Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[F:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20]/[N:21]=[C:10](/[C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=2)\[CH3:11])=[CH:17][CH:16]=1
Reactant: NOCc1ccc(F)cc1
Reactant: COc1ccc(C(C)=O)cc1O
Agent: Cl
Product: COc1ccc(/C(C)=N/OCc2ccc(F)cc2)cc1O
Yield: 80.4 %

Procedure:
Acetophenone 12 (50 mg, 0.301 mmol) was condensed with O-(4-fluorobenzyl)hydroxylamine hydrochloride (29) (58 mg, 0.327 mmol) according to the general procedure II-B defined above. After being heated for 24 h the reaction mixture was cooled and the solvent removed under reduced pressure. The ensuing residue was dissolved in CH2Cl2 (15 mL) and the resulting solution washed with H2O (2×10 mL) then dried (MgSO4), filtered and concentrated under reduced pressure. The oil thus obtained was subjected to flash chromatography (1:19 v/v ethyl acetate/hexane elution) to afford the title compound CP30266 (70 mg, 80%) as a pale-purple waxy-oil, Rf 0.5 in 1:1 v/v ethyl acetate/hexane.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:9]=2)=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCNCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.7 %

Procedure:
To a solution of tert-butyl 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-piperidinecarboxylate (0.69 g, 1.4 mmol) in dry CH2Cl2 (25 ml) at 0° C. was added TFA (5 ml). The solution was stirred at room temperature for 20 hr and the solvent evaporated. NaOH solution (5N, 10 ml) was added and the resulting slurry was extracted with EtOAc (3×50 ml). Wash with brine (1×50 ml). Dry, filter and concentrate to leave a solid which was triturated with diethylether and filtered to leave 5-(4-phenoxyphenyl)-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (433258) as a white solid (500 mg, 91%). M.pt 209-211° C. Rf in 1:1 EtOAc : MeOH=0.1. 1H NMR (d6 DMSO, 250 MHz) 8.13 (1H, s), 7.36-7.48 (4H, m), 7.29 (1H, s), 7.04-7.16 (5H, m), 5.80 (2H, bs), 4.64 (1H, m), 3.10 (2H, m), 2.80 (1H, bs), 2.67 (2H, m), 1.94 (4H, m). Mass spec. C23H23ON5 (385.1902). IR (KBr disc): 3278, 1620, 1585, 1490, 1245 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CO.CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:19][C@H:18]([OH:17])[CH2:20][O:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[CH:25][NH:26]3)[CH2:15][CH:16]=1
Reactant: Clc1cccc2c(C3=CCNCC3)c[nH]c12
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CS(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2c[nH]c3c(Cl)cccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 7-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.50 g, 2.2 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.41 g, 2.2 mmol). The product was isolated as a white foam. Yield 370 mg (41%). mp 85°-90° C. FDMS m/e=421 (M+ of free base). α[D]589 =+3.62 (c=1.00, methanol/dimethylsulfoxide).
Reaction SMILES: [Se](O)(O)=[O:2].[CH3:5][O:6][C:7](=[O:21])[CH2:8][C:9]1[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]2[C:10]=1[N:11]=[C:12]([CH3:20])[CH:13]=[N:14]2>O1CCOCC1.O>[CH3:5][O:6][C:7](=[O:21])[CH2:8][C:9]1[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]2[C:10]=1[N:11]=[C:12]([CH:20]=[O:2])[CH:13]=[N:14]2
Reactant: O=[Se](O)O
Reactant: COC(=O)Cc1c(Cl)ccc2ncc(C)nc12
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)Cc1c(Cl)ccc2ncc(C=O)nc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Selenious acid (645 mg, 5.00 mmol, 1.1 equiv) was added to a solution of (6-chloro-3-methyl-quinoxalin-5-yl)-acetic acid methyl ester in dioxane (30 ml). The reaction mixture was heated to 100° C. After 60 minutes, an additional portion of selenious acid (645 mg) was added, and heating was continued for another 60 minutes. After cooling, the reaction mixture was diluted with water, filtered, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash chromatography (gradient of hexane/EtOAc 100:0 to 80:20) to afford the title compound (966 mg, 81%). MS (ES+): 264 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1>C(O)(=O)C.[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: COc1cccc(Cc2ccncc2)c1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: COc1cccc(CC2CCNCC2)c1
Reaction time: 2 h
Yield: 87.4 %

