Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[NH:9][S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:24][PH:25]([O-])([O-:29])[O:26][CH2:27][CH3:28].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C@@H:8]([NH:9][S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[C:5]1[CH:6]=[CH:7][C:2]([P:25]([CH3:24])(=[O:29])[O:26][CH2:27][CH3:28])=[CH:3][CH:4]=1
Reactant: CCO[PH](C)([O-])[O-]
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccc(Br)cc1)c1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(C)(=O)c1ccc([C@H](N[S@@](=O)C(C)(C)C)c2ccc(F)cc2F)cc1
Reaction time: 8 h
Yield: 44 %

Procedure:
To (S)—N—((S)-(4-bromophenyl)(2,4-difluorophenyl)methyl)-2-methylpropane-2-sulfinamide, 21-b, (2 g, 5 mmol), ethyl methylphosphite (1.08 g, 10 mmol) and Et3N (1.25 g, 12.5 mmol) in THF (20 ml) was added PdCl2(dppf) (360 mg). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into ethyl acetate and washed with brine. The organic layer was concentrated under vacuum and the residue was purified over silica gel (dichloromethane:methanol=50/1) to provide the product, 21-c, (950 mg, 44%).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C[O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([S:17][C:14]2[CH:15]=[CH:16][C:11]([C:10]([OH:18])=[O:9])=[CH:12][CH:13]=2)[CH:3]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: Ic1cccnc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Sc2cccnc2)cc1
Yield: 100.3 %

Procedure:
A mixture of 3-iodopyridine (823 mg, 4.01 mmol), methyl-4-mercaptobenzoate (500 mg, 2.97 mmol), potassium carbonate (677 mg, 4.90 mmol), and copper dust (4 mg, 0.653 mmol) in dimethylformamide (10 mL) are heated to reflux temperature for 18 h. The heat is removed and the reaction is filtered through Celite® with dichloromethane. The filtrate is concentrated in vacuo and the residue is recrystallized from ether and hexane to obtain 689 mg (99%) of the title compound. MS (ES+) m/e 232.0 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=O.[Cl-].[NH4+]>O(CC)CC>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1)([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1)[OH:17]
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)CCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: OC(CCCCBr)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 4 h

Procedure:
To a stirred and refluxing Grignard complex previously prepared starting from 280 parts of 1-bromo-4-fluorobenzene, 34.6 parts of magnesium and 392 parts of 1,1'-oxybisethane, was added dropwise a solution of 116 parts of ethyl 5-bromopentanoate in 392 parts of 1,1'-oxybisethane. Upon complete addition, stirring was continued for 4 hours at reflux temperature. The reaction mixture was decomposed with a saturated ammonium chloride solution and the product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated. The residue was triturated in hexane. The latter was decanted and the residue was crystallized from hexane. The product was filtered off and dried at room temperature, yielding 100 parts of α-(4-bromobutyl)-4-fluoro-α-(4-fluorophenyl)benzenemethanol; mp. 55° C. (int. 49).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:13](O)(=[O:19])[CH2:14][CH2:15][C:16]([CH3:18])=O>CCCCOCCO>[CH3:18][C:16]12[C:5]3[NH:6][C:7]4[C:12]([C:4]=3[CH2:3][CH2:2][N:1]1[C:13](=[O:19])[CH2:14][CH2:15]2)=[CH:11][CH:10]=[CH:9][CH:8]=4
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CC(=O)CCC(=O)O
Solvent: CCCCOCCO
Product: CC12CCC(=O)N1CCc1c2[nH]c2ccccc12

