Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]2[O:17][CH2:16][CH2:15]C[O:13]2)[CH:6]=[C:7](I)[C:8]=1[O:9][CH3:10].[Cu](C#N)[C:19]#[N:20]>CN(C=O)C>[C:19]([C:7]1[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([CH:12]2[O:13][CH2:15][CH2:16][O:17]2)[CH:6]=1)#[N:20]
Reactant: N#C[Cu]C#N
Reactant: COc1cc(C2OCCCO2)cc(I)c1OC
Solvent: CN(C)C=O
Product: COc1cc(C2OCCO2)cc(C#N)c1OC
Temperature: 25 °C
Yield: 78.2 %

Procedure:
2-(3,4-dimethoxy-5-iodophenyl)-1,3-dioxolane (42) (FIG. 22) (2.80 g, 8.0 mmole), copper cyanide (5.7 g, 32.0 mmole) and dry DMF (50 ml) were stirred under an argon atmosphere for 24 hours at 140° C. The reaction was cooled to room temperature, filtered through celite, and the filtrate concentrated to an oil in vacuo. The dark brown oil was purified through a short flash silica column using 2:1 hexane/ethyl acetate as eluent to yield 1.471 g (74%) of a white solid. The product can be recrystallized from hexane/ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([CH3:12])[CH:3]=1.[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: Cc1cc(F)ccc1C(F)(F)F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(F)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
4-Fluoro-2-methyl-1-(trifluoromethyl)benzene (5.6 mmol, 1 g) was dissolved in concentrated sulphuric acid (7 ml) and cooled to 0° C.; KNO3 (1 eq., 5.6 mmol, 566 mg) was added at to 0° C. in one pot and the mixture was stirred at to 0° C. for 4 hours. The crude mixture was poured onto ice and extracted with ethyl acetate; the organics were combined dried over Na2SO4, filtered and the solvent was evaporated to afford the title compound, 1.1 g, 88%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15](=[O:17])[CH3:16])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Br:18]Br.C([O-])(O)=O.[Na+]>C1C=CC=CC=1.Br.C(O)(=O)C>[Br:18][CH2:16][C:15]([C:5]1[CH:6]=[CH:7][C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:17]
Reactant: BrBr
Reactant: COc1cc(C(C)=O)ccc1-c1ccccn1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COc1cc(C(=O)CBr)ccc1-c1ccccn1
Reaction time: 0.5 h

Procedure:
A solution of 1-(3-methoxy-4-pyridin-2-ylphenyl)ethanone (400 mg, 1.7 mmol) in benzene (6 mL) and 30% HBr/Acetic acid (6 mL) was cooled to 0° C. and was treated with a solution of bromine (0.086 mL, 1.67 mmol) in benzene (1 mL) over 1 h. The reaction was stirred for an additional 30 min, then poured into an iced solution of saturated aqueous NaHCO3 (100 mL), and the product was extracted into ethyl acetate (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated to afford 2-bromo-1-(3-methoxy-4-pyridin-2-ylphenyl)ethanone.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CN(C)C=O.Cl[CH2:15][CH:16]([O:21][CH2:22][CH2:23][CH3:24])[O:17][CH2:18][CH2:19][CH3:20].[Cl-].[NH4+]>O>[CH2:18]([O:17][CH:16]([O:21][CH2:22][CH2:23][CH3:24])[CH2:15][S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)[CH2:19][CH3:20]
Reactant: Oc1ccc(S)cc1
Reactant: CCCOC(CCl)OCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOC(CSc1ccc(O)cc1)OCCC
Temperature: 90 °C

Procedure:
The S-monosodium salt of 4-mercaptophenol (0.05 mole) and dimethylformamide (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The mixture is stirred until dissolved, and 1-chloro-2,2-dipropoxyethane (0.05 mole) is added dropwise over a period of about 20 minutes. After the addition is completed, the reaction mixture is blanketed with nitrogen gas and is heated at about 90° C. with stirring for a period of about 48 hours. After this time water (200 ml) is added, and the reaction mixture is neutralized with ammonium chloride. The reaction mixture is then extracted with chloroform, and the organic phase is separated from the aqueous phase. The organic phase is then stripped of solvent, leaving an oil. This oil is distilled under reduced pressure to yield the desired product 4-(2,2-dipropoxyethylthio)phenol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[F:22][C:23]1[C:28](B(O)O)=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:28]4[C:23]([F:22])=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12

