Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][CH2:25][CH2:26][N:27](C)[C:28](=O)OC(C)(C)C)[CH2:19]4)[C:14]([F:36])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.O1CCOCC1>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][CH2:25][CH2:26][NH:27][CH3:28])[CH2:19]4)[C:14]([F:36])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(CCN[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNCCN[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a flask containing tert-butyl 2-((1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexylamino)ethyl(methyl)carbamate, 47b, (0.02 g, 0.04 mmol) in dichloromethane/MeOH mixture was added HCl in Dioxane (3.86 mL of 4 M solution, 15.44 mmol). The solution was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure and used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[F:9][C:10]([F:20])([F:19])[CH2:11][CH2:12][C:13](N(OC)C)=[O:14].[Cl-].[NH4+]>C1COCC1>[O:5]1[CH2:6][CH2:7][O:8][CH:4]1[CH2:3][CH2:2][C:13](=[O:14])[CH2:12][CH2:11][C:10]([F:20])([F:19])[F:9]
Reactant: BrCCC1OCCO1
Reactant: CON(C)C(=O)CCC(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(CCC1OCCO1)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
Mg (92.0 mmol, 2.2 g) in TBF (80 ml), under an argon atmosphere, was treated with 2-(2-bromoethyl)-[1,3]dioxolane (80 mmol, 9.4 ml), while keeping the internal temperature below 35° C. with the aid of an ice bath. After the addition was complete, the mixture was stirred for 2 h at room temperature, then cooled to −78° C. Crude 4,4,4-trifluoro-N-methoxy-N-methyl butyramide (20 g, prepared above) in THF (40 ml) was cooled to −78° C., then the freshly prepared Grignard reagent was transferred via cannula into the amide solution at −78° C. The resulting mixture was allowed to warm to room temperature, held at room temperature overnight, then poured into saturated aqueous ammonium chloride (200 ml). The mixture was extracted with ethyl acetate (3×75 ml). The combined organics were washed with brine (2×75 ml) and concentrated under reduced pressure to provide crude 1-[1,3]dioxolan-2-yl-6,6,6-trifluoro-hexan-3-one (18 g) 1H NMR (CDCl3) δ4.91 (1H, t, J=4.1), 3.97-3.82 (4H, m), 2.70 (2H, t, J=7.3), 2.57 (2H, t, J=7.2), 2.49-2.34 (2H, m), 2.01 (2H, dt, J=7.3, 4.1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[N:12]=1>O1CCOCC1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[CH:9][C:8](=[O:11])[NH:7][C:6]=2[N:12]=1
Reactant: O=C1CNc2ccc(Cl)nc2N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: O=c1cnc2ccc(Cl)nc2[nH]1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
To a mixture of 6-chloro-1,2-dihydropyrido[2,3-b]pyrazin-3(4H)-one (E-26) (3.68 g, 20 mmol, 1.0 eq) in 1,4-dioxane (80 mL), manganese dioxide (19.4 g, 223 mmol, 11.1 eq) was added. The resulting mixture was stirred at reflux for 2 h then cooled to RT, filtered, the cake was washed with ethyl acetate and methanol. The combined filtrates were concentrated in vacuo to afford the desired product 6-chloropyrido[3,2-b]pyrazin-3(4H)-one (E-27) (3 g, 82% yield) as a pale solid. 1H NMR (300 MHz, DMSO-d6) δ: 13.03 (bs, 1H), 8.19 (m, 2H), 7.38 (d, J=8.4 Hz, 1H); ESI-MS m/z: 180.00 [M−H]−.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:23][CH:22]2[CH:18]([CH2:19][NH:20][CH2:21]2)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CCN(C(C)C)C(C)C>C(#N)C.[NH4+].[Cl-]>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:20]2[CH2:19][CH:18]3[CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:23][CH:22]3[CH2:21]2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: Clc1ncnc(Cl)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(c3ncnc(Cl)n3)CC2C1
Yield: 44.1 %

Procedure:
To a solution of 2,4-dichloro-1,3,5-triazine (150 mg, 0.953 mmol) in ACN (5 mL) was added a solution of Intermediate 15 (202 mg, 0.953 mmol) and DIPEA (0.33 mL, 1.91 mmol) in ACN (5 mL) at 0° C. dropwise. After 10 min the mixture was diluted with saturated aqueous NH4Cl solution. The aqueous layer was then extracted with DCM and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography (Hexanes to 80% EtOAc/Hexanes) afforded the desired product as a white solid (137 mg, 44%). MS (ESI) mass calculated for C14H20ClN5O2, 325.13; m/z found, 326.1.