Procedure:
Tryptamine (112.15 g.), levulinic acid (97.6 g., 85.6 ml.) and butyl cellosolve (1 liter) are refluxed under nitrogen for 16 hours and the solvent is removed. The residue is successively washed with water, dilute aqueous sodium hydroxide, water, dilute aqueous hydrochloric acid, water and dried. Trituration of the crude product, decomposition at 252°-262°C., with methanol, and then with benzene, and drying provides 120.4 g. of the title compound, decomposition at 259°-263°C.; λmaxKBr 3.09, 6.01, 6.17, 13.38 μ.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[SH:10].[H-].[Na+].[N+]([C:16]1[O:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=1)([O-])=O>O1CCCC1>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[S:10][C:16]1[O:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=1
Reactant: Sc1nc2ncccc2[nH]1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2nc3ncccc3[nH]2)o1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
1H-Imidazo[4,5-b]pyridine-2-thiol (1.51 g, 10.0 mmol) is suspended into 80 mL of tetrahydrofuran under argon. Then, 0.72 g (15.0 mmol) of sodium hydride is added. The reaction mixture is stirred at room temperature until gas evolution has ceased. 5-Nitro-2-furaldehyde (1.41 g, 10.0 mmol) is then added and the reaction mixture is stirred at room temperature for 2.5 h, upon which it is poured on ice and extracted 3 times with ethyl acetate. The organic extracts are combined, washed with brine, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate, filtered, washed with ethyl acetate and dried under reduced pressure. 1.34 g of 5-(1H-imidazo[4,5-b]pyridin-2-ylsulfanyl)-furan-2-carbaldehyde is obtained as a crystalline light-brown powder. mp: 188° C.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:24][C:25]1([C:28]2[CH:29]=[C:30]([NH:40][C:41]([NH:43][C:44]3[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:47]([O:54][CH:55]4[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]4)=[N:46][CH:45]=3)=[O:42])[N:31]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)[N:32]=2)[CH2:27][CH2:26]1.[CH3:61][C:62]1([C:65](O)=[O:66])[CH2:64][CH2:63]1.CCN(C(C)C)C(C)C>ClCCl>[CH3:61][C:62]1([C:65]([N:58]2[CH2:59][CH2:60][CH:55]([O:54][C:47]3[C:48]4[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:44]([NH:43][C:41]([NH:40][C:30]4[N:31]([C:33]5[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=5)[N:32]=[C:28]([C:25]5([CH3:24])[CH2:27][CH2:26]5)[CH:29]=4)=[O:42])=[CH:45][N:46]=3)[CH2:56][CH2:57]2)=[O:66])[CH2:64][CH2:63]1
Reactant: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2cnc(OC3CCNCC3)c3ccccc23)cc1
Reactant: CC1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2cnc(OC3CCN(C(=O)C4(C)CC4)CC3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Place EDCI (0.147 g, 0.77 mmol), HOBt (0.10 g, 0.77 mmol), 1-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-[1-(piperidin-4-yloxy)-isoquinolin-4-yl]-urea dihydrochloride (Preparation 3, 0.16 g, 0.64 mmol) and 1-methyl-1-cyclopropyl carboxylic acid (1.1 eq) in a flask under N2. Add dichloromethane (5 mL) follow by DIPEA (0.22 mL, 1.28 mmol) and stir at room temperature overnight. Evaporate solvent to give a residue. Subject residue to silica gel chromatography eluting with hexane:AcOEt 50-100% to give 1-{1-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yloxy]-isoquinolin-4-yl}-3-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-urea as a free base. ES+ (m/z) 579.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[O:18]1CCOCC1>O>[NH2:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([NH2:9])=[O:18]
Reactant: COc1ccc(-c2nccc(C#N)c2N)cc1
Reactant: C1COCCO1
Solvent: O
Product: COc1ccc(-c2nccc(C(N)=O)c2N)cc1

Procedure:
1 g of 3-amino-2-(4-methoxyphenyl)-4-pyridinecarbonitrile was heated to reflux for 2 hours in 10 ml of water and 10 ml of dioxan in the presence of 4 g of Dowex 1X4-100 (OH form). The resin was removed by filtration and the filtrate was evaporated in order to remove dioxan. The aqueous residue was extracted with ethyl acetate and the organic phase was washed with water and sodium chloride solution, dried over sodium sulphate and evaporated. Recrystallization of the residue from ethyl acetate/hexane yielded 500 mg of 3-amino-2-(4-methoxyphenyl)-4-pyridinecarboxamide as a yellow solid of melting point 179°-181° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19]>C1(C)C=CC=CC=1.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+]>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH:19]=[CH:18][C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:7]=1)=[O:9]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(Br)n1
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(C=CC(=O)OC(C)(C)C)n1
Temperature: 25 °C