Procedure:
A mixture of 4-(3-methoxybenzyl)pyridine (25 g, 126 mmole) and platinum oxide (2.4 g) in acetic acid (250 ml) was hydrogenated for 2 hr. The catalyst was removed and the solution concentrated in vacuo. The residue was dissolved in water and the solution basified with sodium hydroxide. The basic mixture was extracted with ether. The extracts were dried and concentrated in vacuo. The residue was vacuum distilled to give 4-(3-methoxy-benzyl)piperidine as an oil (22.6 g, 87.6% ). A sample of the hydrochloride was prepared in ether (mp: 146°-147° C.). Calc'd. for C13H19NO.HCl: C, 64.59%; H, 8.34%; N, 5.80%. Found: C, 64.38%; H, 8.34%; N, 5.66%.
Reaction SMILES: [OH:1][C:2]([CH3:20])([C:9]([CH3:19])=[CH:10][CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+].[Br:23]Br>CO.C(=O)([O-])O.[Na+].O.CO>[OH:1][C:2]1([CH3:20])[C:9]([CH3:19])([Br:23])[CH:10]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: BrBr
Reactant: CCOC(=O)CC(C)(O)C(C)=CC=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(O)CC(=O)OC(C=Cc2ccccc2)C1(C)Br
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
The carboxylic acid (1.09 g) prepared by hydrolyzing 12.20 g of ethyl 3-hydroxy-3,4-dimethyl-7-phenyl-4,6-heptadienoate with 4 N sodium hydroxide solution in 60 ml of methanol, was dissolved in a solution of 700 mg of sodium hydrogen carbonate in 40 ml of a solvent mixture of water-methanol (1:1) and a solution of 1.06 g of bromine in 1 ml of methanol was dropwise added thereto under cooling at -30°~35° C. After stirring for 30 minutes, the crystals produced were collected by filtration, washed with water, dried, and recrystallized from a mixture of n-hexane and ethyl acetate (5:1) to give 750 mg of the desired compound melting at 121°-123° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15](Cl)=[O:16].[NH2:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21]([Cl:25])[N:20]=1.O>CN(C)C=O>[Cl:25][C:21]1[N:20]=[C:19]([NH:18][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:13])(=[O:12])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:16])[CH:24]=[N:23][CH:22]=1
Reactant: Nc1cncc(Cl)n1
Reactant: CN1C(C(=O)Cl)=C(O)c2ccccc2S1(=O)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.2 %

Procedure:
1.23 g (4.5 mmols) of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid chloride-1,1-dioxide were dissolved in 10 ml of dimethylformamide, and 1.3 g (10 mmols) of 2-amino-6-chloro-pyrazine were added in portions thereto. The reaction mixture was stirred for 24 hours at room temperature and was then mixed with 40 ml of water. The aqueous mixture was stirred for 20 minutes at room temperature, and then the precipitate which had formed was filtered off, washed and dried. Recrystallization from dioxane yielded 0.4 g (24% of theory) of N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][CH2:13][NH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:37]=[CH:36][C:30]([NH:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=1>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][CH2:13][NH:14][C:33](=[O:34])[CH2:32][NH:31][C:30]2[CH:36]=[CH:37][C:27]([Cl:26])=[CH:28][CH:29]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNc1ccc(Cl)cc1
Reactant: NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: c1ccccc1
Product: O=C(CNc1ccc(Cl)cc1)NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 190 °C
Reaction time: 3 h
Yield: 50.4 %

Procedure:
A mixture of 3,4-dibenzyloxyphenethylamine (36.2 g) and p-chloroanilinoacetic acid (20 g) was stirred for 3 hours at 190° C. The reaction mixture was dissolved in benzene. The solution was washed with a diluted potassium carbonate aqueous solution and dried. The solvent was distilled off from the benzene solution and the residue obtained was purified by column chromatography on silica gel to give N-[2-(3,4-dibenzyloxyphenyl)ethyl]-2-(p-chloroanilino)acetamide (27.2 g), mp 121° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([F:17])=[CH:4][C:3]=1[C:18]1[N:22]([C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[N:21]=[CH:20][C:19]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29].I[C:34]1[C:39]([CH3:40])=[CH:38][N:37]=[C:36]([O:41][CH3:42])[C:35]=1[CH3:43].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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.O>[F:1][C:2]1[CH:7]=[C:6]([C:34]2[C:39]([CH3:40])=[CH:38][N:37]=[C:36]([O:41][CH3:42])[C:35]=2[CH3:43])[C:5]([F:17])=[CH:4][C:3]=1[C:18]1[N:22]([C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[N:21]=[CH:20][C:19]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: COc1ncc(C)c(I)c1C
Reactant: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1cc(F)c(B2OC(C)(C)C(C)(C)O2)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1cc(F)c(-c2c(C)cnc(OC)c2C)cc1F
Temperature: 25 °C