Procedure:
A vial was charged with (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (302.9 mg, 0.661 mmol), 2-fluoro-3-pyridineboronic acid (102 mg, 0.727 mmol), potassium carbonate (457 mg, 3.31 mmol), and tetrakis(triphenylphosphine)palladium(0) (38.2 mg, 0.033 mmol). The vial was flushed with Ar (g), then dioxane (3306 μL) and water (1.7 mL) were added in sequence. The vial was sealed and placed in a 75° C. oil bath for 2 hours. The mixture was diluted with EtOAc (15 mL) and brine (15 mL). The layers were separated, and the aq. layer was extracted with EtOAc (2×15 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 40-g Redi-Sep column, eluting with 0-60% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give (S)-3-bromo-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as an off-white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@@H:7]([CH3:16])[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[C:3]1=[O:17].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[CH:24][C:23]=2[CH:31]=1.[Cl-].[NH4+]>C(#N)C.N1C=CC=CC=1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([S:27]([NH:1][C@H:2]3[CH2:6][CH2:5][N:4]([C@@H:7]([CH3:16])[C:8]([N:10]4[CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)=[O:9])[C:3]3=[O:17])(=[O:29])=[O:28])=[CH:24][C:23]=2[CH:31]=1
Reactant: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](N)C1=O
Reactant: O=S(=O)(Cl)c1cc2cc(Cl)ccc2o1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: c1ccncc1
Product: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](NS(=O)(=O)c2cc3cc(Cl)ccc3o2)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.1 %

Procedure:
To a solution of (3S)-3-amino-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]pyrrolidin-2-one [Intermediate 40] (0.077 g) in anhydrous acetonitrile (2 ml) were added 5-chloro-1-benzofuran-2-sulfonyl chloride [Intermediate 51] (0.043 g) in acetonitrile (2 ml) and pyridine (0.057 ml), and the mixture was stirred at room temperature for 72 h. Saturated ammonium chloride solution (2 ml) was added and the resultant mixture stirred at room temperature for 20 min. The mixture was concentrated under reduced pressure and the residue partitioned between chloroform and hydrochloric acid (2M). The organic layer was washed with saturated sodium bicarbonate and brine. The organic layer was isolated, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (0.043 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:25]([NH2:27])[CH3:26])[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[N:23][CH:22]=[CH:21][N:20]=4)[CH2:15][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.Cl[C:29]1[C:30]2[N:38]=[CH:37][CH:36]=[CH:35][C:31]=2[N:32]=[CH:33][N:34]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:25]([NH:27][C:29]3[C:30]4[N:38]=[CH:37][CH:36]=[CH:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH3:26])[C:8]([N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:24]=[N:23][CH:22]=[CH:21][N:20]=4)[CH2:17][CH2:18]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ncnc2cccnc12
Reactant: Cc1c(F)ccc2cc([C@H](C)N)c(N3CCN(c4cnccn4)CC3)nc12
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(F)ccc2cc([C@H](C)Nc3ncnc4cccnc34)c(N3CCN(c4cnccn4)CC3)nc12
Yield: 46.7 %

Procedure:
Following the procedure described for Intermediate 13, Intermediate 15 (470 mg, 1.1 mmol) and TFA (3 mL) in DCM (6 mL) afforded (S)-1-{7-fluoro-8-methyl-2-[4-(pyrazin-2-yl)piperazin-1-yl]quinolin-3-yl}ethanamine as a white foam, which was used in the next step without any further purification. Following the procedure described for Example 5, (S)-1-{7-fluoro-8-methyl-2-[4-(pyrazin-2-yl)piperazin-1-yl]quinolin-3-yl}-ethanamine (60 mg, 0.16 mmol), 4-chloropyrido[3,2-d]pyrimidine (33 mg, 0.19 mmol) and DIPEA (0.14 mL, 0.8 mmol) in NMP (1.2 mL) afforded the title compound (37 mg, 46%) as a brown solid. δH (DMSO-d6) 8.95-8.89 (2H, m), 8.55 (2H, d, J 14.1 Hz), 8.45 (1H, d, J 1.5 Hz), 8.19-8.14 (2H, m), 7.93-7.88 (2H, m), 7.74 (1H, dd, J 8.9, 6.3 Hz), 7.33 (1H, t, J 9.1 Hz), 5.98-5.90 (1H, m), 3.96-3.87 (2H, m), 3.87-3.75 (4H, m), 3.33-3.25 (2H, m), 2.58 (3H, d, J 2.3 Hz), 1.68 (3H, d, J 6.7 Hz). LCMS (ES+) 496 (M+H)+, RT 4.07 minutes (Method 4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[CH3:12][S:13](Cl)(=[O:15])=[O:14].N1C=CC=CC=1>C1COCC1.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][S:13]([CH3:12])(=[O:15])=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])c(Cl)c1
Reaction time: 24 h
Yield: 99.8 %

