extracted with ethyl acetate and washed with water. The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure to afford a crude product that was purified by sublimating at a temperature of 260° C. to obtain TSTA (1.04 g, yield=82%) as yellow solid.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([C:7]([OH:9])=O)[CH:2]=1.CN1CCOCC1.[CH3:17][CH:18]([CH2:20][C@H:21]([NH2:26])[C:22]([O:24][CH3:25])=[O:23])[CH3:19].Cl>C(Cl)Cl>[CH3:25][O:24][C:22](=[O:23])[C:21]([NH2:26])([C:7]([C:3]1[CH:4]=[N:5][CH:6]=[CH:1][CH:2]=1)=[O:9])[CH2:20][CH:18]([CH3:19])[CH3:17]
Reactant: O=C(O)c1cccnc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)C(N)(CC(C)C)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 72.6 %

Procedure:
To a solution of niacin (1.35 g, 11.0 mmol) in DCM (20 mL) were added N-methyl morpholine (3.34 g, 33.00 mmol) EDCI.HCl (4.2 g, 22.02 mmol), and L-leucinemethyl ester hydrochloride (2.0 g, 11.0 mmol). The mixture was allowed to stir at room temperature (25° C.) over 2.5 h under nitrogen atmosphere. The resulting mixture was diluted with DCM (200 mL), washed with water (3×100 mL) and dried over sodium sulphate. The crude product obtained upon evaporation of the solvent was further purified by silica gel column chromatography to obtain required product as white solid (2.0 g, 72%).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:11]2[NH:10][C:9]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:8]=3[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[O:21]1[CH2:23][CH:22]1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:1]([C:5]1[CH:13]=[CH:12][C:11]2[N:10]([CH2:23][CH:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[OH:21])[C:9]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:8]=3[C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: c1cc(C2CO2)ccn1
Reactant: CN1CCc2[nH]c3ccc(C(C)(C)C)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(C(C)(C)C)ccc3n2CC(O)c2ccncc2)C1
Reaction time: 0.17 h

Procedure:
To a solution of 8-tert-butyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g, 4.1 mmol) in DMF (6 mL) was added sodium hydride (495 mg, 12.3 mmol) under nitrogen at 0° C. and stirred for 10 min. A solution of 4-(oxiran-2-yl)pyridine (898 mg, 7.4 mmol) in DMF (2 mL) was added dropwise into the reaction mixture at RT and stirred for 12 h. The progress of reaction was monitored by TLC and LCMS. The reaction mass was poured in ice-cold water and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (5×50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was re-crystallized with hexane to yield 2-(8-tert-butyl-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].O.[ClH:10].[NH:11]1[CH:15]=[CH:14][N:13]=[C:12]1[C:16]1[CH:17]=[CH:18][C:19]2[C:20]([N:27]=1)=[N:21][C:22](=[O:26])[C:23](=[O:25])[N:24]=2>S1(CCCC1)(=O)=O.O.[OH-].[Na+]>[ClH:10].[NH:11]1[CH:15]=[CH:14][N:13]=[C:12]1[C:16]1[C:17]([N+:7]([O-:8])=[O:6])=[CH:18][C:19]2[C:20]([N:27]=1)=[N:21][C:22](=[O:26])[C:23](=[O:25])[N:24]=2
Reactant: O=[N+]=O
Reactant: O=C1N=c2ccc(-c3ncc[nH]3)nc2=NC1=O
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: O=C1N=c2cc([N+](=O)[O-])c(-c3ncc[nH]3)nc2=NC1=O
Temperature: 120 °C
Reaction time: 4 h

Procedure:
In 10 ml of sulfolane was dissolved 1.01 g of -imidazolylpyrido[2,3-b]pyrazine-2,3-dione hydrochloride monohydrate followed by addition of 1.35 g of nitronium tetrafluoroborate, and the mixture was stirred at 120° C. for 4 hours. The reaction mixture was then allowed to cool to room temperature, diluted with 10 ml of water and neutralized with 1N aqueous sodium hydroxide solution. The resulting crystals were recovered by filtration and rinsed with a small amount of water. The resulting crystals were suspended in 2 ml of water followed by addition of a stoichiometric amount of 1N-hydrochloric acid and, further, 5 ml of ethanol. The crystals were recovered by filtration and dried under reduced pressure to provide 0.63 g of 6-imidazolyl-7-nitropyrido[2,3-b]pyrazine-2,3-dione hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]([CH3:27])[C:4](=[O:28])[CH:3]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[N:7][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:5]([CH3:27])[C:4](=[O:28])[CH:3]=[C:2]3[NH:1][C:29](=[O:31])[CH3:30])=[CH:17][CH:16]=1
Reactant: Cn1c(=O)cc(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 85 °C