Procedure:
Ethyl 5-(4-bromo-2,5-difluorophenyl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxylate obtained in Preparation Example 11-1 (4.31 g), bis(pinacolato)diboron (3.27 g), potassium acetate (3.16 g) and Pd(dppf)Cl2-DCM complex (439 mg) were added to DMF (41.6 mL), and the mixture was stirred at 95° C. in a nitrogen atmosphere. After two hours, the reaction mixture was stirred at 105° C. for four hours. The reaction mixture was cooled to room temperature and filtered through Celite™. The filtrate was concentrated under reduced pressure, brine and ethyl acetate were added to the residue, and the mixture was then stirred at room temperature for five minutes. The mixture was filtered again through Celite™, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered through Celite™. The filtrate was concentrated. The residue was purified by silica gel chromatography (n-heptane/ethyl acetate, 20% to 30% to 80%) to give ethyl 5-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxylate (2.95 g). The resulting ethyl 5-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1((S)-tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxylate (900 mg), 4-iodo-2-methoxy-3,5-dimethylpyridine obtained in Preparation Example 29(3) (634 mg), Pd(PPh3)4 (116 mg) and cesium carbonate (1.96 g) were added to a mixed solvent of 1,4-dioxane (9.3 mL) and water (3.1 mL), and the mixture was heated under reflux for 2.5 hours. The reaction mixture was cooled to room temperature and partitioned by adding ethyl acetate and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane, first time: 15% to 36% to 47%, second time: 10% to 30% to 35%) to give the title compound (280 mg).
Reaction SMILES: C(OC(=O)[N:7](C)[C@@H:8]([C:16](=[O:24])[NH:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][O:20]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.F[C:28](F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:28][C@@:8]([NH2:7])([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]([NH:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][O:20]1)=[O:24]
Reactant: O=C(O)C(F)(F)F
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)NCC1CCCO1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@](N)(Cc1ccccc1)C(=O)NCC1CCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl-((1R)-2-phenyl-1-((tetrahydrofuran-2-ylmethyl)carbamoyl)ethyl)carbamic acid tert-butyl ester (5.5 g; 15.2 mmol) was dissolved in methylene chloride (20 mL) and trifluoroacetic acid (20 mL) was added. The reaction mixture was stirred for 1 hour at room temperature. Methylene chloride (100 mL) and an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9, 50 mL) were added and solid sodium hydrogen carbonate was added until pH 8. The aquous phase was extracted with methylene chloride (100 mL) and the combined organic phases were dried (magnesium sulfate). The solvent was removed in vacuo to afford 3.62 g of (2R)-2-Methyl-amino-3-phenyl-N-((2-tetrahydrofuranyl)methyl)propionamide.
Reaction SMILES: CCO.C1(C)C(S([N:13]2[CH:17]=[CH:16][CH:15]=[C:14]2[C:18](=[O:32])[C:19]2[CH:24]=[CH:23][C:22]([NH:25]C(=O)C(F)(F)F)=[CH:21][CH:20]=2)(=O)=O)=CC=CC=1.[OH-].[K+]>CCOC(C)=O>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:14]2[NH:13][CH:17]=[CH:16][CH:15]=2)=[O:32])=[CH:20][CH:21]=1
Reactant: Cc1ccccc1S(=O)(=O)n1cccc1C(=O)c1ccc(NC(=O)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)c2ccc[nH]2)cc1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To a stirred EtOH (4 mL) solution containing N-toluenesulfonyl-2-(4-(trifluoroacetylamino)benzoyl)pyrrole (0.500 g, 1.15 mmol), was added 40% KOH solution (2 mL) and the mixture was heated at reflux until thin layer chromatography (TLC) analysis showed complete conversion of the starting material. The resulting solution was cooled to room temperature and diluted with EtOAc (20 mL), and the mixture was evaporated to dryness. The crude product was purified by column chromatography (SiO2, EtOAc:Hexanes) to afford the purified product 2-(4-aminobenzoyl)pyrrole (196 mg, 94% yield). 1H NMR (400 MHz, CD2Cl2, 25° C.) δ4.19 (bs, 2H), 6.33 (m, 1H), 6.72 (d, 2H), 6.88 (m, 1H), 7.10 (m, 1H), 7.82 (d, 2H), 9.90 (bs, 1H); 13C NMR (100 MHz, CD2Cl2, 25° C.) δ 110.9, 114.2, 118.0, 124.5, 128.5, 131.8, 131.9, 151.3, 183.5; HRMS (EI): m/z 186.0793 (100) {M}+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[Br-].[CH3:19][N:20]1[CH2:24][CH2:23][CH:22]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:21]1=[O:44].C(N(CC)CC)C>C(O)C>[CH3:19][N:20]1[CH2:24][CH2:23][C:22](=[CH:8][C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:12]([OH:13])=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=2)[C:21]1=[O:44]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CN1CCC([P+](c2ccccc2)(c2ccccc2)c2ccccc2)C1=O
Agent: [Br-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 61.9 %

