Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH3:31][S:32]([NH:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH3:31][S:32]([NH:35][C:36]1[CH:37]=[C:38]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][N:6]=[C:5]3[CH:14]2[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)[CH:39]=[CH:40][CH:41]=1)(=[O:34])=[O:33]
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
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+]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)Nc1cccc(-c2cc(C(N)=O)c3[nH]nc(C4CCN(S(=O)(=O)CCCN5CCCC5)CC4)c3c2)c1
Yield: 17.7 %

Procedure:
Following the general procedure of Example 66, a mixture of 5-bromo-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 27) (24 mg, 0.048 mmols), {3-[(methylsulfonyl)amino]phenyl}boronic acid (31 mg, 0.144 mmols), potassium carbonate (40 mg), and Pd(PPh3)4 (3 mg) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (5 mg, 18%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8]O)[CH:2]=1.C(Br)(Br)(Br)[Br:11].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Br:11][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCc1cccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(3-pyridyl)ethan-1-ol (100 mg, 0.79 mmol) and CBr4 (314 mg, 0.95 mmol) in THF (2 mL) was cooled to 0° C. and PPh3 (313 mg, 1.18 mmol) was added portionwise. The ice-bath was removed and the reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated and diluted with CH2Cl2. The mixture was basified using saturated NaHCO3 and the organic phase was separated. The aqueous phase was re-extracted with CH2Cl2 and the combined organic phase was dried over Na2SO4 and concentrated. Silica gel prep TLC using 95:5 CH2Cl2:MeOH as an eluent afforded 3-(2-bromo-ethyl)-pyridine.
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:33][CH3:34])[C:8]2[N:13]=[C:12]3[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]3=[CH:10][C:9]=2[CH2:19][N:20]([CH2:23][C:24]2[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26]([F:32])[CH:25]=2)[C:21]#[N:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+].[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C=O)C>[CH:1]1([CH2:6][N:7]([CH2:33][CH3:34])[C:8]2[N:13]=[C:12]3[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]3=[CH:10][C:9]=2[CH2:19][N:20]([CH2:23][C:24]2[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26]([F:32])[CH:25]=2)[C:21]2[NH:39][N:38]=[N:37][N:22]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC1CCCC1)c1nc2c(cc1CN(C#N)Cc1cc(F)c(F)c(F)c1)c(C)nn2C
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC1CCCC1)c1nc2c(cc1CN(Cc1cc(F)c(F)c(F)c1)c1nnn[nH]1)c(C)nn2C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a stirred suspension of [6-(cyclopentylmethyl-ethyl-amino)-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-ylmethyl-(3,4,5-trifluoro-benzyl)-cyanamide (0.280 g, 0.590 mmol) and ammonium chloride (0.160 g, 2.95 mmol) in dry DMF (10 mL) was added sodium azide (0.195 g, 2.95 mmol) and the reaction mixture was heated at 100° C. overnight. After the reaction mixture was cooled to RT, ice water was added, and this mixture was stirred for 30 min, and then extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and evaporated to yield the product as oil (yield: 90%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]([O:16][C@@H:17]3[O:25][C@H:24]([CH2:26][OH:27])[C@@H:22]([OH:23])[C@H:20]([OH:21])[C@H:18]3[OH:19])=[N:12][NH:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1)[CH3:2].I[CH2:29][CH3:30]>>[CH2:29]([N:13]1[C:14]([CH3:15])=[C:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:11]([O:16][CH:17]2[O:25][C@H:24]([CH2:26][OH:27])[C@@H:22]([OH:23])[C@H:20]([OH:21])[C@H:18]2[OH:19])=[N:12]1)[CH3:30]
Reactant: CCI
Reactant: CCc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1
Product: CCc1ccc(Cc2c(OC3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(CC)c2C)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 63 using 4-[(4-ethylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole instead of 3-(β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-5-methyl-1H-pyrazole and using iodoethane instead of 1-iodopropane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH:6]=[C:5]2[C:20]([O:22][CH3:23])=[O:21].[CH:24]1([NH:27][C:28](=[O:45])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:30]=2)[CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.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>[CH:24]1([NH:27][C:28]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8](=[O:12])[N:7]([CH2:13][C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[CH:6]=[C:5]4[C:20]([O:22][CH3:23])=[O:21])[CH:30]=2)=[O:45])[CH2:25][CH2:26]1
Reactant: COC(=O)c1cn(Cc2ccncc2)c(=O)c2ccc(Br)cc12
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
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+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(Cc2ccncc2)c(=O)c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc12
Temperature: 80 °C