Procedure:
Methyl 6-bromo-2-pyridinecarboxylate (1) (5.0 g, 23.1 mmol), sodium acetate (5.7 g, 3.0 eq), tris-O-tolylphosphine (0.7 g, 2.3 mmol), allylpalladium chloride dimer (0.34 g, 0.93 mmol) and tert-butyl acrylate (3.6 g, 1.2 eq) are mixed in toluene (25 ml), and the resulting slurry is heated under a nitrogen atmosphere at 110 LC for approximately 12-16 hours. After cooling to ambient temperature, the precipitate is removed by filtration, and rinsed with ethyl acetate. The filtrate is washed with 1M aqueous citric acid, water, and brine, and then dried with MgSO4 and filtered. The solvent is removed, and the resulting yellow solid is crystallized from EtOAc/hexane to give the pure product as a yellow solid. MS: m/z (EI+) 264.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:27][CH3:28]>CN(C=O)C.[Cl-].[Na+].O>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:19])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[C:11]([CH2:15][C:16]([O:18][CH2:27][CH3:28])=[O:17])[CH:12]=[CH:13][CH:14]=2)[O:5]1
Reactant: CCI
Reactant: CC1(C)OB(c2cccc(CC(=O)O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (0.50 g, 1.91 mmol) in 20 mls of dry DMF was added cesium carbonate (1.24 g, 3.82 mmole) and iodoethane (0.20 mls, 2.48 mmol). This mixture was stirred at room temperature for 16 hours, then diluted with brine, extracted twice with EtOAc, extracts washed with brine (2×), dried over sodium sulfate and concentrated under reduced pressure to give 360 mgs (65%) of ethyl 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate as a clear oil.
Reaction SMILES: [K].[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH2:10](Br)[C:11]#[CH:12]>CN(C)C=O>[CH2:12]([N:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]1=[O:9])[C:11]#[CH:10]
Reactant: C#CCBr
Reactant: O=c1ncc(Cl)c[nH]1
Agent: [K]
Solvent: CN(C)C=O
Product: C#CCn1cc(Cl)cnc1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
A mixture of the potassium salt of 5-chloropyrimid-2-one (0.009 mol) and propargyl bromide (0.013 mol) in dimethylformamide (40 ml) was stirred at room temperature for 18 h. The solvent was then removed at reduced pressure (1 mm Hg) and the residue was extracted with chloroform (150 ml). The chloroform solution was passed through a column of Al2O3 (Woelm; 30 g, activity III). Evaporation of the chloroform eluates left a solid which was triturated with a little ether before recrystallization from EtOAc; yield 56%, m.p. 130° C. (Found: C, 50.11; H, 2.95. Calc. for C7H5ClN2O: C, 49.87; H, 2.99).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[C:6]=2[N:7]=1.[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl>COCCOC.O>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34]([C:2]2[N:3]=[CH:4][C:5]3[N:10]=[N:9][N:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][CH:16]=[CH:15]5)[C:6]=3[N:7]=2)[CH:33]=[N:32]1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: Clc1ncc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: c1cnc2ccc(Cn3nnc4cnc(-c5cnn(CCOC6CCCCO6)c5)nc43)cc2c1
Temperature: 80 °C
Yield: 39 %

Procedure:
To a solution of 6-((5-chloro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)methyl)quinoline (393 mg, 1.33 mmol) in DME (8 mL) was added 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (642 mg, 1.99 mmol) and Cs2CO3 (1.30 g, 3.98 mmol) in H2O (1.3 mL). The reaction mixture was degassed twice. The palladium catalyst Pd(dppf).CH2Cl2 (63 mg, 0.077 mmol) was added and the reaction mixture was degassed for two more times, and heated to 80° C. for 15 h under nitrogen. After cooling to room temperature, the solvent was removed under reduced pressure. Flash chromatography of the residue over silica gel, using 50% hexane in EtOAc to 100% EtOAc to 10% MeOH in EtOAc, gave the desired product (237 mg, 39%). 1H NMR (300 MHz, CDCl3) δ 1.23-1.82 (m, 6H), 3.42-4.59 (m, 7H), 6.04 (s, 2H), 7.41 (m, 1H), 7.82-7.85 (m, 1H), 7.90 (m, 1H), 8.08-8.15 (m, 2H), 8.31 (s, 1H), 8.34 (s, 1H), 8.90-8.92 (m, 1H), 9.46 (s, 1H); LCMS (APCI) m/z 457.2 (M+H+).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([NH:13][C:14](=[O:25])[C@H:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[H-].[Na+].[CH2:28]([SH:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CN(C=O)C>[CH3:1][S:2][C:3]1[C:4]([NH:13][C:14](=[O:25])[CH:15]([S:34][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: CCCCCCCC[C@@H](Br)C(=O)Nc1c(SC)ccc2ncccc12
Reactant: CCCCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCC(SCCCCCC)C(=O)Nc1c(SC)ccc2ncccc12
Temperature: 25 °C
Yield: 65.1 %

