Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(C)(C)C.[C:6]([O:10][C:11](=[O:19])[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)([CH3:9])([CH3:8])[CH3:7].CN(C)[CH:22]=[O:23]>C(OCC)C>[C:6]([O:10][C:11](=[O:19])[NH:12][C:13]1[C:18]([CH:22]=[O:23])=[CH:17][CH:16]=[CH:15][N:14]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1ccccn1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1ncccc1C=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyllithium (1.7 M, 14.5 mL, 24.6 mmol, 2.39 equiv) was added to a solution of pyridin-2-yl-carbamic acid tert-butyl ester (5-1, 2.00 g, 10.3 mmol, 1 equiv) in ethyl ether (100 mL) at −78° C., and the resulting mixture was warmed to 0° C. and stirred for 1 h. N,N-Dimethylformamide (8.00 mL, 103 mmol, 10.0 equiv) was added with rapid stirring. The mixture was stirred at 0° C. for 10 min, then partitioned between half-saturated aqueous ammonium chloride solution (100 mL). The aqueous layer was further extracted with ethyl acetate (100 mL), and the combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (40% ethyl acetate in hexanes) to afford (3-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (5-2) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][O:10][CH3:11])[C:3]=1[CH3:12].C([Li])CCC.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.Cl>C1COCC1>[CH3:11][O:10][CH2:9][O:8][C:4]1[C:3]([CH3:12])=[C:2]([B:18]([OH:23])[OH:19])[CH:7]=[CH:6][CH:5]=1
Reactant: COCOc1cccc(Br)c1C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1cccc(B(O)O)c1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
16.2 g (70 mmol) of 1-bromo-3-methoxymethoxy-2-methylbenzene are dissolved in 200 mL of anhydrous THF and the mixture is cooled to −78° C. 33.7 mL (84 mmol) of 2.5M butyllithium are added slowly and the mixture is then maintained at −78° C. for 1 hour. 19.4 mL (84 mmol) of triisopropyl borate are then added dropwise over a period of 15 minutes. The medium is stirred for 30 minutes at the same temperature and then poured into 300 mL of 1N hydrochloric acid. After the usual treatment, the whitish solid residue obtained is rinsed with heptane and then dried under reduced pressure. A flaky white solid is obtained (m=11.8 g; Y=86%).
Reaction SMILES: O1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:18]4=[N:28][N:29]=[C:30]([C:31]5[N:32]=[CH:33][NH:34][CH:35]=5)[N:17]4[CH:16]=[CH:15][C:14]=3[N:13]=2)=[CH:8][CH:7]=1.Cl.Cl.[NH2:38][OH:39]>O1CCOCC1.O>[NH:34]1[CH:35]=[C:31]([C:30]2[N:17]3[C:18]([C:19]4[CH:20]=[C:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:12]([C:9]5[CH:8]=[CH:7][C:6]([CH:2]=[N:38][OH:39])=[CH:11][CH:10]=5)=[N:13][C:14]=4[CH:15]=[CH:16]3)=[N:28][N:29]=2)[N:32]=[CH:33]1
Reactant: c1ccc(-c2cc3c(ccn4c(-c5c[nH]cn5)nnc34)nc2-c2ccc(C3OCCO3)cc2)cc1
Reactant: NO
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: ON=Cc1ccc(-c2nc3ccn4c(-c5c[nH]cn5)nnc4c3cc2-c2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 22-1 (0.8 g, 1.7 mmol) in 1,4-dioxane (3 ml) was added 3N HCl (1.1 ml, 3.4 mmol) dropwise. After stirring for 10 min the solution was treated with hydroxylamine hydrochloride (0.5 g, 6.9 mmol) in water (0.5 ml). The mixture was stirred for 1 h and was then quenched with NaHCO3(s) until pH=8. Upon solvent removal the residue was taken up in water, filtered, and dried azeotropically with toluene to afford 22-2 as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][C:20](B(O)O)=[CH:21][CH:22]=2)[CH:17]=[N:16]1>CN(C=O)C.CCOC(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>[Cl:1][C:2]1[N:6]=[C:5]([C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[N:15]([CH3:14])[N:16]=[CH:17]3)[S:4][N:3]=1