Procedure:
A mixture of the product of step i) (0.7 g), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.565 g) and potassium carbonate (0.518 g) in degassed N,N-dimethylformamide (15 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (0.25 g) and the mixture heated at 80° C. under nitrogen for 40 hours. The reaction mixture was concentrated to dryness and the residue purified (SiO2, 5% methanol in dichloromethane as eluent) to give the sub-title compound (0.70 g).
Reaction SMILES: [NH4+].Cl[C:3]1[N:8]=[C:7]([OH:9])[C:6]([F:10])=[C:5]([CH2:11][CH3:12])[N:4]=1.C(O)C>[Pd].O>[CH2:11]([C:5]1[N:4]=[CH:3][N:8]=[C:7]([OH:9])[C:6]=1[F:10])[CH3:12]
Reactant: CCc1nc(Cl)nc(O)c1F
Agent: [Pd]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCc1ncnc(O)c1F
Temperature: 4 °C

Procedure:
To a mixture of the compound of part (iii) (34 kg), ethanol (170 L) and water (5 kg) was added 5% w/w palladium-on-carbon (50% w/w water content) (3.4 kg) and the mixture hydrogenated at 50° C. and 345 kPa (50 psi) until completion of the reaction. Water (10.5 L) w as added and the catalyst removed by filtration. The filtrate was concentrated under reduced pressure to a small volume and extracted with dichloromethane (2×58 L). The combined organic extracts were concentrated under reduced pressure and toluene (150 L) added. The mixture was concentrated under reduced pressure to 50 L in volume, toluene (50 L) added and cooled to 4° C. for 4 hours. The precipitated product was collected by filtration, washed with toluene (10 L) and dried (Yield=20 kg), m.p. 112-4° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([F:8])[CH:3]=1.C(N(CC)CC)C.[C:16]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=1)#[CH:17]>O1CCCC1.[Cu]I>[F:8][C:4]1[CH:3]=[C:2]([C:17]#[C:16][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=2)[CH:7]=[CH:6][N:5]=1
Reactant: C#Cc1ccnc(SC)n1
Reactant: Fc1cc(I)ccn1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1nccc(C#Cc2ccnc(F)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Iodo-2-fluoropyridine (1.09 g, 4.9 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). To this solution was added triethylamine (0.9 mL, 6.5 mmol), copper (I) iodide (80 mg, 0.4 mmol) and dichlorobis(triphenylphosphine) palladium (II) (60 mg, 0.32 mmol). 4-Ethynyl-2-(methylsulfanyl)pyrimidine (example 4, 0.75 g, 4.9 mmol) in tetrahydrofuran was added dropwise to the resulting solution. After the addition was complete the reaction was stirred at room temperature overnight. The mixture was concentrated to give a syrup, that was purified by silica gel chromatography (1:1 ethyl acetate:hexane) to give after removal of solvents 0.84 g (70%) of 4-[(2-fluoro-4-pyridinyl)ethynyl]-2-(methylsulfanyl)pyrimidine as a white solid. 1H NMR (CDCl3): δ 8.61 (d, 1H), 8.32 (d, 1H), 7.39 (d, 1H), 7.17 (m, 2H), 2.64 (s, 3H); 19F NMR (CDCl3): 8–66.82; MS m/z 246 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4](O)=[O:5].CC[N:15]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.N>O1CCCC1>[NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: Nc1cc(Cl)cc(F)c1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NC(=O)c1c(N)cc(Cl)cc1F
Reaction time: 24 h
Yield: 92.7 %