Procedure:
(R)-N-(6-Methylthioquinolin-5-yl)-2-bromodecanoic amide (43 mg, 0.10 mmol) in 1 ml of DMF was cooled to 0° C. To this was added a cooled suspension of NaH (9 mg, 0.38 mmol) and hexanethiol (67 mg, 0.57 mmol) in 1 ml DMF. The reaction was allowed to warm to rt over a period of 12 hours and quenched with 5 ml of saturated NH4Cl. The aqueous layer was extracted with ethyl acetate (3×10 ml). Purification of the organic phase by silica gel column chromatography (eluent: 100% CHCl3) yielded 30 mg (65% yield) of the desired product. 1H NMR (CDCl3) δ8.85 (1H, d, J=3 Hz), 8.62 (1H, s), 8.05 (3H, d, J=9 Hz), 8.00 (1H, d, J=9 Hz), 7.65 (1H, d, J=9 Hz), 7.40 (1H, dd, J=9, 9 Hz), 3.55 (1H, t, J=8 Hz), 2.80 (2H, t, J=8 Hz), 2.50 (3H, s), 2.20-1.30 (22H, m), 0.91 (6H, t, J=9 Hz).
Reaction SMILES: Br[C:2]1[C:3]([C:9]2[C:10]([F:34])=[C:11]([N:16]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[S:17]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[F:27])(=[O:19])=[O:18])[CH:12]=[CH:13][C:14]=2[F:15])=[N:4][N:5]([CH2:7][CH3:8])[CH:6]=1.[N:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:7]([N:5]1[CH:6]=[C:2]([C:38]2[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=2)[C:3]([C:9]2[C:10]([F:34])=[C:11]([N:16]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[S:17]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[F:27])(=[O:19])=[O:18])[CH:12]=[CH:13][C:14]=2[F:15])=[N:4]1)[CH3:8]
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: CCn1cc(Br)c(-c2c(F)ccc(N(COCCOC)S(=O)(=O)c3cc(F)ccc3F)c2F)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CCn1cc(-c2ccncc2)c(-c2c(F)ccc(N(COCCOC)S(=O)(=O)c3cc(F)ccc3F)c2F)n1
Yield: 86 %

Procedure:
In a vial suitable for microwave irradiation N-[3-(4-Bromo-1-ethyl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-N-(2-methoxy-ethoxymethyl)-benzenesulfonamide (288 mg, 0.509 mmol) was dissolved in dimethoxyethane (4.5 mL) and Ar was bubbled through the solution for 5 minutes. Water (0.5 mL) was added, followed by 4-pyridylboronic acid pinacol ester (209 mg, 1.018 mmol, 2 eq), cesium carbonate (497 mg, 1.527 mmol, 3 eq) and Pd(dppf)Cl2.DCM (42 mg, 0.051 mmol, 0.1 eq). The vial was sealed and irradiated in the microwave oven at 100° C. for 30 minutes. The reaction mixture was then filtered over a Celite pad and concentrated under reduced pressure. The residue was taken up with ethyl acetate and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4 and evaporated to dryness. The crude product was purified by chromatography on silica gel (DCM/MeOH 97:3) to give 247 mg (86% yield) of N-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-N-(2-methoxy-ethoxymethyl)-benzenesulfonamide as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[CH2:14][N:15]=[N+:16]=[N-:17]>C1C=CC=CC=1.C1CCCCC1>[CH3:1][O:2][C:3]([C:5]1[N:17]=[N:16][N:15]([CH2:14][C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[Cl:11])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])=[O:4]
Reactant: COC(=O)C#CC(=O)OC
Reactant: [N-]=[N+]=NCc1ccccc1Cl
Solvent: C1CCCCC1
Solvent: c1ccccc1
Product: COC(=O)c1nnn(Cc2ccccc2Cl)c1C(=O)OC

Procedure:
A solution of 8 g (0.054 mol) of acetylene-dicarboxylic acid dimethyl ester in 25 ml of benzene is added dropwise to a solution of 8.4 g (0.05 mol) of o-chlorobenzyl azide in 50 ml of benzene that is boiling under reflux. After a further hour under reflux, the whole is diluted with 75 ml of cyclohexane and, after cooling, the substance that has crystallised out is filtered off with suction. After washing with a mixture of diethyl ether and hexane (1:1), there is obtained 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester having a melting point of 88°-91°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][S:12](=[S:30])([O:14][CH:15](Br)[CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH3:28])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:11][S:12](=[S:30])([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:7][C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[CH:3][CH:4]=1)=[O:8])=[O:13]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCOCCOCCOCCOCC(Br)OS(C)(=O)=S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=S)OCCOCCOCCOCCOCCOC(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 25.5 %