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[CH3:22][S:23][CH2:24][C:25]1[CH:26]=[C:27]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1>CS(C)=O>[F:1][C:2]1[C:20]([N:34]2[CH2:33][CH2:32][N:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][S:23][CH3:22])[CH:26]=3)[CH2:36][CH2:35]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: CSCc1cccc(N2CCNCC2)c1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Solvent: CS(C)=O
Product: CSCc1cccc(N2CCN(c3cc4nc5c(cc4cc3F)c(=O)c(C(=O)O)cn5C)CC2)c1
Yield: 79.9 %

Procedure:
7-Fluoro-1-methyl-8-[4-[3-(methylsulphanylmethyl)phenyl]piperazin-1-yl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 1, but from 0.45 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 0.66 g of [3-(methylsulphanylmethyl)phenyl]piperazine in 15 cm3 of dimethyl sulphoxide. After washing 2 times with 15 cm3 of ethanol, 0.61 g of 7-fluoro-1-methyl-8-[4-[3-(methylsulphanylmethyl)phenyl]piperazin-1-yl]-4-oxo-1,4-dihydrobenzo-[b][1,8]naphthyridine-3-carboxylic acid was obtained in the form of a yellow solid melting at about 240-5° C.
Reaction SMILES: ClC1C=C(C2SC(C(O)=O)=CC=2C2C=CC=C(C#N)C=2)C=C(F)C=1.[Cl:25][C:26]1[CH:27]=[C:28]([C:33]2[S:37][C:36]([C:38]([O:40]CC)=[O:39])=[CH:35][C:34]=2[C:43]2[CH:48]=[CH:47][C:46]([F:49])=[C:45]([C:50]#[N:51])[CH:44]=2)[CH:29]=[C:30]([F:32])[CH:31]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([C:33]2[S:37][C:36]([C:38]([OH:40])=[O:39])=[CH:35][C:34]=2[C:43]2[CH:48]=[CH:47][C:46]([F:49])=[C:45]([C:50]#[N:51])[CH:44]=2)[CH:29]=[C:30]([F:32])[CH:31]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)c(C#N)c2)c(-c2cc(F)cc(Cl)c2)s1
Agent: N#Cc1cccc(-c2cc(C(=O)O)sc2-c2cc(F)cc(Cl)c2)c1
Product: N#Cc1cc(-c2cc(C(=O)O)sc2-c2cc(F)cc(Cl)c2)ccc1F

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 19A starting with the compound from Example 18A. 82.3 mg (97% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19]C)[CH:3]=1.[C:21]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])([CH3:23])[CH3:22]>>[Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:17][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:27])[CH3:26])=[CH:15][CH:16]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:27])[CH3:26])[CH:3]=1
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(O[Si](C)(C)C(C)(C)C)cc(Br)c3o2)cc1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 24, Route a, Step a, from 7-bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole, and tertbutyl(chloro)dimethylsilane. The desired product was obtained as a white solid, m.p. 90-91° C.; MS m/e 534 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:21](Cl)([Cl:23])=[O:22].N1C=CC=CC=1>C1COCC1>[Cl:23][C:21]([O:13][C:8]([C:9]([CH3:11])([CH3:12])[CH3:10])=[C:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][CH:19]=1)[N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)=[O:22]
Reactant: CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)C(OC(=O)Cl)=C(Oc1ccc(Cl)cc1)n1cncn1
Reaction time: 72 h
Yield: 36 %

Procedure:
To a solution of 29.4 g (0.01 mole) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)-2-butanone in 250 ml of THF was added 20 ml of liquid phosgene, followed by 9 ml of pyridine. After 3 days, the mixture was filtered and the filtrate evaporated in vacuum to a residual oil. The oil was dissolved in hot 1-chlorobutane and the solution filtered to remove a little white solid. The filtrate was cooled, precipitating a white solid. The solid was isolated by filtration, providing 12.9 g (36% of theoretical) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)-1-buten-2-yl chloroformate, m.p. 159°-161°. The infrared spectrum showed absorption at ca 1800 cm-1.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH:19]1[CH2:23][CH2:22][O:21][CH2:20]1)[N:14]=[CH:13][C:12]([C:24]#[N:25])=[C:11]2[NH:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[C:29]([Cl:41])[CH:28]=1)=[O:6].[Na+].[I-].Cl.[CH3:45][NH:46][CH3:47].C(=O)([O-])[O-].[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:41][C:29]1[CH:28]=[C:27]([NH:26][C:11]2[C:10]3[C:15](=[CH:16][C:17]([O:18][CH:19]4[CH2:23][CH2:22][O:21][CH2:20]4)=[C:8]([NH:7][C:5](=[O:6])/[CH:4]=[CH:3]/[CH2:2][N:46]([CH3:47])[CH3:45])[CH:9]=3)[N:14]=[CH:13][C:12]=2[C:24]#[N:25])[CH:32]=[CH:31][C:30]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1
Reactant: CNC
Reactant: N#Cc1cnc2cc(OC3CCOC3)c(NC(=O)/C=C/CBr)cc2c1Nc1ccc(OCc2ccccn2)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CN(C)C/C=C/C(=O)Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c(C#N)cnc2cc1OC1CCOC1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
(E)-4-bromo-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-butenamide (2.35 g, 3.704 mmol) was dissolved in DMF (chromatographically pure) (40 mL). The solution was cooled in an ice-water bath under argon atmosphere. To the solution was added NaI (278 mg, 1.852 mmol). The mixture was stirred for 30 min. To the mixture were added dimethylamine hydrochloride (604 mg, 7.408 mmol), potassium carbonate (2.556 g, 18.519 mmol) and tetrabutyl ammonium iodide (59 mg, 0.185 mmol). The resultant mixture was stirred at the room temperature overnight. After the reaction finished, the reaction solution was poured into staturated NaHCO3 solution (400 mL) to precipitate a yellow solid. The solid was extracted with ethyl acetate three times (550 mL in total). The ethyl acetate layers were combined. The organic phase was washed with water (300 mL) and saturated NaCl solution (300 mL), successively. The resultant organic phase was dried over anhydrous MgSO4 for half-hour, filtered and rotary-evaporated to dryness. The resultant substance was purified with column chromatography (eluent: chloroform:methanol=9:1) to give a yellow solid (1.375 g). Yield: 62.0%.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.CN(C)[CH:24]=[O:25]>O1CCCC1>[F:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(F)c(C=O)c1
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
Diisopropylamine (0.35 mL, 2.5 mmol) was dissolved in tetrahydrofuran (3.5 mL) and the temperature was adjusted to 0° C. Then, n-butyllithium (hexane solution) (1.24 mL, 2.0 mmol) was dropped thereto, followed by stirring for 10 minutes. Thereafter the reaction temperature was brought to −78° C. 4-Fluorobenzonitile (0.2 g, 1.65 mmol) was added thereto, stirring for 1 hour. Then, dimethylformamide (0.19 mL, 2.5 mmol) was dropped thereto, followed by stirring for 20 minutes and then the conventional treatment was performed. The residue was purified by thin-layer chromatography (hexane: ethyl acetate=8:1), to give 2-fluoro-5-cyanobenzaldehyde (0.11 g, 43.4%).