Procedure:
To a solution of 2-amino-4-chloro-6-fluorobenzoic acid (3.22 g, 17.04 mmol) in tetrahydrofuran (100 mL) was added EDCI.HCl (6.5 g, 34.1 mmol, Aldrich), HOBT (4.6 g, 34 mmol) and ammonia as a 0.5M solution in dioxanes (170 mL, 85 mmol, Aldrich). The resultant slurry was stirred for 24 hours, and then solids removed by filtration through celite. The filtrate was taken to a residue under reduced pressure and partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by chromatography on SiO2 (Ethyl acetate/Hexanes) to afford analytically pure 2-amino-4-chloro-6-fluorobenzamide as a white crystalline solid (2.98 g, 92% Yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.40 (s, 2 H), 6.44 (dd, J=10.81, 2.02 Hz, 1 H), 6.57 (s, 1 H), 7.56 (s, 1 H), 7.60 (s, 1 H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:14]#N)[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=[O:30])C>ClCCl>[F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:14]=[O:30])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: N#CC1(c2ccc(OC(F)(F)F)cc2)CCC1
Reactant: CCOC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=CC1(c2ccc(OC(F)(F)F)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a solution of Example 31A (4.82 g, 0.02 mol) in dry dichloromethane (100 mL) at −78° C. under an argon atmosphere was added diisobutylaluminum hydride (24 mL, 1M solution in toluene). The reaction mixture was stirred at the same temperature for 1 hour and then quenched by dropwise addition of potassium sodium tartrate (10% solution in water). The resulting mixture was warmed to room temperature, stirred vigorously for 40 minutes and then diluted with dichloromethane. The organic phase was separated and the aqueous phase extracted with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with 100% petroleum ether to petroleum ether: ethyl acetate=50:1 to 30:1) to give title compound as a viscous oil (2.7 g, yield 55.3%). LC-MS: m/z (M+H)+ 245.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=2[C:9]#[N:10])[CH:6]=1.[CH3:18][N+:19]([CH3:21])=[CH2:20].[I-]>CN(C=O)C>[CH3:18][N:19]([CH2:21][C:6]1[N:5]([C:7]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=2[C:9]#[N:10])[CH:4]=[N:3][C:2]=1[CH3:1])[CH3:20]
Reactant: C=[N+](C)C
Reactant: Cc1cn(-c2ccc([N+](=O)[O-])cc2C#N)cn1
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2C#N)c1CN(C)C
Yield: 35 %

Procedure:
In analogy to example 5b, 2-(4-methyl-imidazol-1-yl)-5-nitro-benzonitrile (+regioisomer) was reacted with Eschenmoser's salt in DMF for 16 h at 90° C. Evaporation of the solvent, aqueous workup and chromatography afforded the title compound as a yellow oil that was sufficiently pure to be used in the next step (yield: 35%). MS: m/e=286.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12][C@H:11]2[CH3:24])=[O:9])=[C:4]([O:27][C:28]#[N:29])[CH:3]=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CC(C)=O.O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12][C@H:11]2[CH3:24])=[O:9])=[C:4]([O:27][C:28]2[N:30]=[N:31][NH:32][N:29]=2)[CH:3]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1OC#N
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1Oc1nn[nH]n1
Temperature: 25 °C

Procedure:
To a solution of 2-(4-chloro-2-cyanato-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-ethanone (0.17 g, 0.427 mmol) in acetone (2 mL) was added sodium azide (0.061 g, 0.94 mmol) and the reaction was stirred at reflux for 3 hours, then cooled to ambient temperature and stirred 18 hours. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by anion exchange chromatography to give the title compound as its acetic acid addition salt (0.073 g, LRMS: 461.2, 463.3).
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([NH2:22])[C:15]=1[NH2:23]>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[C:15]([NH:23][C:1](=[O:10])[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[C:16]=1[NH:22][C:1](=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(OC)c(N)c1N
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2c(OC)ccc(OC)c2NC(=O)c2ccc(OC)cc2)cc1
Yield: 63.6 %