Procedure:
A mixture of 3-chloro-4-nitroaniline (4.85 g, 28.1 mmol), methanesulfonyl chloride (3.29 mL, 42.2 mmol) and pyridine (6.82 mL, 84 mmol) in THF (100 mL) was stirred for 24 h. Poured in 1M HCl (500 mL). The resulting precipitate was filtered and air-dried to provide the title compound as a solid (7.03 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[CH:21]=[C:20]([Si](C)(C)C)[C:11]3[C:12]4[C:13]([NH:19][C:10]=3[C:9]2=[O:26])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=4)=[CH:5][CH:4]=1.[I:29]I>C(O)C.C(Cl)Cl.F[B-](F)(F)F.[Ag+]>[I:29][C:20]1[C:11]2[C:12]3[C:13]([NH:19][C:10]=2[C:9](=[O:26])[N:8]([CH2:7][C:6]2[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:21]=1)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3
Reactant: II
Reactant: COc1ccc(Cn2cc([Si](C)(C)C)c3c([nH]c4ncc(C)cc43)c2=O)cc1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(Cn2cc(I)c3c([nH]c4ncc(C)cc43)c2=O)cc1
Reaction time: 0.25 h

Procedure:
In a 2 L round bottom flask, 7-(4-methoxybenzyl)-3-methyl-5-trimethylsilyl-7,9-dihydro-8H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-8-one (18.6 g, 47.505 mmol) was suspended in ethanol (1 L) and DCM (150 mL), then cooled in an ice bath. To the cooled mixture was added silver tetrafluoroborate (AgBF4, 10.17 g, 52.255 mmol) and after 15 minutes of stirring, iodine (18.08 g, 71.257 mmol) was added. The reaction was stirred at 0° C. for one hour followed by five hours at ambient temperature. The crude yellow solid was collected by filtration, suspended in 10% wt Na2S2O3 (700 mL) and stirred for 1 h. The solid was collected by filtration and again washed with 10% wt Na2S2O3. The product (light yellow solid) was collected by filtration, washed with water and diethyl ether and dried under high vacuum. The material was taken forward without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.59 (s, 3H) 3.81 (s, 3H) 5.26 (s, 2H) 6.90 (d, J=8.84 Hz, 2H) 7.34 (d, J=8.59 Hz, 2H) 7.44 (s, 1H) 8.51 (s, 1H) 8.92 (s, 1H). ESI-MS: m/z 446.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([I:11])=[N:9][NH:10][C:4]=2[CH:3]=1.[H-].[Na+].[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([I:11])=[N:9][N:10]([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:4]=2[CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Clc1cc2[nH]nc(I)c2cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.83 h
Yield: 93.1 %

Procedure:
A solution of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (1.874 g, 6.71 mmol) in THF (20 mL) was treated with NaH (60% in mineral oil; 0.402 g, 10.06 mmol) at 0° C. and the mixture was stirred for 50 min. Trityl chloride (2.244 g, 8.05 mmol) was added at the same temperature and the mixture was stirred for 16 h at room temperature, quenched with saturated NH4Cl and extracted with EtOAc. The organic phase was washed with water, brine, dried (Na2SO4) and concentrated in vacuo to afford a residue, which was purified by chromatography on silica gel (SNAP 50 g, from 0 to 10% EtOAc in hexanes, 5 CV; 10% EtOAc in hexanes, 15 CV) to yield 6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (3.26 g, 6.25 mmol, 93%) as a light yellow solid. MS ESI calc'd. for C25H18ClIN3[M+1]+522, found 522.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:16])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:18]([C:24]([CH3:26])=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:24]([CH3:26])[N:16]=2)[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncc(Br)cc1OCc1ccccc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCc3ccccc3)cc(Br)cn12

Procedure:
Under argon, 200 g (0.72 mol) of 3-(benzyloxy)-5-bromopyridine-2-amine, 590 g (3.58 mol) of ethyl 2-chloroacetoacetate and 436 g of 3 A molecular sieve were suspended in 6 l of ethanol and boiled at reflux for 72 h. The reaction mixture was filtered off through kieselguhr and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate 9:1, then 6:4) and the product fractions were concentrated. This gave 221 g (79% of theory) of the target compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)#[N:15]>O1CCCC1.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.6 %