Procedure:
1.2 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde, 2.5 g of (N-methyl-2-pyrrolidone-3-yl)triphenylphosphonium bromide and 1.0 ml of triethylamine were heated under reflux in ethanol for two hours. After distilling the ethanol off, the residue was dissolved in chloroform, washed with water followed by a saturated saline solution and dried over anhydrous magnesium sulfate. After distilling the chloroform off, the residue was subjected to column chromatography with the use of silica gel and benzene/acetone and recrystallized from a mixture of ethyl acetate and hexane to give 1.0 g of the title compound.
Reaction SMILES: [C@@H:1]12[O:9][CH2:8][C@@H:6]([O:7]1)[CH:5]=[CH:4][C@@H:2]2[OH:3].[S:10](Cl)([CH3:13])(=[O:12])=[O:11].Cl>N1C=CC=CC=1>[S:10]([O:3][C@H:2]1[CH:4]=[CH:5][C@H:6]2[CH2:8][O:9][C@@H:1]1[O:7]2)([CH3:13])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1C=C[C@H]2CO[C@@H]1O2
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)O[C@H]1C=C[C@H]2CO[C@@H]1O2
Yield: 63.7 %

Procedure:
0.25 g (1.98 mmol) of 1,6-anhydro-3,4-dideoxy-β-D-threo-hex-3-enopyranose were dissolved in 2 ml of pyridine, and 0.34 g (3.00 mmol) of mesyl chloride were dropped in this mixture under ice-water cooled conditions. The resultant solution was stirred at 0° C. for 3.5 hours and then stored in a refrigerator overnight. This reaction solution was added to 1N hydrochloric acid under ice-water cooled conditions, and extraction was performed using diethyl ether. The resultant diethyl ether solution was washed with an aqueous sodium hydrogencarbonate solution and then with an aqueous sodium chloride solution. The washed solution was dried using magnesium sulfate. The solvent was distilled at a reduced pressure, and the residue was recrystallized using a solvent mixture of hexane, diethyl ether, and ethyl acetate (a mixing ratio of 5:5:2), thereby obtaining 0.26 g (yield: 62.6%) of 1,6-anhydro-3,4-dideoxy-2-O-mesyl-β-D-threo-hex-3-enopyranose.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]12[C:15](=[O:16])[NH:14][C:12]3[C:13]1=[C:8]([CH:9]=[CH:10][CH:11]=3)[NH:7][C:6](=[O:17])[CH2:5]2.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CN(C=O)C>[CH3:3][C:4]12[C:15](=[O:16])[N:14]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]3[C:13]1=[C:8]([CH:9]=[CH:10][CH:11]=3)[NH:7][C:6](=[O:17])[CH2:5]2
Reactant: CC12CC(=O)Nc3cccc(c31)NC2=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)C2(C)CC(=O)Nc3cccc1c32
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (71 mg of a 60% dispersion in mineral oil, 1.78 mmol) was added to a solution of (±)-2a-methyl-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3H)-dione from Step C (298 mg, 1.47 mmol) in DMF (3 mL) at 0° C. After 1 h, tert-butyl bromoacetate (0.219 mL, 1.48 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was quenched with H2O (5 mL) and extracted with CH2Cl2 (3×10 mL) then EtOAc (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=317 (M+1).
Reaction SMILES: [CH2:1]([C@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.FC1C=CC(C2(CCO)[O:36]C(=O)NCC2)=CC=1>>[CH3:14][C:13]([CH3:15])([CH3:16])[C@@H:11]([N:7]1[CH2:6][CH2:5][C:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([CH2:1][CH2:2][OH:36])[O:9][C:8]1=[O:10])[CH3:12]
Reactant: O=C1NCCC(CCO)(c2ccc(F)cc2)O1
Reactant: C=CC[C@@]1(c2ccc(F)cc2)CCN([C@@H](C)C(C)(C)C)C(=O)O1
Product: C[C@H](N1CCC(CCO)(c2ccc(F)cc2)OC1=O)C(C)(C)C