Procedure:
Using the procedure described in Example 93, Part A, 4-anisoyl chloride (4.9 mmol) and 3,6-dimethoxy-1,2-benzenediamine (2.0 mmol) yielded 555 mg (65%) of the title compound.
Reaction SMILES: [Cu][C:2]#[N:3].[NH2:4][C:5]1[N:10]=[C:9]([CH3:11])[C:8](Br)=[CH:7][CH:6]=1.[C-]#N.[Na+]>CN(C)C=O.O>[NH2:4][C:5]1[N:10]=[C:9]([CH3:11])[C:8]([C:2]#[N:3])=[CH:7][CH:6]=1
Reactant: Cc1nc(N)ccc1Br
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N)ccc1C#N
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Copper(I) cyanide (12 mmol) is added to 10 mmol of 6-amino-3-bromo-2-methylpyridine dissolved in dimethylformamide. The mixture is refluxed for 10 hours, then cooled to 80° C. and poured into a solution of sodium cyanide (40 mmol) in water. After stirring for 1 hour at ambient temperature, the mixture is extracted with ethyl acetate. The organic phase is washed and then dried and evaporated to yield the expected product in the form of an ochre solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:20]([O:12][C:11](=[O:13])[C@@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
To a solution of 11.19 g (59.1 mmol) of (R)-N-tert-butoxycarbonylalanine in 70 mL of N,N-dimethylformamide was added 6.7 g (48.5 mmol) of K2CO3, and 6.9 mL (58.0 mmol) of benzyl bromide. The reaction was stirred at 80° C. for 40 min, then poured into 350 mL of H2O. The aqueous mixture was extracted with diethyl ether (3×50 mL), then the combined ether layers were back extracted with H2O (2×50 mL), and brine (1×50 mL), dried over MgSO4, filtered, and concentrated in vacuo to furnish the titled compound as a colorless oil. MS (ESI) m/z=280 (M+H)+, 297 (M+NH4)+, 302 (M+Na)+: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.25 (d, J=7.5 Hz, 3 H) 1.37 (s, 9 H) 4.06 (m, 1 H) 5.07 (d, J=12.9 Hz, 1 H) 5.15 (d, J=12.5 Hz, 1 H) 7.34 (m, 6 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[C:10](=S)=[S:11].[OH-].[Na+]>C(O)C>[SH:11][C:10]1[NH:1][C:2]2[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: S=C=S
Reactant: Cc1ccc(N)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2nc(S)[nH]c2c1

Procedure:
A mixture of 12.2 g (0.1 mole) of 3,4-diaminotoluene, 35 ml of carbon disulfide, and 4.0 g (0.1 mole) of sodium hydroxide was heated at reflux in 350 ml of ethanol. After 2.5 hours the mixture was concentrated in vacuo. The residue was suspended in 200 ml of 4% aqueous hydrochloric acid, and the product was collected by filtration, washed sequentially with water and diethyl ether, and air dried to yield 12.2 g of 2-mercapto-5-methylbenzimidazole, as confirmed by the nmr and infrared spectra. The title compound (2.0 g) was prepared by the method of Example 84 using 1.6 g (9.7 mMol) of 2-mercapto-5-methylbenzimidazole instead of 2-mercaptobenzimidazole. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis. Anal. Calc'd. for C14H14N4S: C, 60.19; H, 5.01; N, 20.05; S, 11.47. Found: C, 59.80; H, 5.05; N, 20.00; S, 11.17.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:4][N:3]=1.FC(F)(F)S(O[CH2:26][CH:27]([F:29])[F:28])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([N:14]2[CH2:19][CH2:18][N:17]([CH2:26][CH:27]([F:29])[F:28])[CH2:16][CH2:15]2)=[CH:4][N:3]=1
Reactant: COc1ccc2c(Cl)ncc(N3CCNCC3)c2c1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(Cl)ncc(N3CCN(CC(F)F)CC3)c2c1
Yield: 16.3 %