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[N:22]=[C:21]([NH:23][C@H:24]([CH3:27])[CH2:25][OH:26])[C:20]2[N:19]=[CH:18][C:17](=[O:28])[NH:16][C:15]=2[N:14]=1)(=O)=O.[Cl:29]C1C=C(CS)C=CC=1>>[Cl:29][C:7]1[CH:2]=[C:3]([CH2:9][S:10][C:13]2[N:22]=[C:21]([NH:23][C@H:24]([CH3:27])[CH2:25][OH:26])[C:20]3[N:19]=[CH:18][C:17](=[O:28])[NH:16][C:15]=3[N:14]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](CO)Nc1nc(S(=O)(=O)Cc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Reactant: SCc1cccc(Cl)c1
Product: C[C@H](CO)Nc1nc(SCc2cccc(Cl)c2)nc2[nH]c(=O)cnc12
Yield: 35.9 %

Procedure:
The titled compound (66 mg) was prepared by the method of Example 13, step (c) using the product from Example 13, step (a) (0.20 g) and 3-chloro-benzenemethanethiol (92 mg).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].Br[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:24][C:25]([F:28])([F:27])[F:26])[C:19]=2[F:23])[CH:14]=1.C1(C)C=CC=CC=1>CN(C)C=O.[Cu](I)I.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>[F:23][C:19]1[C:20]2[C:15](=[CH:14][C:13]([C:11]#[C:10][C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)=[CH:22][CH:21]=2)[CH:16]=[CH:17][C:18]=1[O:24][C:25]([F:28])([F:27])[F:26]
Reactant: Fc1c(OC(F)(F)F)ccc2cc(Br)ccc12
Reactant: C#Cc1ccc(CCC)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCc1ccc(C#Cc2ccc3c(F)c(OC(F)(F)F)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.6 %

Procedure:
10 g of 4-propyl-1-ethynylbenzene and 19.5 g of 2-bromo-5-fluoro-6-trifluoromethoxynaphthalene were dissolved in 50 ml of N,N-dimethylformamide (DMF). To the solution wore then added 50 mg of copper iodide (I) and 100 mg of tetrakis(triphenylphosphine)palladium (0). The reaction mixture was then stirred at room temperature for 5 hours. To the reaction solution was then added toluene. Insoluble matters were removed by filtration. The residue was then washed with water and saturated brine. The solvent was then distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate 9/1), and then recrystallized from ethanol to obtain 8.6 g of 1-fluoro-2-trifluoromethoxy-6-[(4-propylphenyl)ethynyl]naphthalene.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.CON(C)[C:14](=[O:29])[C:15]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:17])[CH3:16].CO.Cl>C1COCC1.CCOCC>[CH3:17][C:15]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([CH3:16])[CH:14]=[O:29]
Reactant: CON(C)C(=O)C(C)(C)NC(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C=O)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
Diisobutylaluminum hydride (1.77 mL, 1M solution in toluene, 0.708 mmol) was added to a stirred solution of benzyl {2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxoethyl}carbamate (198.5 mg, 0.708 mmol) in dry THF (7.1 mL) at −78° C. under N2. The reaction was stirred at −78° C. for 4 h. MeOH (100 μt) and 1N HCl (250 μL) were added and the reaction was allowed to warm to room temperature. The mixture was diluted with Et2O (50 mL) and washed with 1N HCl (2×50 mL), 50% saturated NaHCO3 (50 mL) and water (50 mL), then dried (MgSO4) and concentrated in vacuo to give benzyl (1,1-dimethyl-2-oxoethyl)carbamate. Rf=0.40 (20% EtOAc in hexanes). LCMS calc.=244.1; found=244.1 (M+Na)+. 1H NMR (500 MHz, CDCl3) δ 9.43 (s, 1H), 7.38-7.30 (m, 5H), 5.34 (s, 1H), 5.09 (s, 2H), 1.37 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])=[CH:4][CH:3]=1.[N+:23]([O-])([OH:25])=[O:24]>C(O)(=O)C>[N+:23]([C:22]1[CH:21]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])([O-:25])=[O:24]