Reactant: Clc1nsc(Cl)n1
Reactant: Cn1ncc2cc(B(O)O)ccc21
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+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ncc2cc(-c3nc(Cl)ns3)ccc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 3,5-dichloro-1,2,4-thiadiazole (100 mg, 0.645 mmol), Na2CO3 (0.968 mL, 1.935 mmol) and (1-methyl-1H-indazol-5-yl)boronic acid (114 mg, 0.645 mmol) in DMF (4 mL) was degassed under N2 for 10 min. Pd(Ph3P)4 (149 mg, 0.129 mmol) was added and the mixture was stirred at 80° C. for 2 h. The reaction mixture was cooled to ambient temperature and diluted with EtOAc. The organics were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by preparative TLC (5% MeOH/DCM) to afford the title compound as a solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.12 (s, 3H) 7.50 (d, J=8.79 Hz, 1H) 7.94 (d, J=8.79 Hz, 1H) 8.11 (s, 1H) 8.39 (s, 1H). LC/MS (m/z) ES+=251(M+1).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:26]([CH3:27])=[CH:25][C:18]2[N:19]=[C:20]([CH:22]3[CH2:24][CH2:23]3)[S:21][C:17]=2[C:16]=1Br)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[O:29]1[C:40]2[C:41]3[C:36]([C:37](B(O)O)=[CH:38][CH:39]=2)=[N:35][CH:34]=[CH:33][C:32]=3[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>CC(N(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>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:26]([CH3:27])=[CH:25][C:18]2[N:19]=[C:20]([CH:22]3[CH2:24][CH2:23]3)[S:21][C:17]=2[C:16]=1[C:37]1[C:36]2[C:41]3=[C:32]([CH2:31][CH2:30][O:29][C:40]3=[CH:39][CH:38]=1)[CH:33]=[CH:34][N:35]=2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1cc2nc(C3CC3)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: OB(O)c1ccc2c3c(ccnc13)CCO2
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: CC(=O)N(C)C
Product: Cc1cc2nc(C3CC3)sc2c(-c2ccc3c4c(ccnc24)CCO3)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C

Procedure:
To a solution of (S)-2-(7-bromo-2-cyclopropyl-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (18) (23 mg, 0.047 mmol) in DMA (2 ml), was added 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid (25 mg, 0.099 mmol), 2N K2CO3 solution (0.11 ml, 0.22 mmol) and Pd(PPh3)4 (6 mg, 0.005 mmol). The reaction mixture was reacted at 85° C. for 2 hs. The reaction was cooled down, washed by saturated NaHCO3 solution, extracted by EtOAc. The organic phase was combined, dry over MgSO4, filtered, concentrated and purified by silica gel column, eluting by 0-50% EtOAc in hexanes. Two isomers were separated and went through the chemistry sequence as above. LCMS-ESI+: calc'd for C33H38N2O4S: 559.2 (M+H+). Found: 559.1 (M+H+).
Reaction SMILES: NC(N)=O.[CH:5]1([NH:10][S:11]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([NH2:21])[C:15]=2[OH:22])(=[O:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]([NH:21][C:16]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([S:11]([NH:10][CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9]2)(=[O:13])=[O:12])[C:15]=1[OH:22])=[O:32]
Reactant: O=C=Nc1ccccc1Cl
Reactant: Nc1ccc(Cl)c(S(=O)(=O)NC2CCCC2)c1O
Agent: NC(N)=O
Product: O=C(Nc1ccccc1Cl)Nc1ccc(Cl)c(S(=O)(=O)NC2CCCC2)c1O
Yield: 43.3 %

Procedure:
Following the general procedure for urea formation outlined in example 15, (N-cyclopentyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (0. 15 g, 0.52 mmol) and 2-chlorophenylisocyanate (62 μL, 0.52 mmol) were coupled to form the desired urea (0.1 g, 43%). LC-MS n/z 444(M+).