Procedure:
Under the argon atmosphere, 4-methylpiperazine (2.00 g, 20.0 mmole) and potassium carbonate (3.41 g, 24.7 mole ) were added to a solution of 4-cyanobenzyl bromide (3.20 g, 16.3 mole) in tetrahydrofuran (30 ml). After stirring at room temperature for 18 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated aqueous saline, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4(4-methyl-1-piperazinylmethyl)benzonitrile as a colorless crystalline powder (1.49 g, 42.4%).
Reaction SMILES: Cl.[NH:2]1[CH2:5][C:4](=[CH:6][C:7]#[N:8])[CH2:3]1.[F:9][C:10]1[C:24]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:22]=[CH:21][C:11]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)=[O:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:9][C:10]1[C:24]([C:25]([F:27])([F:26])[F:28])=[N:23][CH:22]=[CH:21][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH:17]([N:2]2[CH2:5][C:4](=[CH:6][C:7]#[N:8])[CH2:3]2)[CH2:18][CH2:19]1)=[O:13]
Reactant: O=C1CCN(C(=O)c2ccnc(C(F)(F)F)c2F)CC1
Reactant: N#CC=C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: N#CC=C1CN(C2CCN(C(=O)c3ccnc(C(F)(F)F)c3F)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To a 0.25-L flask equipped with a nitrogen inlet, a thermocouple, and a magnetic stirrer were added 2-(azetidin-3-ylidene)acetonitrile hydrochloride (2a, 4.5 g, 34.46 mmol), 1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-one (7, 10 g, 34.46 mmol, 1.0 equiv), and methylenechloride (100 mL) at ambient temperature and the resulting mixture was then treated with sodium triacetoxyborohydride (14.6 g, 68.93 mmol, 2.0 equiv) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hours before being quenched with saturated sodium bicarbonate (NaHCO3) aqueous solution (50 mL). The two phases were separated and the aqueous phase was extracted with dichloromethane (200 mL). The combined organic phase was washed with water (50 mL) and brine (50 mL) and concentrated under reduced pressure to afford the crude desired product (10), which was purified by column chromatography (SiO2, 0-10% of ethyl acetate in hexane gradient elution) to afford 2-(1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-ylidene)acetonitrile (10, 9.5 g, 12.7 g theoretical, 74.8%) as a white solid. For 10: 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J=4.7 Hz, 1H), 7.54 (t, J=4.6 Hz, 1H), 5.29 (p, J=2.4 Hz, 1H), 4.18-4.08 (m, 1H), 4.08-4.03 (m, 2H), 3.98-3.94 (m, 2H), 3.57-3.39 (m, 2H), 3.17-3.04 (m, 1H), 2.56 (tt, J=7.4, 3.5 Hz, 1H), 1.86-1.77 (m, 1H), 1.75-1.64 (m, 1H), 1.54-1.43 (m, 1H), 1.43-1.31 (m, 1H) ppm; 13C NMR (101 MHz, CDCl3) δ 161.34, 160.73, 152.62 (d, J=269.1 Hz), 145.75 (d, J=6.1 Hz), 136.73 (qd, J=36.1, 12.0 Hz), 134.56 (d, J=16.9 Hz), 126.89, 120.58 (qd, J=275.0, 4.9 Hz), 115.11, 92.04, 62.05, 60.57 (2C), 44.47, 39.42, 29.38, 28.47 ppm; C17H16F4N40 (MW 368.33), LCMS (EI) m/e 369 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]2[CH:9]=[C:8](C(O)=O)[S:7][C:6]=2[CH:13]=1.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:13]=1
Reactant: O=C(O)c1cc2c(F)cc(Br)cc2s1
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: Fc1cc(Br)cc2sccc12
Yield: 97 %

Procedure:
Using analogous reaction condition and reagents as described in Example 25 for the preparation of I-25c above, 6-bromo-4-fluoro-benzo[b]thiophene-2-carboxylic acid (I-26c: 1.8 g, 6.47 mmol) in DMA (4 mL) and DBU (4.0 g, 26.54 mmol) were heated in microwave to afford the crude product. Purification by column chromatography on silica gel (100% hexane) afforded 1.45 g of the product (97% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:8]2[N:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.[B:15]1(B2OCC(C)(C)CO2)[O:20]CC(C)(C)C[O:16]1>>[F:14][C:5]1[CH:4]=[CH:3][C:2]([B:15]([OH:20])[OH:16])=[CH:7][C:6]=1[C:8]1[N:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Reactant: Fc1ccc(Br)cc1-c1cccnn1
Product: OB(O)c1ccc(F)c(-c2cccnn2)c1