Procedure:
The product of Example 4 (18 mg) was combined with pyridine (2 mL), acetic anhydride (0.2 mL), and DMAP (5 mg). The reaction was heated to 85° C. for 1 hr at which point LC/MS indicated significant imide formation. The reaction was concentrated and redissolved in 1,4-dioxane before adding aqueous 1 M NaOH (1 mL). After 15 hours at room temperature the reaction was diluted with EtOAc and washed with brine before drying (Na2SO4). The concentrated residue was purified by preparative TLC (silica gel) eluted with EtOAc affording the title compound. HPLC/MS: 471.9 (M+1), 473.9 (M+3); Rt=3.79 inn.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-])=O>CCOC(C)=O.CO.[Pd]>[NH2:14][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:5]=1[NH:4][CH2:3][CH2:2][OH:1])[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1ccc(NCCO)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc(C(=O)O)ccc1NCCO
Yield: 101.9 %

Procedure:
A solution of intermediate 156 (1.33 g, 5.9 mmol) in AcOEt/MeOH was stirred under H2 in the presence of 10% palladium on carbon for 18 h, filtered through Celite®, concentrated and then triturated with DCM to give compound 157 (1.18 g, >99% yield).
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([CH3:8])[C@@H:6]([CH3:9])[CH2:5][N:4]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][CH:11]=2)[CH2:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][O:32][C:33]2[CH:34]=[C:35]([NH2:38])[NH:36][N:37]=2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1.C[Al](C)C.C1(C)C=CC=CC=1>>[CH3:30][O:29][C:27]1[CH:26]=[C:25]([CH2:31][O:32][C:33]2[CH:34]=[C:35]([NH:38][C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([N:4]4[CH2:5][C@H:6]([CH3:9])[N:7]([CH3:8])[C@H:2]([CH3:1])[CH2:3]4)=[CH:20][CH:19]=3)[NH:36][N:37]=2)[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Reactant: CCOC(=O)c1ccc(N2C[C@@H](C)N(C)[C@@H](C)C2)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4C[C@@H](C)N(C)[C@@H](C)C4)cc3)[nH]n2)cc(OC)c1
Yield: 5.6 %

Procedure:
N-[5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-[(3R,5 S)-3,4,5-trimethylpiperazin-1-yl]benzamide was prepared following the procedure for Example 100, but starting from ethyl 4-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)benzoate (0.276 g, 1.00 mmol) and 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.249 g, 1 mmol) and a 2M solution of trimethylaluminium in toluene (1.25 mL, 2.5 mmol). The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.027 g, 5.63%) as a white solid.
Reaction SMILES: C([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1)=O.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)(C)C.O>[OH:18][N:17]=[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH2:4]1
Reactant: COC(=O)c1ccc(C=O)cc1[N+](=O)[O-]
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COC(=O)C1=C([N+](=O)[O-])CC(=NO)C=C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
A solution of methyl 4-formyl-2-nitrobenzoate (2.0 g, 9.4 mmol) in isopropanol (50 ml) and water (25 ml) was treated with hydroxylamine hydrochloride (0.7 g) and sodium acetate (0.72 g) and stirred for 2 hours at room temperature. The solvent was then evaporated and the residue was treated with water (25 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over sodium sulfate and concentrated to give methyl 4-hydroxylimino-2-nitrobenzoate (1.8 g). 1H-NMR (400 MHz, CDCl3): 11.90 (1H, s), 8.20 (1H, d), 8.00 (1H, d), 7.89 (1H, d), 3.85 (3H, s) ppm.
Reaction SMILES: Br[CH:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[N-:23]=[N+]=[N-].[Na+]>CN(C)C=O.O>[NH2:23][C:18]1[C:17](=[O:20])[CH2:16][CH2:15][C@@:14]2([CH3:21])[C:19]=1[CH:2]=[CH:3][C@@H:4]1[C@@H:13]2[CH2:12][CH2:11][C@@:9]2([CH3:10])[C@H:5]1[CH2:6][CH2:7][C:8]2=[O:22]
Reactant: C[C@]12CCC(=O)C=C1C(Br)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]12CCC(=O)C(N)=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 100 °C
Yield: 36 %