Procedure:
4-aminobenzoic acid (0.145 g, 1.06 mmol) and 1-bromo-3,6,9,12-tetraoxatetradecyl methanethiosulfonate (0.42 g, 1.06 mmol) were dissolved in dry DMF (30 mL). Cesium carbonate (0.385 mg, 1.1 mmol) was added and the mixture was stirred at room temperature for 3 days. The solvent was evaporated. The residue was pied by column chromatography on SiO2. Elution was with dichloromethane/methanol (100:3) and after evaporation, 16-(4-aminophenyl)-16-oxo-3,6,9,12,1 5-pentaoxahexadecyl methanethiosulfonate (0.120 g, 0.27 mmol; 25% yield) remained as a pale yellow oil. 1H NMR (500 MHz, (CD3)2SO) δ 7.62 (d, J=8.7 Hz, 2H), 6.55 (d, J=8.7 Hz, 2H), 5.94 (s, br., 2H), 4.25 (t, J=4.8 Hz, 2H), 3.70-3.67 (m, 4H), 3.57-3.55 (m, 2H), 3.54-3.47 (m, 13H), 3.36 (t, J=5.9 Hz, 2H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8]1[C:13]([Cl:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:30]=[CH:29][C:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:27][CH3:28])[CH2:23][CH2:24][C:18]=3[CH:17]=2)[N:9]=1.CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:14][C:13]1[C:8]([NH:7][C@H:3]2[CH2:4][CH2:5][CH2:6][C@H:2]2[NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[N:9][C:10]([NH:15][C:16]2[CH:30]=[CH:29][C:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:27][CH3:28])[CH2:23][CH2:24][C:18]=3[CH:17]=2)=[N:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@H]4CCC[C@H]4N)n3)cc2CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@H]4CCC[C@H]4NS(C)(=O)=O)n3)cc2CC1

Procedure:
To a solution of N*4*-((1S,2R)-2-Amino-cyclopentyl)-5-chloro-N*2*-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-pyrimidine-2,4-diamine (132 mg, 0.298 mmol) in DCM (2 mL) was added Et3N (62.0 μL, 0.447 mmol) at 0° C. under argon. Stirred reaction for 10 min. before adding methanesulfonyl chloride (34.6 μL, 0.447 mmol) dropwise via syringe. Reaction stirred for 20 minutes at 0° C. The reaction mixture was diluted with DCM and washed with 1N NaOH (2×). Dried organic layer over MgSO4, filtered and concentrated. The residue was purified by column chromatography to yield (58 mg, 38%). mp: 73-74° C., MS (ESI+): 509 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.14 (s, 1H), 7.97 (s, 1H), 7.51 (s, 1H), 1.33 (d, J=7.5 Hz, 1H), 7.32 (s, 1H), 6.96 (d, J=8 Hz, 1H), 6.40 (d, J=7 Hz, 1H), 4.34 (m, 1H), 3.89 (br s, 1H), 3.44 (t, J=6 Hz, 2H), 3.23 (s, 3H), 2.75 (br s, 8H), 2.62 (m, 8H), 2.50 (m, 5H), 2.02 (m, 2H), 1.76 (m, 2H), 1.66 (m, 1H), 1.54 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([C:18]([O:20]C)=[O:19])[CH:12]=[CH:11]3)[CH:5]=[N:4][CH:3]=1.C.[ClH:23]>>[ClH:23].[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([C:18]([OH:20])=[O:19])[CH:12]=[CH:11]3)[CH:5]=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc2cc(Cn3cncc3C)ccc2c1
Agent: Cl
Product: Cc1cncn1Cc1ccc2cc(C(=O)O)ccc2c1
Yield: 85 %

Procedure:
3.31 g (11.8 mmol) of methyl 6-(5-methyl-1-imidazolyl)methyl-2-naphthoate in 40 ml of 2N HCl are heated under reflux for three hours, and active charcoal is added and the mixture is filtered hot. The hydrochloride of the acid crystallizes out on cooling. 3.03 g (85%) of 6-(5-methyl-1-imidazolyl)methyl-2-naphthoic acid hydrochloride are obtained after filtration with suction, washing with acetone and drying. Melting point: 289°-290° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl.Cl>[CH:25]([S:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:6][CH:7]=1)(=[O:28])=[O:27])=[CH2:24]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)Nc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of tert-butyl 4-aminophenylcarbamate (2.63 g, 12.63 mmol) and triethylamine (7.04 mL, 50.51 mmol) were combined in dichloromethane (50 mL) and cooled in an ice bath. After drop wise addition of 2-chloroethanesulfonyl chloride (1.45 mL, 13.9 mmol), the solution was stirred at ambient temperature for 4 h then diluted with 0.5M HCl and extracted into dichloromethane. The product was purified by column chromatography on silica gel, eluting with 1% methanol/dichloromethane to give 2.48 g (66%).