Procedure:
To a solution of 1-chloro-6-methoxy-4-(piperazin-1-yl)isoquinoline (0.2 g, 0.720 mmol) in DMF (5 ml) was added 2,2-Difluoroethyl trifluoromethanesulfonate (0.154 g, 0.720 mmol) followed by sodium carbonate (0.114 g, 1.080 mmol). The reaction mass was stirred until judged complete. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get desired compound (0.04 g, 15.93%) as semi solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.18-8.15 (d, J=12 Hz, 1H), 7.93 (s, 1H), 7.45-7.42 (d, J=12 Hz, 1H), 7.37 (s, 1H), 6.36-5.76 (tf, 1H), 3.97 (s, 3H), 3.10 (m, 4H), 2.84 (m, 4H); 19F NMR: δ ppm −118.59 (1F); MS: MS m/z 342.19 (M++1).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)CCC.[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[N:22]=1>O1CCCC1.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:20][C:21]1[N:22]=[C:23]([C:6]2[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1cccc(-c2ccncc2)n1
Yield: 53.8 %

Procedure:
4-Tri-n-butylstannylpyridine (3.30 g, 8.9 mmol) was added to a degassed and stirred solution of 2,6-dibromopyridine (2.00 g, 8.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (5 mol %) in tetrahydrofuran (30 ml) under an atmosphere of nitrogen then heated to reflux for 48 h. Solvent was removed in vacuo and purification by chromatography on silica gel eluting with dichloromethane followed by trituration with isohexane gave 6-bromo-2,4′-bipyridinyl (1.05 g) as a white solid: δH (400 MHz, CDCl3) 7.52-7.57 (1H, m), 7.66-7.70 (1H, m), 7.86 (2H, m), 8.10-8.50 (1H, m), 8.72-8.76 (1H, m), 8.77-8.81 (1H, m); m/z (ES+) 234/236 (M++H).
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH2:16][CH2:17][S:18][CH2:19][CH2:20][CH3:21])[CH2:4][CH:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)[OH:6])[CH3:2].ClC1C=CC=C(C(OO)=[O:30])C=1>>[CH2:1]([N:3]([CH2:15][CH2:16][CH2:17][S:18]([CH2:19][CH2:20][CH3:21])=[O:30])[CH2:4][CH:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)[OH:6])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCSCCCN(CC)CC(O)c1ccc(C#N)cc1
Product: CCCS(=O)CCCN(CC)CC(O)c1ccc(C#N)cc1
Yield: 73.9 %

Procedure:
0.9 g of 4-[2-[ethyl[3-(propylthio)propyl]amino]-1-hydroxyethyl]-benzonitrile was oxidized with 0.7 g of m-chloroperbenzoic acid in analogy with example 2. Yield: 0.7 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.O.[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:17][N:18]1[CH:22]=[C:21]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:20]=[N:19]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Temperature: 25 °C
Yield: 63 %

Procedure:
5-(2-Chloropyridin-4-yloxy)pyridin-2-amine (0.47 g, 2.121 mmol) was dissolved in DMF (11 ml). Water (3.67 ml) was added to the mixture, followed by 1-methyl-4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazole (0.662 g, 3.18 mmol), and cesium carbonate (2.63 g, 8.06 mmol). Argon was bubbled through the mixture for several minutes, and then palladium tetrakistriphenylphosphine (0.245 g, 0.212 mmol) was added. The flask was fitted with a condenser and argon was flushed through the system. The reaction mixture was then placed in a 90° C. oil bath under a balloon of argon and heated for 23 hours. The solution was then cooled to RT and diluted with THF (75 mL) and washed with brine (2×50 mL). The combined aqueous layers were then back extracted with THF (40 mL). The combined organic layers were dried (MgSO4), concentrated under reduced pressure and purified via silica gel chromatography (THF-ethyl acetate) to yield 5-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-2-amine as an off-white solid (0.357 g, 63% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.31 (d, 1H), 8.22 (s, 1H), 7.92 (s, 1H), 7.80 (d, 1H), 7.27 (dd, 1H), 7.14 (d, 1H), 6.85 (s, 1H), 6.57 (dd, 1H), 6.01 (s, 2H), 3.84 (s, 3H); MS (ESI) m/z: 268.1 (M+H+).