Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.O.[F-:4].[Al+3:5].[F-:6].[F-:7].O.O.O.[F-:11].[CH2:12]([N+:14]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH3:15])[CH3:13]>>[F:4][Al-:5]([F:11])([F:7])[F:6].[CH2:12]([N+:14]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH3:15])[CH3:13]
Reactant: [F-]
Reactant: [Al+3]
Agent: CC[N+](C)(CC)CC
Solvent: O
Product: F[Al-](F)(F)F
Reaction time: 0.5 h

Procedure:
6.90 g (50.0 mmol) of aluminum fluoride trihydrate was weighed and placed in a round flask made of PFA, and air in the flask was evacuated and then replaced by argon gas. While feeding argon gas to the flask through its inlet, 100 ml of dehydrated acetonitrile was added and the flask was sealed followed by stirring for 30 minutes. Then, while feeding argon gas similarly, 9.46 g (50.0 mmol) of triethylmethylammonium fluoride trihydrate was added portion wise, and the resultant mixture was further stirred for about 3 hours. The unreacted solid was filtered off, and then the solvent was distilled off to obtain about 9 g of white crude crystal of triethylmethylammonium tetrafluoroaluminate. This was subjected to recrystallization from 10 g of isopropanol. The amount of the product was 5.50 g, and the yield was 50% based on the charged raw material. Identification was made by elemental analysis and NMR, and a melting point was measured by TG-DTA.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6]1[CH:15]=[C:14]([CH:16]=[C:17]([CH2:20][O:21][CH3:22])[C:18]#[N:19])[C:9]2[CH:10]=[CH:11][CH2:12][O:13][C:8]=2[C:7]=1[O:23][CH3:24]>CO.O>[CH3:4][O:5][C:6]1[CH:15]=[C:14]([CH2:16][CH:17]([CH:20]([O:2][CH3:1])[O:21][CH3:22])[C:18]#[N:19])[C:9]2[CH:10]=[CH:11][CH2:12][O:13][C:8]=2[C:7]=1[O:23][CH3:24]
Reactant: C[O-]
Reactant: COCC(C#N)=Cc1cc(OC)c(OC)c2c1C=CCO2
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(CC(C#N)C(OC)OC)c2c(c1OC)OCC=C2
Yield: 62.2 %

Procedure:
A mixture of sodium methoxide (8.86 g, 0.164 mole), and 3-(7,8-dimethoxy-2H-1-benzopyran-5-yl)-2-methoxymethylpropenenitrile (Example 37A, 23.1 g, 0.080 mole) in methanol (60 mL) was heated at reflux for 24 hr, allowed to cool and diluted with water (200 mL). The resultant mixture was extracted with toluene (1×200 mL and 2×100 mL). The combined toluene portions were extracted with water (3×100 mL) and dried over magnesium sulfate. The toluene solution was concentrated leaving a brown oil which was distilled under reduced pressure to give 15.9 g (62%) of a yellow oil which was used without further purification.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][C:15](F)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[CH:6][CH:5]=1>>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][C:15]([NH:2][CH3:1])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[CH:6][CH:5]=1
Reactant: CN
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(F)c([N+](=O)[O-])c1
Product: CNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 20 h