Procedure:
3-(5-Bromo-2-fluorophenyl)pyridazine (304 mg, 1.20 mmol) was reacted with bis(neopentyl glycolato)diboron (298 mg, 1.32 mmol) using the method in Example 51 to give 4-fluoro-3-(pyridazin-3-yl)phenylboronic acid as a white solid: m/z (ES+) 219 (M++H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([N:22]5[CH2:26][CH2:25][CH2:24][C@H:23]5[C:27](O)=[O:28])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:30]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.C[N+:39](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+].CN(C)C(=O)C>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([N:22]5[CH2:26][CH2:25][CH2:24][C@H:23]5[C:27]([NH2:39])=[O:28])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:30]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCC[C@H]3C(=O)O)cc1OCC2
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCC[C@H]3C(N)=O)cc1OCC2
Reaction time: 1 h

Procedure:
A mixture of 55 mg (0.135 mmol) of (S)-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxylic acid, N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (57.0 mg, 0.150 mmol), N,N-Diisopropylethylamine (52.2 uL, 0.300 mmol) and Ammonium chloride (8.02 mg, 0.150 mmol) in N,N-Dimethylacetamide (3.0 mL, 32 mmol) was stirred for 1 hour. The mixture was concentrated in vacuum, the residue triturated with water, 0.01 N aq HCL, water, dried in vacuum and subjected to RP HPLC and then chiral purification to give 375. Yield 12 mg. M/z 408.2, calc. 407.21. 1H NMR (400 MHz, DMSO) δ 8.19 (d, J=8.9, 1H), 7.87 (s, 1H), 7.77 (s, 1H), 7.40 (s, 1H), 7.04 (s, 1H), 6.36 (dd, J=9.0, 2.4, 1H), 6.07 (d, J=2.4, 1H), 5.91 (dq, J=13.3, 6.5, 1H), 4.44 (d, J=6.5, 4H), 4.01-3.93 (m, 1H), 3.57 (t, J=7.0, 1H), 3.24 (d, J=9.0, 1H), 2.23 (dd, J=12.1, 6.9, 1H), 1.98 (dd, J=14.8, 11.3, 3H), 1.47 (dd, J=6.6, 3.3, 6H)
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:25])(=[N:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:18])[CH:12]=2)=[CH:5][C:4]=1[N:26]=[CH:27][N:28](C)[CH3:29])#N.[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.ClCCl.CO>CO>[CH2:23]([O:22][C:20]([N:19]=[S:17]([CH3:25])([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][NH:9][C:6]2[CH:5]=[C:4]3[C:3]([C:29]([NH:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)=[N:28][CH:27]=[N:26]3)=[CH:8][CH:7]=2)[CH:12]=1)=[O:18])=[O:21])[CH3:24]
Reactant: Nc1cccnc1
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(CNc2ccc(C#N)c(N=CN(C)C)c2)c1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N=S(C)(=O)c1cccc(CNc2ccc3c(Nc4cccnc4)ncnc3c2)c1
Yield: 68 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylamino}phenyl)-N,N-dimethylformimidamide (50 mg, 0.12 mmol) with 3-aminopyridine (14 mg, 0.14 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 68% yield (38 mg).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[Cl:8][C:9]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:10]=1C=O.N1CCCCC1.Cl>N1C=CC=CC=1>[Cl:8][C:9]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:1]=[CH:2][C:3]([OH:5])=[O:4]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A 250 ml round-bottomed flask, Teflon stirrer, reflux condenser, and gas inlet were oven-dried for 12 hours at 160° C. The apparatus was rapidly assembled, flushed with dry nitrogen gas, and allowed to cool to room temperature. After cooling, the flask was charged with malonic acid (110 mmole), pyridine (75 ml), 2,3-dichlorobenzaldehyde (17.50 g, 100 mmole) and piperidine (2 ml, 20 mmole). The reaction mixture was stirred and brought to relux. After 16 hours of stirring under reflux, the reaction mixture was cooled to room temperature and poured onto a mixture of ice (100 ml) and concentrated hydrochloric acid (100 ml) resulting in the precipitation of a white solid to form a slurry. The resulting slurry was stirred for 2 hours, filtered, washed with cold water (2×250 ml), and dried in vacuo to give 20.01 g (92%) of 2,3-dichlorocinnamic acid.