Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([CH3:10])[N:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([F:21])[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCOC(C)=O.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>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([CH3:10])[N:5]=[CH:4][CH:3]=2)=[C:14]([F:21])[CH:13]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: Cc1nccc(Cl)c1C=O
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: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nccc(-c2ccc(Cl)cc2F)c1C=O
Temperature: 90 °C
Yield: 93.5 %

Procedure:
A mixture of 4-chloro-2-methylnicotinaldehyde (100 mg, 0.643 mmol), (4-chloro-2-fluorophenyl)boronic acid (123 mg, 0.707 mmol), Cs2CO3 (628 mg, 1.928 mmol) and Pd(Ph3P)4 (52.0 mg, 0.045 mmol) in toluene (5 mL) was heated at 90° C. for 16 h. After cooling, the reaction mixture was diluted with EtOAc (10 mL) and water (10 mL). The ethyl acetate layer was concentrated and purified by silica gel chromatography (2:1 Hexane-EtOAc) to afford 4-(4-chloro-2-fluorophenyl)-2-methylnicotinaldehyde (0.15 g, 0.601 mmol, 35% yield) as a yellow solid. LCMS (ESI) m/e 250.04 [(M+H)+, calcd for C13H10ClFNO 250.0]; LC/MS retention time (Method G): tR=0.96 min.
Reaction SMILES: [C:1]([N:5]([C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:25]=1)[C:22](O)=[O:23].CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[C:1]([N:5]([C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)[NH:6][C:22](=[O:23])[C:21]1[CH:25]=[C:17]([Br:16])[CH:18]=[N:19][CH:20]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N(N)C(=O)c1ccc(Cl)cc1
Reactant: O=C(O)c1cncc(Br)c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)N(NC(=O)c1cncc(Br)c1)C(=O)c1ccc(Cl)cc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A solution of N'-t-butyl-N'-(4-chlorobenzoyl)-hydrazine (0.5 g, 0.0022 mol) and 5-bromonicotinic acid (0.44 g, 0.0022 mol) in 10 ml of methylene chloride containing triethylamine (0.33 g) was added to a solution of methanesulfonyl chloride (0.25 g, 0.0022 mol) in 10 ml of methylene chloride at 0° C. The resulting mixture was stirred at 23° C. for 2 hours and then was allowed to stand overnight at 23° C. Aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was re-extracted with methylene chloride. The organic extracts were evaporated to give a yellow solid which was triturated with hexane/methylene chloride to afford N'-t-butyl-N-(5-bromonicotinoyl)-N'-(4-chlorobenzoyl)hydrazine as an off-white solid. m.p. 193-197° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH2:25][CH3:26])[N:18]=[C:19]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:12]2[N:11]=1)[CH3:2].[S:27](Cl)([Cl:30])(=[O:29])=[O:28]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:27]([Cl:30])(=[O:29])=[O:28])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH2:25][CH3:26])[N:18]=[C:19]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:12]2[N:11]=1)[CH3:2]
Reactant: CCOc1ccccc1-c1nn2c(C3CCCC3)nc(CC)c2c(=O)[nH]1
Reactant: O=S(=O)(Cl)Cl
Product: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C3CCCC3)nc(CC)c2c(=O)[nH]1

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 0.34 g (0.96 mmol) of 2-(2-ethoxyphenyl)-5-ethyl-7-cyclopentyl-3H-imidazo[5.1-f][1,2,4]triazin-4-one (Example 16A). This gives 0.43 g (98%) of sulphonyl chloride as a colourless foam which is directly reacted further.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([NH2:19])=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]#[N:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C(N)=O)cc2C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1Cc2ccc(C#N)cc2C1
Reaction time: 8 h
Yield: 490.9 %

Procedure:
A solution of N-t-butoxycarbonyl-5-aminocarbonylisoindoline (D14) (140 mg) in pyridine (3 ml) at rt was treated with 4-toluenesulfonyl chloride (305 mg) and then stirred overnight. Following evaporation the residue was dissolved in EtOAc (10 ml), washed with saturated NaHCO3 solution (10 ml), water (10 ml), brine (10 ml), dried (MgSO4) and concentrated. The residue was chromatographed on a silica gel flash column [step gradient 5-20% EtOAc in light petroleum 40-60] to give the title compound (D15) (0.64 g). MS electrospray (+ion) 189 (MH+-t-Bu). 1H NMR δ (CDCl3): 7.56 (2H, m), 7.38 (1H, m), 4.71 (4H, m), 1.52 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)C.[C:16](OC)(=[O:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19].N1CCCCC1>C1(C)C=CC=CC=1.O>[CH3:21][O:20][C:18]([C:17]1[C:16](=[O:22])[NH:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[CH:8][C:9]=2[O:10][CH3:11])=[O:19]
Reactant: COC(=O)CC(=O)OC
Reactant: COc1cccc(C=O)c1N
Solvent: O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cccc(OC)c2[nH]c1=O
Temperature: 25 °C
Yield: 61.3 %