Procedure:
To a stirred solution of 1.1 g of 6-bromoandrost-4-en-3,17-dione in 57.4 ml of dimethylformamide are added 0.250 g of sodium azide dissolved in 2 ml of water. The resulting mixture is heated at 100° C. for 90 minutes, cooled and worked up as described in the example 1. There are obtained 0.325 g of the title compound, m.p. 148°-150° C. (dec.).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[N:4][N:3]1[C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=O.Cl.[NH2:20][CH2:21][C:22]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[N:4][N:3]1[C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=1)[C:14]([NH:20][CH2:21][C:22]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:16]
Reactant: NCC1(O)CCCCCC1
Reactant: Cc1ccc(-n2ncc(=O)[nH]c2=O)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2ncc(=O)[nH]c2=O)cc1C(=O)NCC1(O)CCCCCC1
Yield: 41.2 %

Procedure:
A slurry of 5-(3,5-Dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-methyl-benzoic acid (5.0 g, 20.2 mmol), 1-aminomethyl-cycloheptanol HCl (5.4 g, 30.3 mmol), EDCI (5.8 g), and DMAP (7.4 g, 60.6 mmol) in DMF (67.3 mL) was stirred at ambient temperature for 14 hours. The reaction was then poured into 1N HCl (50 mL) and diluted with water (15 fold). The aqueous was extracted with CH2Cl2 (3×). The organics were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a tan solid. The crude was recrystallized from CH2Cl2 to give the title compound as an off-white solid (3.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:11])[C:8]=1[O:9][CH3:10])[NH2:5].[C:12](Cl)(Cl)=[O:13]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:5]=[C:12]=[O:13])[CH:6]=[C:7]([Cl:11])[C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)Cl
Reactant: COc1c(Cl)cc(N)cc1Br
Solvent: Cc1ccccc1
Product: COc1c(Cl)cc(N=C=O)cc1Br
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A mixture of 3-bromo-5-chloro-4-methoxyaniline (13.0 g) in toluene (100 ml) was dropwise added to a toluene solution containing 20 g of phosgene at 10° to 20° C. The resulting mixture was gradually heated and, after being refluxed for 30 minutes, cooled to room temperature. The solvent was removed by distillation under reduced pressure to give 3-bromo-5-chloro-4-methoxyphenyl isocyanate (14.4 g). The thus obtained crude substance was added to an isopropanol solution (50 ml) containing triethylamine (1 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of benzene and tetrahydrofuran as the eluent to give isopropyl N-(3-bromo-5-chloro-4-methoxyphenyl)carbamate (Compound No. 33) (16.4 g) in a yield of 92% (calculated from the starting 3-bromo-5-chloro-4-methoxyaniline).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:39])([F:38])[C:13]([CH2:33][NH:34][CH2:35][CH2:36][CH3:37])([OH:32])[CH2:14][NH:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:34]([CH2:35][CH2:36][CH3:37])[CH2:33][C:13]([OH:32])([CH2:14][NH:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:12]([F:38])([F:11])[F:39])=[O:6]
Reactant: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: O=C(O)c1ccccc1F
Product: CCCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1F

Procedure:
Prepared similarly to Example 11 from 2-fluorobenzoic acid and 1,1,1-trifluoro-3-[(6-methyl-1-phenyl-1H-indazol-4-yl)amino]-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[OH:31])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:32][O:33][CH2:34][CH2:35][O:36][CH2:37]Cl>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=5)=[CH:18]4)=[CH:13][C:12]=3[O:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COCCOCCl
Reactant: COC(=O)c1ccc(-c2ccc3cc(O)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Product: COCCOCOc1cc2ccc(-c3ccc(C(=O)OC)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Yield: 54.1 %