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]3[NH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[N:13][C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[N:1]1([C:7]2[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]3[N:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:13]([CH2:31][C:32]4[C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH:35]=[CH:34][CH:33]=4)[C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: BrCc1cccc2ccccc12
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)(F)F)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)(F)F)n2Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
A mixture of methyl 5-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-7-carboxylate prepared as described in Example 45 (1.5 g, 4.56 mmol) and potassium carbonate (1.889 g, 13.67 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was stirred at rt for 10 min. After addition of 1-(bromomethyl)naphthalene (1.511 g, 6.83 mmol), the mixture was warmed to 80° C. and stirred for 3 h at this temperature. The resulting mixture was cooled to rt and poured over ice. The precipitate formed was collected by filtration and air dried (2.4 g total). The crude material was purified on silica gel (ISCO, 0-5% MeOH in DCM) to give methyl 6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylate (1.48 g, 3.15 mmol, 69.2% yield). A portion of this material (138 mg) was purified by reverse phase-HPLC (25 to 95% AcCN in water, plus 0.1% TFA) to give the desired product (93.4 mg, 0.195 mmol, 4.28% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (d, J=8.34 Hz, 1H), 8.01 (d, J=7.33 Hz, 1H), 7.85 (d, J=8.08 Hz, 1H), 7.60-7.73 (m, 3H), 7.39 (d, J=2.27 Hz, 1H), 7.31 (t, J=7.83 Hz, 1H), 6.24 (br. s., 1H), 6.22 (s, 2H), 3.95 (s, 3H), 3.64-3.73 (m, 4H), 3.06-3.19 (m, 4H). MS(ES+) m/e 470 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21](O)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.[CH3:24][S:25]([NH2:28])(=[O:27])=[O:26].Cl.C(N=C=NCCCN(C)C)C.CN(C1C=CC=CN=1)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([CH2:24][S:25]([NH2:28])(=[O:27])=[O:26])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: NS(=O)(=O)CC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(F)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
6 g (0.019 mol) of the compound from Example XV, 1.9 g (0.019 mol) of dried methanesulphonamide, 3.8 g (0.019 mol) of N-ethyl-N'-dimethylaminopropylcarbodiimide hydrochloride and 2.4 g (0.019 mol) of dimethylaminopyridine are dissolved in 40 ml of dichloromethane and the mixture is stirred at room temperature for 60 h. It is then evaporated to dryness in vacuo, the residue is taken up in 40 ml of dichloromethane and the solution is washed twice with 20 ml of water. After drying the organic phase using Na2SO4, it is evaporated in vacuo and the residue is separated by column chromatography (silica gel 60, eluent dichloromethane/ethyl acetate/glacial acetic acid=10:1:1).
Reaction SMILES: [CH:1]([N:4]1[C:8]([NH:9][C:10]2[C:11](=[CH:15][C:16]([S:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[C:12](O)=O)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:31]>>[CH:1]([N:4]1[C:8]2=[N:9][C:10]3[C:11]([C:12]([Cl:31])=[C:7]2[CH:6]=[N:5]1)=[CH:15][C:16]([S:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])(=[O:21])=[O:20])=[CH:17][CH:18]=3)([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCN(CC)S(=O)(=O)c1ccc(Nc2ccnn2C(C)C)c(C(=O)O)c1
Agent: [NH4+]
Agent: [OH-]
Product: CCN(CC)S(=O)(=O)c1ccc2nc3c(cnn3C(C)C)c(Cl)c2c1
Temperature: 25 °C

Procedure:
A mixture of N-(1-isopropylpyrazol-5-yl)-5-(diethylaminosulfonyl) anthranilic acid (12.0 g, 0.031 mol) and POCl3 (80 mL) was refluxed for 6 hours. The reaction mixture was cooled to room temperature and then was poured into ice-water and neutralized with concentrated NH4OH. The mixture was extracted with CH2Cl2 and the CH2Cl2 layer was dried over MgSO4 and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with CH2Cl2 /ether (9/1) to afford 10 g of crude 1-isopropyl-6-(diethylaminosulfonyl)-4-chloro-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:19]([C:21]1([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)#[CH:20]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C.[I-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:20]#[C:19][C:21]2([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: C#CC1(O)CCCCC1