Procedure:
To a solution/suspension of 2-amino-3-methoxybenzaldehyde (1.8 g, 11.9 mmol) in dry toluene (30 mL) under nitrogen was added acetic acid (0.1 mL) followed by dimethyl malonate (3.4 mL, 29.8 mmol) and piperidine (2.9 mL, 29.8 mmol). The reaction mixture was heated at reflux for 2 h. After cooling to r.t., the mixture was diluted with water (30 mL) and extracted with EtOAc (2×150 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was triturated in EtOAc/Et2O and the resulting solid was filtered off and dried in vacuo to give the title compound (1.7 g, 61%) as a pale yellow solid. δH (DMSO-d6) 10.65 (br s, 1H), 8.52 (s, 1H), 7.42 (d, J 8.0 Hz, 1H), 7.27 (d, J 8.0 Hz, 1H), 7.21 (t, J 6.0 Hz, 1H), 3.94 (s, 3H), 3.84 (s, 3H). LCMS (ES+) 234 (M+H)+, RT 2.13 minutes (Method 5).
Reaction SMILES: C(OC([NH:11][CH2:12][CH:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][CH2:12][CH:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:26])([F:27])[F:28])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(CNC(=O)OCc1ccccc1)c1ccccc1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(CN)c1ccccc1C(F)(F)F

Procedure:
1.035 g (2.54 mmol) of ethyl 3-{[(benzyloxy)carbonyl]amino}-2-[2-(trifluoromethyl)phenyl]propanoate [for the preparation see Example 193A in WO 2007/134862] were dissolved in 24 ml of ethanol and hydrogenated in the presence of 100 mg of 10% palladium on carbon for 3 h at atmospheric pressure. The catalyst was then filtered off and the filtrate was freed from the solvent on a rotary evaporator. The residue corresponded to the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([N:20]2[C:24]([CH3:25])=[C:23](I)[C:22]([CH3:27])=[N:21]2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[C:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)(O)=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>CCO>[CH2:1]([N:3]([CH2:29][CH3:30])[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([N:20]2[C:24]([CH3:25])=[C:23]([C:37]3[CH:38]=[CH:39][C:34]([CH:31]=[O:32])=[CH:35][CH:36]=3)[C:22]([CH3:27])=[N:21]2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(OC)c2)n2nc(C)c(I)c2C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(OC)c2)n2nc(C)c(-c3ccc(C=O)cc3)c2C)cc1
Temperature: -78 °C
Yield: 92.9 %