Procedure:
40 mL liquid methylamine was added to a stirred mixture of N-(4-bromo-phenyl)-4-fluoro-3-nitro-benzamide (1.5 g, 4.4 mmol) in a pressure tube. The mixture was stirred for 20 h at 60° C. The mixture was cooled and concentrated i.vac. The residue was taken up in ethyl acetate, filtered with celite and silica gel and dried.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([C:38]3([C:42]#[N:43])[CH2:41][CH2:40][CH2:39]3)[CH:35]=[N:36][CH:37]=2)O1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:33]=[C:34]([C:38]6([C:42]#[N:43])[CH2:41][CH2:40][CH2:39]6)[CH:35]=[N:36][CH:37]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CC1(C)OB(c2cncc(C3(C#N)CCC3)c2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(C5(C#N)CCC5)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 1-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-cyclobutanecarbonitrile (Stage 221.1.1) to give the title compound as an off-white foam. (HPLC: tR 2.43 min (Method A); M+H=450 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.01 (s, 1H), 8.74-8.73 (m, 1H), 8.70-8.68 (m, 1H), 8.17-8.12 (m, 2H), 8.06-8.03 (m, 1H), 7.90-7.88 (m, 1H), 7.63-7.61 (m, 1H), 3.89 (s, 3H), 3.59 (s, 3H), 2.86-2.71 (m, 4H), 2.13-2.01 (m, 2H), 1.97 (s, 3H))
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:26])=[C:6]([CH:25]=1)[C:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][CH2:15][N:14]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[C:13]=2[CH:24]=1)=O.B(F)(F)F.CCOCC.[SiH](CC)(CC)CC>ClCCCl.CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:26])=[C:6]([CH:25]=1)[CH2:7][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][CH2:15][N:14]([C:18](=[O:23])[C:19]([F:21])([F:22])[F:20])[C:13]=2[CH:24]=1
Reactant: O=C(c1ccc2c(c1)N(C(=O)C(F)(F)F)CCO2)c1cc(Br)ccc1Cl
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Solvent: ClCCCl
Product: O=C(N1CCOc2ccc(Cc3cc(Br)ccc3Cl)cc21)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a stirred solution of 1-[6-(5-bromo-2-chloro-benzoyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone (36 g, 80.35 mmol) in 1,2-dichloroethane:MeCN 1:2 (180 mL) was added BF3.OEt2 (13.2 mL, 104 mmol) and Et3SiH (26.9 mL, 168.7 mmol) at 0° C. The reaction mixture was stirred overnight at room temperature then quenched by the addition of aq. NaHCO3 (˜200 mL). The resulting mixture was extracted with ethyl acetate (3×200 mL), and the combined organic layers were washed with brine (200 mL) and dried over sodium sulfate. Crude product obtained after evaporation of solvent was purified by silica gel column chromatography to furnish 1-[6-(5-bromo-2-chloro-benzyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone (30 g).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[C:8]([C:11]1[CH:12]=[C:13]([C:16]([NH:18][N:19]([CH2:35][C@@H:36]([OH:40])[C:37]([OH:39])=[O:38])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=3[F:34])=[CH:23][CH:22]=2)=[O:17])[NH:14][N:15]=1)(=[O:10])[CH3:9].C1COCC1>>[C:8]([C:11]1[CH:12]=[C:13]([C:16]([NH:18][N:19]([CH2:35][C@@H:36]([O:40][C:1](=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4])[C:37]([OH:39])=[O:38])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=3[F:34])=[CH:23][CH:22]=2)=[O:17])[NH:14][N:15]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)[nH]n1
Reactant: CC(C)CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](OC(=O)CC(C)C)C(=O)O)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
Isovaleryl chloride (51.4 μL, 421.2 μmol) and (R)-3-[N′-(5-acetyl-2H-pyrazole-3-carbonyl)-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid (20.0 mg, 42.1 μmol) were combined in THF (205 μL, 2.5 mmol), and stirred overnight at room temperature. The solvent was evaporated and the residue was purified (reverse phase HPLC column) to yield the title compound (11.8 mg) as a TFA salt. MS m/z [M+H]+ calc'd for C27H28ClFN4O6, 559.17. found 559.1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]([NH2:12])=O)[CH:7]=[CH:6][S:5]2.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]#[N:12])[CH:7]=[CH:6][S:5]2
Reactant: Cc1nc2sccn2c1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1nc2sccn2c1C#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.4 %

Procedure:
To a mixture of 6-methylimidazo[2,1-b][1,3]thiazole-5-carboxamide (544 mg, 3.0 mmol) produced in the above, pyridine (0.7 mL, 9.0 mmol) and tetrahydrofuran (10 mL) was added dropwise under ice-cooling trifluoroacetic anhydride (0.6 mL, 4.5 mmol). After stirring at room temperature for 1 day, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→50/50). The obtained solution was concentrated under reduced pressure to give the title compound (433 mg, 86%) as a pale-brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[NH:4][C:5](=[O:9])[CH2:6][C:7]#[N:8].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[NH:4][C:5](=[O:9])[C:6]([C:7]#[N:8])=[CH:16][N:17]([CH3:18])[CH3:19]
Reactant: N#CCC(=O)Nc1ccccc1Cl
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C#N)C(=O)Nc1ccccc1Cl

Procedure:
As for Example 1, 2'-chloro-2-cyanoacetanilide, white crystalline product, m.p. 122.5°-123° C. (prepared as described in U.S. Pat. No. 3,116,312), is heated with N,N-dimethylformamide dimethylacetal to give 2'-chloro-2-cyano-3-dimethylaminoacrylanilide as colorless prisms, m.p. 104°-105° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:22]=[C:21]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]2[CH:40]([F:42])[F:41])[N:20]=1>C1COCC1.C(O)(=O)C.O>[F:42][CH:40]([F:41])[C:32]1[N:31]([C:21]2[N:22]=[C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:24]=[C:19]([NH:1][C:2]3[N:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[N:20]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1
Reactant: Nc1cccnn1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2cccnn2)nc(N2CCOCC2)n1
Reaction time: 0.25 h
Yield: 18.2 %