Procedure:
(S)-6-allyl-3-((2S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one [Isomer 2] (500 mg, 1.57 mmol) was converted to (R)-3-(S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one [Isomer 2] (300 mg, 59%) following a procedure analogous to that described immediately above. LC-MS Method 1 tR=1.112, min, m/z=324.2; 1H NMR (CDCl3): 0.85-0.99 (m, 12H), 2.09-2.18 (m, 1H), 2.19-2.34 (m, 3H), 2.73-2.84 (m, 1H), 3.12-3.28 (m, 1H), 3.48-3.57 (m, 1H), 3.69-3.76 (m, 1H), 4.26-4.35 (m, 1H), 7.02-7.08 (m, 2H), 7.24-7.32 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=2)=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].Cl.[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)N>CO>[Cl:24][C:25]1[CH:31]=[C:30]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([NH:13][C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH3:22])=[CH:18][CH:19]=4)[C:3]=23)[CH:29]=[CH:27][CH:26]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOc1ccc(Nc2n[nH]c(N=CN(C)C)c2C#N)cc1
Agent: Cl
Solvent: CO
Product: CCOc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 10 °C

Procedure:
A mixture of 5.8 g (19.44 mmol) of 4-cyano-5-(dimethylamino-methyleneamino)-3-(4-ethoxy-phenylamino)-pyrazole, 3.51 g (21.4 mmol) of 3-chloro-aniline hydrochloride and 40 ml of methanol is heated under reflux for 15 hours. Cooling to 10° C., filtering and washing the filter residue with methanol and diethyl ether yield the title compound; m.p. 232-233° C.; EI-MS: (M)+ =380.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[N:13][C:14]([CH:18]2[CH2:20][CH2:19]2)=[C:15]([Cl:17])[CH:16]=1)[C:5]#[N:6].[CH3:21][O:22][C:23]1[C:28](B(O)O)=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:17][C:15]1[CH:16]=[C:11]([O:10][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[C:28]2[C:23]([O:22][CH3:21])=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:12]=[N:13][C:14]=1[CH:18]1[CH2:20][CH2:19]1
Reactant: COc1ncccc1B(O)O
Reactant: N#Cc1ccc(Oc2cnc(C3CC3)c(Cl)c2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncccc1-c1cc(C#N)ccc1Oc1cnc(C2CC2)c(Cl)c1
Temperature: 75 °C
Yield: 92.3 %

Procedure:
3-bromo-4-(5-chloro-6-cyclopropylpyridin-3-yloxy)benzonitrile (Preparation 38, 485 mg, 1.37 mmol), 2-methoxypyridin-3-ylboronic acid (233 mg, 1.53 mmol) and cesium carbonate were suspended in dioxane (6 mL) and water (3 mL). The suspension was degassed 20 minutes with nitrogen then tetrakis-triphenylphosphinepalladium (80 mg, 0.07 mmol) were added and the reaction mixture was heated overnight at 75° C. The solution was concentrated in vacuo to a quarter of the volume then diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography to afford the title compound as a foam (478 mg, 91%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([C:22](=[CH2:27])[C:23]([F:26])([F:25])[F:24])=[N:17][N:16]=[CH:15]2>CO.[Pd]>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([CH:22]([CH3:27])[C:23]([F:26])([F:24])[F:25])=[N:17][N:16]=[CH:15]2
Reactant: C=C(c1nncc2cc(-c3cc(C(=O)OC)ccc3C)ccc12)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(C)c(-c2ccc3c(C(C)C(F)(F)F)nncc3c2)c1
Yield: 45.3 %

Procedure:
A solution of methyl 4-methyl-3-(1-(1,1,1-trifluoroprop-2-en-2-yl)phthalazin-6-yl)benzoate (200 mg, 537 μmol) in methanol (3000 μl) was added palladium (10 wt. % on activated carbon; 22.9 mg, 215 μmol) and hydrogenated (double-walled balloon pressure) at room temperature for 20 h, during which LC-MS indicated complete conversion. The reaction was filtered via a pad of Celite®, and the filtrate was concentrated in vacuo and purified by CombiFlash (20% to 80% EtOAc/Hexanes) to afford methyl 4-methyl-3-(1-(1,1,1-trifluoropropan-2-yl)phthalazin-6-yl)benzoate (91.1 mg, 45.3% yield) as a golden yellow foam. MS (ES+): 375.2 (M+H)+.