Procedure:
To a stirring solution of N,N-Diethyl-4-[(4-iodo-3,5-dimethyl-pyrazol-1-yl)-(3-methoxy-phenyl)-methyl]-benzamide (300 mg, 0.58 mmol) in 40 mL EtOH/H20 (9:1) at room temperature was added 4-carboxybenzeneboronic acid (261 mg, 1.74 mmol), sodium carbonate (184 mg, 1.74 mmol) and tetrakistriphenylphosphine palladium (0) (200 mg, 0.174 mmol). The mixture was cooled to −78° C., de-oxygenated under reduced pressure and purged with nitrogen gas. The mixture was refluxed for 3 h, cooled to room temperature, filtered through a Celite pad and concentrated under reduce pressure. Purification of the crude material was accomplished by flash chromatography on a 2×15 cm column, eluting with 50% ethyl acetate/hexanes, collecting 8 mL fractions. The product containing fractions were collected and concentrated to give the desired product (267 mg, 93%) as a clear colorless solid. 300 MHz 1H NMR (CDCl3) δ 10.1 (s, 1H), 7.90 (d, J=8.3 Hz, 2H), 7.21-7.42 (m, 7H), 6.78-6.86 (m, 3H), 6.57 (s, 1H), 3.75 (s, 3H), 3.52 (brs, 2H), 3.27 (brs, 2H), 2.26 (s, 6H), 1.24 (brs, 3H), 1.22 (brs, 3H); MS (M+1) 496.2.
Reaction SMILES: C(N[C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])=O.[H-].[Na+].IC.[CH3:17][N:18]([CH:20]=[O:21])C>>[CH:20]([N:18]([C:5]1[CH:4]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])[CH3:17])=[O:21]
Reactant: O=CNc1cccc(C(=O)O)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(C=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
3-Formylamino benzoic acid (2.28 g, 13.8 mmol) was taken up in DMF (25 ml) and added dropwise to a suspension of sodium hydride (1.05 g, 80% disp. in oil) in DMF (15 ml) at 0° C. The mixture was allowed to warm to r.t. over 1 h and then iodomethane (0.95 ml) added. A second portion of iodomethane (0.95 ml) was added after 1 h and the mixture stirred at r.t. overnight. The solvent was removed by evaporation and the product partitioned between ethyl acetate and 1M HCl. The organic layer was washed with brine, then filtered (Whatman® 1 PS phase separator) and evaporated. The residue was chromatographed on silica (eluant 60% ethyl acetate in hexanes) to provide the title compound as a colourless solid (2.30 g, 86%). A portion of the ester (900 mg, 4.66 mmol) was taken up in dioxan/water (2/1, v/v, 30 ml) and treated with LiOH.H2O (378 mg, 9 mmol) at r.t. with stirring overnight. The mixture was acidified with 1M HCl and extracted twice with EtOAc. The combined extracts were washed with brine, filtered (Whatman® 1 PS phase separator) and evaporated. The acid (420 mg, 50%) was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4].[CH:28]1([Mg]Br)[CH2:30][CH2:29]1>C1COCC1>[CH:28]1([C:3]([C:5]2[CH:6]=[CH:7][C:8]([N:11]3[CH2:16][CH2:15][N:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH2:13][CH2:12]3)=[CH:9][CH:10]=2)([OH:4])[C:2]([F:1])([F:26])[F:27])[CH2:30][CH2:29]1
Reactant: O=C(c1ccc(N2CCN(S(=O)(=O)c3ccccc3)CC2)cc1)C(F)(F)F
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)N1CCN(c2ccc(C(O)(C3CC3)C(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
A 100 mL round-bottom flask was charged with 2,2,2-trifluoro-1-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)ethanone (0.50 g, 1.26 mmol) and 10 mL of THF. After cooling to 0° C., cyclopropylmagnesium bromide (5.02 mL, 0.5 M in THF, 2.51 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. After 10 min, the mixture was quenched with saturated aqueous NH4Cl (15 mL), extracted with EtOAc (2×50 mL), dried (MgSO4), and concentrated to give an oil. This oil was purified via column chromatography (40 g of silica, 0 to 40% EtOAc in hexanes) to give 1-cyclopropyl-2,2,2-trifluoro-1-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)ethanol (0.375 g) as a mixture of two enantiomers.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:11][CH:10]=1.[CH3:22][N:23]=[C:24]=[S:25].CCOCC>CCCCCC>[Cl:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:17][C:18]([F:21])([F:19])[F:20])[C:24]([NH:23][CH3:22])=[S:25])=[CH:11][CH:10]=1
Reactant: CN=C=S
Reactant: FC(F)(F)CNCc1ccc(Cl)nc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: CNC(=S)N(Cc1ccc(Cl)nc1)CC(F)(F)F
Yield: 55.3 %

Procedure:
In 35 me of toluene, 3,79 g (0.0169 mole) of N-(6-chloro-3-pyridylmethyl)-N-(2,2,2-trifluoroethyl)amine and 2.46 g of methyl isothiocyanate were stirred for 18 hours under reflux. The toluene was distilled off, and the residue was dissolved in 120 me of AcOEt, washed with 1N HCl (two times) and aqueous sodium chloride solution in this order and dried over MgSO4. The AcOEt was distilled off to give oil. To this oily product were added Et2O and hexane, followed by cooling to give crystals. After addition of hexane to the mixture, the crystals were collected by filtration and dried to give 2.78 g of N-(6-chloro-3-pyridylmethyl)-N-(2,2,2-trifluoroethyl)-N'-methylthiourea as white crystals.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]([C:20]2[N:21]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:22]=[C:23]3[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]3)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])=[C:6]([CH3:36])[CH:5]=1.[OH-].[Li+]>C(OC(C)=O)(C)C.[Cl-].[Na+].O>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([N:21]2[C:20]([N:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:11](=[O:12])[NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:37])=[O:2])=[CH:5][C:6]=3[CH3:36])=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[CH:27]3)=[N:22]2)=[CH:30][CH:31]=1
Reactant: COC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(C)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: O
Product: Cc1cc(C(=O)O)ccc1NC(=O)N(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 2.2, 4-{3-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-3-cyclohexyl-ureido}-3-methyl-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 14 h at ambient temperature to give the title compound as yellow solid. MS: m/e=503.0 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][S:17](=[O:33])(=[O:32])[NH:18]C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][S:17](=[O:32])(=[O:33])[NH2:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCS(=O)(=O)NC(c2ccccc2)c2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CCCS(N)(=O)=O)CC1
Reaction time: 8 h
Yield: 79.3 %