Procedure:
To a solution of 0.159 g (1.67 mmol) of 3-aminopyridazine in THF (3 mL) at 0° C. was added 0.93 mL of NaHMDS (2 M solution in THF), and the mixture was stirred for 15 min. A solution of 0.317 g (0.84 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in THF (6 mL) was added and the resulting mixture was stirred for 1 hr at RT. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried and concentrated. Chromatography on alumina, eluting first with hexane-EtOAc (8:2) then with CH2Cl2/EtOAc (2:1) to CH2Cl2/EtOAc (1:1) gave a white powder. Recrystallization from ethanol/CH2Cl2 gave 0.065 g (18% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(3-pyridazinyl)-1,3,5-triazin-2-amine: mp 271-273° C.; 1H NMR (DMSO-d6) δ 11.16 (br s, 1H), 8.98 (dd, J=4.7, 1.4 Hz, 1H), 8.67 (d, J=8.0 Hz, 1H), 8.61 (d, JHF=8.4 Hz, 1H), 8.08 (t, JHF=52.8 Hz, 1H), 7.86 (dd, J=7.7, 0.7 Hz, 1H), 7.73 (dd, J=9.1, 4.7 Hz, 1H), 7.53-7.43 (m, 2H), 3.86 (s, 4H), 3.75 (s, 4H); Anal. Calcd. for C19H17F2N9O: C, 53.65; H, 4.1; N, 29.6. Found: C, 53.7; H, 4.2; N, 29.5%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][C:7]=1Br.O1CCC[CH2:14]1.C[Mg]Br>C1COCC1.C1(C)C=CC=CC=1.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][C:7]=1[CH3:14]
Reactant: COC(=O)c1cnc(Br)c(Br)c1
Reactant: C1CCOC1
Agent: Cl[Ni]Cl
Agent: C[Mg]Br
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(C)c(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.6 %

Procedure:
To a solution of methyl 5,6-dibromopyridine-3-carboxylate (0.5122 g; 1.737 mmol) in tetrahydrofuran (10.0 mL; 123 mmol) at 0° C. (using an oven-dried flask) was added 1,3-bis(diphenylphosphino)propane nickel(II) chloride (98.0 mg; 0.179 mmol). After 5 minutes, methylmagnesium bromide (1.4 mol/L) in THF:toluene (1:3) (1.6 mL; 2.2 mmol) was added dropwise. After addition was complete, the reaction mixture was stirred at room temperature. After 8 hours, methylmagnesium bromide (1.4 mol/L) in THF:toluene (1:3) (1.0 mL) was added and the reaction stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The organic portion was dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (25 g silica, solvent gradient: 0-30% ethyl acetate in dichloromethane) to yield 174.1 mg (44%) of the title compound. LCMS (ESI): M+H=230.2; 1H NMR (400 MHz, DMSO) δ 8.93 (d, J=1.4 Hz, 1H), 8.39 (d, J=1.4 Hz, 1H), 3.89 (s, 4H), 2.67 (s, 4H).
Reaction SMILES: O.OO.[O:4]1CCCC1.[F:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13](B(O)O)=[CH:12][N:11]=1>O>[F:9][C:10]1[N:11]=[CH:12][C:13]([OH:4])=[CH:14][C:15]=1[CH3:16]
Reactant: C1CCOC1
Reactant: Cc1cc(B(O)O)cnc1F
Agent: OO
Solvent: O
Product: Cc1cc(O)cnc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Hydrogen peroxide water (4.37 ml, 42.8 mmol) was added to a tetrahydrofuran solution (50 ml) of 2-fluoro-3-methylpyridine-5-boronic acid (5.1 g, 32.9 mmol), and stirred overnight at room temperature. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with aqueous 5% sodium thiosulfate solution and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 6-fluoro-5-methylpyridin-3-ol (4.03 g, yield: 96%) as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[CH:4]=[C:3]1[CH3:22].[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.CO>CN(C=O)C.O>[CH3:28][O:27][C:23](=[O:26])[CH2:24][CH2:25][N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]([CH2:11][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:2]([CH3:1])[C:3]([CH3:22])=[CH:4]3)[C:13]1=[O:21]
Reactant: C=CC(=O)OC
Reactant: Cc1cc2cccc(Cn3c(=O)[nH]c4ccccc43)c2n1C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COC(=O)CCn1c(=O)n(Cc2cccc3cc(C)n(C)c23)c2ccccc21
Yield: 41.1 %