Procedure:
Following the basic procedure of Example 12, by reacting 980 mg (2.4 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 330 μl (28.6 mmol) of methoxyethoxymethyl chloride, 650 mg (55%) of the expected compound were obtained in the form of an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10](Cl)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[N:15]=1.C1N2CCN(CC2)C1>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:20][C:16]2[N:15]=[N:14][CH:19]=[CH:18][CH:17]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: Nc1cccnn1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: N#Cc1cc(S(=O)(=O)Nc2cccnn2)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.7 %

Procedure:
To a solution of 3-cyano-4-fluorobenzenesulfonyl chloride (11.55 g, 52.63 mmol) in anhydrous acetonitrile (250 mL) was added pyridazin-3-amine (5 g, 52.63 mmol) followed by DABCO (5.9 g, 52.63 mmol) at 0° C. The reaction was stirred at room temperature for 18 hours, and then filtered. The filtrate was concentrated in vacuo and purified using silica gel column chromatography to afford the title compound (4.5 g, 30%)
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][N:38]=1>C(OCC)(=O)C>[F:43][C:40]1[CH:41]=[CH:42][C:37]([C:16]2[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:14][CH:15]=2)=[N:38][CH:39]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Fc1ccc(Br)nc1
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccc(-c2ccc(F)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromo-5-fluoropyridine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.363, m/z=390.9; 1H NMR (CDCl3) 1.11 (s, 3H), 1.19 (s, 3H), 1.53 (d, 3H), 2.16-2.30 (m, 4H), 2.32-2.43 (m, 1H), 2.86 (m, 1H), 5.71 (m, 1H), 7.03 (d, 2H), 7.30 (m, 1H), 7.36 (m, 4H), 7.44 (m, 1H), 7.69 (dd, 1H), 7.68 (d, 2H), 8.43 (d, 1H). The compound was dissolved in refluxing ethyl acetate and allowed to cool slowly to rt to afford a solid with mp 159-160° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:36])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[C:19]([F:21])[CH:20]=3)[N:14]=1)[N:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10](=[O:29])[C:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:8]2)=[O:4].[NH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:22]([N:11]1[C:12]2[C:7](=[C:6]([OH:36])[C:5]([C:3]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:21])[CH:20]=2)[CH:8]=[C:9]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:10]1=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1nc(-c2cncc(F)c2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cncc(F)c2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 38.8 %

Procedure:
A mixture of 1-benzyl-8-(5-fluoro-pyridin-3-yl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (32 mg, 0.067 mmol), β-alanine (593 mg, 6.7 mmol) and NaOMe solution (10 mL, 5.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration. The crude solid was purified by silica gel chromatography (5-80% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 14 mg of the title compound as a light yellow solid. MS: (+) m/z 539.29 (M+1).
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:29][O:30][CH2:31]Cl.O>C1COCC1.C1(C)C=CC=CC=1>[CH3:29][O:30][CH2:31][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: COCCl
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1(COC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (2.57 g) in THF (26 ml) was added 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (24.0 ml) under at −70° C. After 15 minutes, chloromethyl methyl ether (1.2 ml) was added and it was stirred at 0° C. for 2 hours. Water was added and extracted with EtOAc. The organic phase was washed with water and brine, dried over MgSO4, evaporated under reduced pressure. The residue was purified by silica gel column to give 1-tert-butyl 4-ethyl 4-(methoxymethyl)piperidine-1,4-dicarboxylate (2.05 g) as oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[Br:16][C:17]1[C:22]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:21][CH:20]=[C:19]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:18]=1.CN1C(=O)CCC1>C1COCC1>[Br:16][C:17]1[C:22]([CH:23]=[CH:24][C:25]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[O:26])=[CH:21][CH:20]=[C:19]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:18]=1
Reactant: CC(C)(C)c1ccc(C=CC(=O)O)c(Br)n1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1ccc(C=CC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)c(Br)n1
Yield: 32.7 %

Procedure:
3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (116 mg, 0.454 mmol) was reacted with 3-(2-bromo-6-tert-butyl-pyridin-3-yl)-acrylic acid (1.0 eq, 129 mg) DMTMM (1.0 eq, 126 mg) and NMP (1.2 eq, 60 μl) in THF to give the title compound (72 mg, 32.8%) after purification by column chromatography (Hex/EtOAc=1/1).