Procedure:
A suspension of 4-[3-(benzhydryl-sulfamoyl)-propyl]-piperazine-1-carboxylic acid tert-butyl ester (650 mg, 1.37 mmol) and palladium hydroxide (1.154 g, 1.64 mmol, 20% w from Aldrich) in methanol (10 mL) was hydrogenated at room temperature overnight using a Parr apparatus (50 psi). The reaction mixture was filtered through a Celite cake, and the filtrate was concentrated. Purification of the crude residue by flash column chromatography (40 g of silica gel, eluting with methanol and ethyl acetate) gave 4-(3-sulfamoyl-propyl)-piperazine-1-carboxylic acid tert-butyl ester as an off-white solid (334 mg).
Reaction SMILES: Br[Mg][C:3]#[CH:4].[O:5]=[C:6]1[CH2:9][CH:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7]1>O1CCCC1>[C:3]([C:6]1([OH:5])[CH2:9][CH:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7]1)#[CH:4]
Reactant: CCOC(=O)C1CC(=O)C1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC1(O)CC(C(=O)OCC)C1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure A. To a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed bromo(ethynyl)magnesium (0.5M in THF, 50 mL, 1.20 equiv). This was followed by the addition of a solution of ethyl 3-oxocyclobutane-1-carboxylate (3.0 g, 21.10 mmol, 1.00 equiv) in tetrahydrofuran (3 mL) dropwise with stirring at −70° C. in 15 min. The resulting solution was stirred for 30 min at −70° C. The reaction was then quenched by the addition of 10 mL of sat. aq. ammonium chloride. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 2.6 g (66%) of ethyl 3-ethynyl-3-hydroxycyclobutane-1-carboxylate as light yellow oil (single undetermined diastereomer).
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:10])=[C:7]([O:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:38](=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:28])[C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)=[O:10])=[C:7]([O:31][CH:32]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:34][CH2:33]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(C(=O)Nc2cnccc2NC(=O)c2ccc(C(C)(C)C)cc2OC2CCNCC2)cc1
Product: COc1ccc(C(=O)Nc2cnccc2NC(=O)c2ccc(C(C)(C)C)cc2OC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 105.4 %

Procedure:
In a 4 mL screw cap vial, N4-[4-tert-butyl-2-(piperidin-4-yloxy)benzoyl]-N3-(4-methoxybenzoyl)-3,4-pyridinediamine (38 mg, 76 μmol) was dissolved in 1 mL of freshly prepared dry 95:5 MeOH:AcOH. Benzaldehyde (24.1 mg, 227 μmol, 3 eq) was added and the vial was capped. After 10 minutes, sodium cyanoborohydride solution (0.5 mL of a 19.0 mg/mL freshly prepared stock in dry 95:5 MeOH:AcOH, 9.51 mg NaCNBH3, 151 μmol, 2 eq) was then added to the solution. The vial was re-capped and shaken overnight at room temperature. The mixture was then purified using the method described in Example 34-B to provide the desired compound as a yellow solid (47.5 mg, 106%).
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[NH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=1)(=[O:3])[CH3:2].C(O[CH:27](OCC(C)(C)C)[N:28]([CH3:30])[CH3:29])C(C)(C)C>>[CH3:27][N:28]([CH3:30])[CH:29]=[CH:2][C:1]([C:4]1[C:9](=[O:10])[NH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1cc(C(C)=O)c(=O)[nH]c1C(=O)OCC
Reactant: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Product: CCOC(=O)c1cc(C(=O)C=CN(C)C)c(=O)[nH]c1C(=O)OCC
Temperature: 25 °C
Yield: 70 %