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)c1ccc(C#CC2(O)CCCCC2)cc1
Temperature: 70 °C
Yield: 109.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (716 mg, 2.0 mmol) and triethylamine (2 mL, 0.01 mmol) in N,N-dimethylformamide (2 mL) was treated with 1-ethynyl cyclohexanol (621 mg, 5.0 mmol). The resulting reaction mixture was degassed with argon and then treated with cooper iodide (10 mg, 0.05 mmol) and bis(triphenylphosphine)palladium (II) chloride (15 mg, 0.02 mmol). The reaction was then heated at 70° C. for 24 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and then washed with a half-saturated aqueous sodium chloride solution (1×20 mL). The aqueous layer was back extracted with ethyl acetate (1×40 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 ethyl acetate/hexanes) afforded 3-cyclopentyl-2-[4-(1-hydroxy-cyclohexylethynyl)-phenyl]-propionic acid methyl ester (774 mg, 98%) as a cream solid: mp 76-78° C.; EI-HRMS m/e calcd for C23H30O3 (M+) 354.2194, found 354.2194.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[NH:11][C:12]([C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])=[C:13]([CH3:15])[N:14]=1.Cl.C(N(CC)CC)C.[NH2:32][CH2:33][C@H:34]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)[OH:35]>C(O)(=O)C>[Cl:42][C:38]1[CH:37]=[C:36]([C@H:34]([OH:35])[CH2:33][NH:32][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:10]2[NH:11][C:12]([C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: COc1nccc(I)c1-c1nc(C)c(C(=O)N2CCOCC2)[nH]1
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2c(NC[C@@H](O)c3cccc(Cl)c3)cc[nH]c2=O)[nH]c1C(=O)N1CCOCC1
Temperature: 90 °C
Yield: 25.7 %

Procedure:
(2-(4-Iodo-2-methoxypyridin-3-yl)-4-methyl-1H-imidazol-5-yl)(morpholino)methanone (0.007 g, 0.017 mmol) was dissolved in acetic acid (1 mL) and concentrated hydrochloric acid (1 mL) and this mixture was stirred at 100° C. for 1 hour. The mixture was then evaporated and the residue was dissolved in N,N-dimethylformamide (2 mL) and treated with triethylamine (100 μL, 0.72 mmol) and the hydrochloric acid salt of (S)-2-amino-1-[3-chlorophenyl]ethanol (0.010 g, 0.048 mmol). The mixture was heated at 90° C. for 4 hours, then the solvent was evaporated and the residue was purified by Prep HPLC (ammonium acetate/acetonitrile/water) to give the title compound (0.002 g, 25%) as a white solid. HPLC 100% (220 nm), LCMS (+ESI, M+H+) m/z 458; 1H NMR (400 MHz, methanol-d4) δ (ppm): 2.37 (3H, s), 3.45-4.0 (10H, m), 4.7-4.9 (1H, m, overlapped by D2O), 6.10 (1H, d, J=7.8 Hz), 7.10 (1H, d, J=7.6 Hz), 7.14-7.24 (3H, m), 7.36 (1H, s), 10.26 (1H, br s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([O:16][CH3:17])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.ClC(OCC)=O.[F:31][C:32]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:33]=1[C:34](=[NH:37])[NH:35][NH2:36]>C1COCC1>[F:31][C:32]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:33]=1[C:34](=[NH:37])[NH:35][NH:36][C:10](=[O:12])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:13]([O:16][CH3:17])([CH3:15])[CH3:14]
Reactant: N=C(NN)c1cc(F)ccc1F
Reactant: COC(C)(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(C)(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)NNC(=N)c1cc(F)ccc1F
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