Procedure:
To a solution of 1-(1,2-dimethyl-1H-indol-7-ylmethyl)-1,3-dihydro-benzimidazol-2-one (170 mg, 0.58 mmol) in DMF (3.0 mL) are added methyl acrylate (0.06 mL, 0.6 mmol) and 40% benzyltrimethyl ammonium hydroxide in MeOH (0.06 mL, 0.15 mmol). The resulting mixture is stirred at room temperature for 18 h after which time water (20 mL) was added. The mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined, dried over MgSO4 and concentrated to give crude product. Purification by flash column chromatography using 20-50% EtOAc in Hexanes affords 90 mg (41%) of 3-[3-(1,2-dimethyl-1H-indol-7-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid methyl ester.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([F:38])=[CH:12][C:13]=1[C:14]1[C:19]2[S:20][C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][NH:34][C:33]4=[O:37])[N:24]=3)=[CH:22][C:18]=2[CH:17]=[CH:16][CH:15]=1)(C)(C)C>ClCCl>[NH3:7].[NH2:7][C:8]1[C:13]([C:14]2[C:19]3[S:20][C:21]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH2:30][CH2:31][N:32]5[CH2:36][CH2:35][NH:34][C:33]5=[O:37])[N:24]=4)=[CH:22][C:18]=3[CH:17]=[CH:16][CH:15]=2)=[CH:12][C:11]([F:38])=[N:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(F)cc1-c1cccc2cc(-c3ccnc(NCCN4CCNC4=O)n3)sc12
Solvent: ClCCl
Product: N
Product: Nc1cnc(F)cc1-c1cccc2cc(-c3ccnc(NCCN4CCNC4=O)n3)sc12
Temperature: 25 °C
Yield: 7 %
Yield: 8.2 %

Procedure:
Dissolve the [6-fluoro-4-(2-{2-[2-(2-oxo-imidazolidin-1-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophen-7-yl)-pyridin-3-yl]-carbamic acid tert-butyl ester into dichloromethane and adsorb onto silica gel (10 g) via concentration in vacuo. Dry under high vacuum for 24 hours. Place silica gel into a round bottom flask and heat in a temperature controlled oil bath to 98-99° C. while under high vacuum for 2 hours. Cool to room temperature. Extract product from silica gel with 10% 7 N ammonia in methanol/90% dichloromethane. Concentrate in vacuo. Chromatograph on silica eluting with a gradient of 100% dichloromethane to 7% 2 N ammonia in methanol/93% dichloromethane to afford the title compound (65.2 mg, 8.2%). MS (ES) m/z 450 [M+1]+.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][OH:16]>CO>[C:1](=[N:15][OH:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: NO
Solvent: CO
Product: ON=C(c1ccccc1)c1ccccc1
Temperature: 5 °C

Procedure:
A 500 mL 3-neck flask was fitted with thermometer, dropping funnel and nitrogen blanket. Benzophenone (36.5 g; 0.2 mol) in absolute methanol (100 mL) was placed in the flask and cooled in an ice bath (5° C.) with stirring using a magnetic stirring bar. Hydroxylamine solution (133 mL) was slowly added and after completion of addition (15 minutes), the mixture was heated at reflux (65° C.). pH 8.6. After a total of 18 hours of heating under reflux, it was cooled and transferred to a 500 mL round bottom flask and concentrated on a rotovap. On cooling in ice bath, it was filtered and benzophenone oxime was collected as white crystalline solid (32.5 g; 89% yield). Purity, >97%.
Reaction SMILES: [C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:28][I:29]>C(OCC)C>[I-:29].[C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][N+:22]([CH3:28])([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CI
Reactant: CN1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Solvent: CCOCC
Product: C[N+]1(C)CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.8 %

Procedure:
A suspension of 2-(4-(Adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (0.2 g, 0.50 mmol), prepared from example 3, and methyl iodide (0.286 g, 2.01 mmol) in diethyl ether (2 mL) was stirred at room temperature overnight. The reaction mixture was filtered and dried in vacuum oven at 50° C. to afford a 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1,1-dimethylpiperazin-1-ium iodide as a white solid (0.27 g, 97.5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5](=[CH:9][C:10]=1[N+:13]([O-:15])=[O:14])[C:6]([OH:8])=[O:7]
Reactant: COc1cc(Cl)ccc1C(=O)O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1cc(Cl)c([N+](=O)[O-])cc1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of 33 g of 4-chloro-o-anisic acid in sulfuric acid (100 ml) was added 20 g of potassium nitrate under ice-cooling and the resulting mixture was stirred for 2 hours. The reaction mixture was added to ice/water and extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 41 g of the title compound was obtained as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][C:3]=1[CH:21]=[CH2:22].[H][H]>CO.[Pd]>[CH2:21]([C:3]1[CH:4]=[C:5]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH:6]=[N:7][C:2]=1[CH3:1])[CH3:22]
Reactant: C=Cc1cc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cnc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1cc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cnc1C
Reaction time: 24 h
Yield: 45.5 %