Procedure:
Diethyl 5-acetyl-1,6-dihydro-6-oxo-2,3pyridinedicarboxylate, (25 g, 0.089 mol) and N,N-dimethylformamide dineopentyl acetal (50 mL, 98%, 40.62 g, 0.176 mol) are heated for 30 minutes at 80°-100° C. After cooling to room temperature, the product is obtained as a precipitate and is filtered and washed with hexane to yield 23.4 g, 70% yield, of solid which is recrystallized from isopropanol to give a pure product, melting point 182°-183° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].B1C2CCCC1CCC2.C([O-])([O-])=O.[K+].[K+].[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:47][C:35]3=[N:36][C:37]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])=[C:38](I)[CH:39]=[C:34]3[C:33]=2[C:48]([NH:50][CH3:51])=[O:49])=[CH:28][CH:27]=1>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.O>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:47][C:35]3=[N:36][C:37]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:43])=[O:44])=[C:38]([CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH:39]=[C:34]3[C:33]=2[C:48](=[O:49])[NH:50][CH3:51])=[CH:28][CH:27]=1
Reactant: C=CCCC(=O)OCC
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(I)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])[O-]
Solvent: O
Product: CCOC(=O)CCCCc1cc2c(C(=O)NC)c(-c3ccc(F)cc3)oc2nc1N(C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 5.1 mg ethyl pent-4-enoate and 79 μl 9-BBN (2 M solution in THF) is stirred at rt for 1 h. 10 μl of water is added and stirred at rt for 10 min. 30 μl of 2 M K2CO3 solution is added and stirred at rt for 30 min. 10 mg of 2-(4-fluorophenyl)-5-iodo-N-methyl-6-(N-methylmethylsulfonamido)furo[2,3-b]pyridine-3-carboxamide and 1.1 mg of Pd(PPh3)4 are added, bubbled with N2, and microwaved at 120 C for 20 min. The crude reaction mixture is purified with preparative HPLC to afford the title compound (M+H)+=506.3; Retention time=1.28 min, Method A.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([S:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])(=[O:20])=[O:19])[CH:16]=3)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:10]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:43]1[CH:44]=[C:45]([NH:49][CH:50]([CH:59]([CH3:61])[CH3:60])[C:51]([NH:53][CH2:54][C:55]([F:58])([F:57])[F:56])=[O:52])[CH:46]=[N:47][CH:48]=1>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>[CH3:60][CH:59]([CH3:61])[CH:50]([NH:49][C:45]1[CH:44]=[C:43]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([S:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])(=[O:19])=[O:20])[CH:16]=3)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[CH:10]=2)[CH:48]=[N:47][CH:46]=1)[C:51](=[O:52])[NH:53][CH2:54][C:55]([F:58])([F:57])[F:56]
Reactant: CC(C)C(Nc1cncc(Br)c1)C(=O)NCC(F)(F)F
Reactant: COC(=O)CCS(=O)(=O)c1cnc2c(c1)c(B1OC(C)(C)C(C)(C)O1)cn2COCC[Si](C)(C)C
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: [Na+]
Product: COC(=O)CCS(=O)(=O)c1cnc2c(c1)c(-c1cncc(NC(C(=O)NCC(F)(F)F)C(C)C)c1)cn2COCC[Si](C)(C)C
Temperature: 100 °C
Yield: 50.2 %

Procedure:
To methyl 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-ylsulfonyl)propanoate 4-1c (3.26 mmol) was added aqueous sodium carbonate (4.89 ml, 9.79 mmol), 2-[(5-bromopyridin-3-yl)amino]-3-methyl-N-(2,2,2-trifluoroethyl)butanamide (1386 mg, 3.91 mmol) and Tetrakis (188 mg, 0.163 mmol). The reaction mixture was heated at 100° C. in a sealed vessel for 1 h. The reaction was cooled, quenched with water (50 mL), and product extracted with ethyl acetate (100 mL). The organic extract was dried over sodium sulfate, filtered and concentrated to oil. The oil was chromatographed on silica (100 g) using 50-100% ethyl acetate/hexanes to give the desired product 4-1d (1.1 g).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.S(Cl)([Cl:14])=O>C(Cl)Cl>[Cl:14][CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1
Reactant: OCc1cn2ccccc2n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
In a round bottomed flask containing 2-hydroxymethyl-imidazo[1,2-a]pyridine (800 mg, 5.4 mmol) in DCM (8 mL), was added at R.T. thionyl chloride (1.96 mL, 27 mmol). The solution became clear and 10 min later, a precipitated was formed. The reaction mixture was stirred at R.T. for 2 hours and the solvent was removed under reduced pressure to afford 1.10 g of a brownish solid as the chlorhydrate form of 2-(chloromethyl)-imidazo[1,2-a]pyridine (Yield: 100%).