Reactant: O=[N+]([O-])O
Reactant: CCCCCCCCCCCCOC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Product: CCCCCCCCCCCCOC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reaction time: 0.33 h
Yield: 95.8 %

Procedure:
A solution of 10 g of dodecyl 4-hydroxybenzoate and 60 ml of acetic acid was heated at 30° to 35° C. and a solution of 2 ml of fuming nitric acid and 10 ml of acetic acid was added dropwise thereto over a 20 minute period with stirring. After the completion of the addition, the mixture was stirred for 1 hour. The crystals deposited in the reaction mixture were collected by filtration, washed with water and recrystallized from ethanol to obtain 11.0 g (yield 95.8%) of the desired compound having a melting point of 70° C.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[C:6]([C:10](=O)[CH3:11])[CH:7]=[N:8][CH:9]=1)[CH3:3].[NH2:13][OH:14].Cl>CCO.O.[OH-].[Na+]>[CH2:1]=[C:2]([C:4]1[CH:5]=[C:6]([C:10](=[N:13][OH:14])[CH3:11])[CH:7]=[N:8][CH:9]=1)[CH3:3]
Reactant: C=C(C)c1cncc(C(C)=O)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=C(C)c1cncc(C(C)=NO)c1
Yield: 79.4 %

Procedure:
To a stirred solution of 1-(5-(prop-1-en-2-yl)pyridin-3-yl)ethanone (460 mg, 2.86 mmol) in 95% EtOH was added a solution of NH2OH.HCl (1.19 g, 17.14 mmol) in a mixture of water (5.8 mL) and 10% NaOH (5.8 mL) and refluxed for 2.5 h. All solvent was removed. The residue was dissolved in CHCl3, washed with water, dried with Na2SO4 and concentrated under reduced pressure to yield 400 mg of crude 1-(5-(prop-1-en-2-yl)pyridin-3-yl)ethanone oxime.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.Cl.[CH2:14](O)[CH3:15]>>[Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:14][CH3:15])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.00 g of 2-[4-(bromomethyl)phenyl]acetic acid was suspended in 5 mL of a 4M solution of hydrogen chloride in ethanol, and this suspension was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure to yield 0.954 g of ethyl 2-[4-(bromomethyl)phenyl]acetate as light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[C:15]([CH3:25])[N:14]=3)=[O:9])=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[N:14][C:15]([CH3:25])=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:28])[CH:11]=2)=[O:9])=[CH:26][CH:27]=1
Reactant: Cc1nc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2cc1C#CCO
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(cc1C#CCO)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a mixture of the N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-7-methyl[1,8]naphthyridine-3-carboxamide (0.081 g, 0.212 mmol) and potassium carbonate (0.117 g, 0.848 mmol) in 5 mL DMF is added methyl iodide (0.036 g, 0.254 mmol). The mixture is stirred at room temperature for 30 min then diluted with water. The resulting precipitate is filtered and dried. The crude solid is triturated with EtOAc/hexanes to yield 0.072 g (86%) of the desired product as a pale yellow solid. Physical characteristics are as follows: m.p. 217-218° C.; 1H NMR (DMSO-d6) δ10.13, 8.99, 8.46, 7.39, 5.47, 4.55, 4.40, 3.99, 2.75; IR (drift) 3395, 1661, 1604, 1561, 1544, 1503, 1413, 1357, 1261, 1032, 1017, 842, 811, 800, 601 cm1; MS (EI) m/z (rel. intensity) 395 (M+, 8), 255 (29), 229 (17), 228 (99), 198 (41), 169 (14), 140 (54), 89 (15), 77 (14), 73 (22), 73 (17); HRMS (FAB) calcd for C21H18ClN3O3 +H1 396.1115, found 396.1121.