Procedure:
6-Methyl-5-vinyl-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (0.26 g, 0.86 mmol, from Example 35 above) was dissolved in MeOH (15 mL) and treated with 10% Pd/C (50 mg) and 1 atm hydrogen gas. After 1 day, the catalyst was removed, the solvent evaporated, and the residue was chromatographed (silica gel; hexanes-EtOAc, 1:1) to provide 5-ethyl-6-methyl-3-(1-t-butyloxycarbonyl-2-(S)-azetidinylmethoxy)pyridine (0.12 g, 45%): MS (CI/NH3) m/z: 307 (M+H)+ ; 1H NMR (300 MHz, CDCl3) δ 1.23 (t, J=7 Hz, 3H), 1.42 (s, 9H), 2.23-2.38 (m, 2H), 2.47 (s, 3H), 2.60 (q, J=7 Hz, 2H), 3.86-3.93 (m, 2H), 4.12 (dd, J=3, 9 Hz, 1H), 4.29 (dd, J=5,10 Hz, 1H), 4.43-4.53 (m, 1H), 7.04 (d, J=3 Hz, 1H), 8.05 (d, J=3 Hz, 1H). The product from above (0.26 g, 0.85 mmol) was treated with 10 mL of 1:1 TFA-methylene chloride at 0° C. for 1 hour. The residue was diluted with saturated sodium bicarbonate and extracted into CHCl3. The organic layer was washed with water, dried over MgSO4, and evaporated to provide of the free base of the title compound (132 mg, 75%). This was dissolved in ether and treated with 1 M HCl in ether and the resulting salt collected by filtration to provide the title compound (52 mg, 25%). The mother liquor was evaporated to further provide 73 mg of the title compound: mp 150-153° C.; [α]D -7.6 (c 0.62, MeOH); 1H NMR (300 MHz, CD3OD) δ 1.34 (t, J=7 Hz, 3H), 2.63-2.76 (m, 2H), 2.72 (s, 3H), 4.04-4.19 (m, 2H), 4.49-4.63 (m, 2H), 4.88-4.97 (m, 1H), 8.14 (d, J=2 Hz, 1H), 8.40 (d, J=2 Hz); MS (CI/NH3): m/z 207 (M+H+). Anal. Calcd for C12H18N2O.2HCl.0.1 H2O: C, 51.29; H, 7.25; N, 9.97. Found: C, 51.21; H, 7.14; N, 9.77.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1.[CH3:10][N:11](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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:10]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1)#[N:11]
Reactant: CN(C)C=O
Reactant: CCc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCc1cccc(C#N)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Argon was bubbled into a solution of 1-bromo-3-ethylbenzene (2.5 g, 13.5 mmol) in DMF (37 ml) for 10 min. and then zinc cyanide (1.75 g, 14.9 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.56 g, 1.35 mmol) were added. After stirring at 80° C. overnight the reaction mixture was diluted with ethyl acetate (35 ml) then filtered through celite to remove the precipitate. The filtrate was washed with water (3×), saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified by flash column chromatography using 2% ethyl acetate in hexane affording a colorless liquid (1.42 g). GC-MS (M+): 131.18.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[S:17]([O-:20])(=[O:19])=[O:18].[Na+:21]>[Cl-].[Na+]>[O:4]1[CH2:5][CH2:6][N:1]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[S:17]([O-:20])(=[O:19])=[O:18])[CH2:2][CH2:3]1.[Na+:21]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)[O-])c1
Agent: [Cl-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(S(=O)(=O)[O-])c1
Temperature: 110 °C
Yield: 90 %

Procedure:
To 80 ml of morpholine, 82.5 g (0.3 mol) of sodium 2-chloro-5-nitrobenzenesulfonate was added with stirring. The reaction mixture was heated at about 110° C. on an oil bath with stirring for 30 minutes. After cooling, 100 ml of a saturated aqueous sodium chloride solution was added to the mixture. The crystals thus-precipitated were collected by filtration and washed with acetone to obtain 88 g (yield: 90%) of sodium 2-morpholino-5-nitrobenzenesulfonate.