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([F:16])([F:15])[F:14])[CH:10]([C:17](OCC)=[O:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([F:16])([F:14])[F:15])[CH:10]([CH2:17][OH:18])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CN(Cc2ccccc2)CC1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of 1.8 g (6 mmol) of 1-benzyl-3-(RS)-carboethoxy-4-(RS)-trifluoromethylpyrrolidine in 20 mL of THF at 0° C. was added 4.8 mL (4.8 mmol) of a 1M solution of LAH in THF and the reaction was stirred at rt for 30 min. The reaction mixture was quenched with 5N NaOH solution and extracted with ether. The combined organic fractions were washed with 2N NaOH solution and sat'd NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, acetone:hexanes, 1:8) to give 1.5 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:18]([C@H:21]2[C@H:26]([O:27]CC3C=CC=CC=3)[C@@H:25]([O:35]CC3C=CC=CC=3)[C@H:24]([O:43]CC3C=CC=CC=3)[C@@H:23]([CH2:51][O:52]CC3C=CC=CC=3)[O:22]2)=[CH:17][C:3]=1[CH2:4][C:5]1[N:10]=[N:9][C:8]([C:11]2[O:12][C:13]([CH3:16])=[CH:14][N:15]=2)=[CH:7][CH:6]=1.I[Si](C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:18]([C@H:21]2[C@H:26]([OH:27])[C@@H:25]([OH:35])[C@H:24]([OH:43])[C@@H:23]([CH2:51][OH:52])[O:22]2)=[CH:17][C:3]=1[CH2:4][C:5]1[N:10]=[N:9][C:8]([C:11]2[O:12][C:13]([CH3:16])=[CH:14][N:15]=2)=[CH:7][CH:6]=1
Reactant: Cc1cnc(-c2ccc(Cc3cc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)ccc3Cl)nn2)o1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: Cc1cnc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)nn2)o1
Temperature: 50 °C
Yield: 11.7 %

Procedure:
To a solution of 2-(6-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)benzyl)pyridazin-3-yl)-5-methyloxazole (1.2 mmol) from Step 2 in acetonitrile (5 mL) was added Iodotrimethylsilane (3 mL). The resulting reaction mixture was heated to 50° C. overnight. After cooling to 0° C., the reaction quenched with methanol and concentrated in vacuo. Purification by reverse phase preparative HPLC (Gilson®, SunFire™ Prep, 5 to 50% acetonitrile in water gradient) provided the title compound (62 mg, 0.14 mmol, 11%) as a yellow solid.
Reaction SMILES: C([C:3]1([C:22]([O-:24])=[O:23])[NH:8][C:7]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)=[CH:6][CH:5]=[CH:4]1)C.[CH2:25](O)[CH3:26]>[Pd]>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([C:7]2[N:8]=[C:3]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:4]=[CH:5][CH:6]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCO
Reactant: CCC1(C(=O)[O-])C=CC=C(C2=CCN(C(=O)OC(C)(C)C)CC2)N1
Agent: [Pd]
Product: CCOC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
1′-tert-Butyl 6-ethyl-3′,6′-dihydro-2,4′-bipyridine-1′,6(2′H)-dicarboxylate (31.5 g) is dissolved in ethanol (315 ml) and hydrogenated at room temperature under 1 bar of H2 in the presence of Pd/C (10%, 4.5 g) for 12 hours. Filtration and removal of the solvent under reduced pressure gives ethyl 6-[1-(tert-butoxycarbonyl)piperidin-4-yl]pyridine-2-carboxylate (30.5 g).