The crude (R)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-methylbutanoic acid (4 g, 16.2 mmol) was converted to a mixed anhydride by adding Et3N (3.38 ml, 24.26 mmol), ethyl chloroformate (1.931 g, 17.79 mmol) in anhydrous THF (32.4 ml, 0.5 M) at −5° C. to 0° C. The mixture was stirred at −5° C. for 30 min. The resulting solid was filtered off and additional anhydrous THF was added to wash the precipitate. The resulting reaction solution was then added to a THF solution of 2,5-difluorobenzimido-hydrazide (2.77 g, 16.18 mmol) at −5° C. Then the reaction was gradually warmed to room temperature and stirred for overnight. Once the reaction was complete, the mixture was partitioned between EtOAc and H2O. The organic layer was separated and washed with H2O, brine, then dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give the crude product, which was purified on silica gel column (50% EtOAc in Hexanes) to afford (R)-tert-butyl (1-(2-((2,5-difluorophenyl)(imino)methyl)hydrazinyl)-3-methoxy-3-methyl-1-oxobutan-2-yl)carbamate (1 g, 15%). LC/MS (uplc): MH+ 401.2, 0.61 min.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][N:21](S(C4C=CC(C)=CC=4)(=O)=O)[C:18]3=[N:19][CH:20]=2)=[CH:11][C:5]=1[C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[C:2]=[O:3].C(N(C(C)C)C(C)C)C.[CH:51]([OH:54])([CH3:53])[CH3:52]>C(Cl)Cl>[CH:51]([O:54][C:2](=[O:3])[NH:1][C:4]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][NH:21][C:18]3=[N:19][CH:20]=2)=[CH:11][C:5]=1[C:6](=[O:7])[N:8]([CH3:9])[CH3:10])([CH3:53])[CH3:52]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N=C=O)c(C(=O)N(C)C)c3)cc12
Reactant: CC(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(NC(=O)OC(C)C)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Yield: 48.7 %

Procedure:
Into a 3 mL reation vial were added 2-isocyanato-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (30 mg, 0.053 mmol), methylene chloride (1 mL), iPr2EtN (21 μL, 0.060 mmol), and isopropyl alcohol (50 μL, 6.5 mmol). The solution was stirred at room temperature for at least 12 h and monitored by HPLC. The reaction mixture was concentrated then re-dissolved in MeOH (1 mL), and cooled to 0° C. and treated with 100 μL 50% (w/w) aqueous KOH for 30 min or until Ts-removal was complete. The reaction was quenched by addition of 500 μL glacial acetic acid and then concentrated in vacuum. Purification by mass-triggered HPLC (formic acid ACN/H2O gradient) followed by lyophilization provided 12.2 mg of the title compound as a white powder. 1H-NMR (500 MHz, d6-DMSO) δ=11.91 (br.s, 1H), 8.96 (br.s., 1H), 8.53 (d, J=2.0 Hz, 1H), 8.15 (d, J=2.0 Hz, 1H), 7.73 (m, 3H), 7.60 (d, J=9.0 Hz, 1H), 7.59 (s, 1H), 7.29 (dd, J=1.5, 7.2 Hz, 1H), 7.12 (d, J=7 Hz, 1H), 7.04 (t, J=7 Hz, 1H), 4.84 (m, 1H), 3.81 (s, 3H), 2.97, 2,92 (br s, 6H), 1.23 (d, J=6, 6H); MS: m/z 473.1 [M+H+].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:24][CH2:23][O:22][CH2:21]3)[N:17]=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(O)=O.CO>[N:11]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:24][CH2:23][O:22][CH2:21]3)[N:17]=[C:16]([NH2:25])[N:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(C3CCOC3)nc(N)n2)CC1
Agent: Cl
Solvent: CO
Solvent: O=CO
Product: Nc1nc(C2CCOC2)cc(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A solution of 4-[2-amino-6-(tetrahydro-furan-3-yl)-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (600 mg, 1.72 mmol) in formic acid (10 mL) was treated with 6.0 N HCl (2 mL) and stirred for 2 h at rt. The mixture was diluted with MeOH (10 mL) and concentrated. This process was repeated twice, yielding 295 mg of a white solid as the hydrochloride salt. The crude material was chromatographed (2 M NH3 in MeOH/CH2Cl2) to afford 133 mg (50%) of the free base as an off-white solid. MS (ESI): mass calcd. for C12H19N5O, 249.1; m/z found, 250.2 [M+H]+. 1H NMR (CDCl3): 6.86 (s, 1H), 4.78 (br s, 2H), 3.98-4.07 (m, 2H), 3.83-3.90 (m, 2H), 3.54-3.58 (m, 4H), 3.22 (p, J=15.0, 7.3, 1H), 2.89-2.93 (m, 4H), 2.10-2.30 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:25])([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH2:18][F:19])([CH2:16][F:17])[CH:13]=[C:12]([C:20](=S)[NH:21][CH3:22])[C:11]=2[CH:24]=1)[C:3]([F:6])([F:5])[F:4].C(I)C.[H-].[Na+].[N:31]#[C:32][NH2:33].Cl>O1CCCC1>[C:32]([NH:33][C:20]([C:12]1[C:11]2[CH:24]=[C:7]([C:2]([F:25])([F:1])[C:3]([F:4])([F:5])[F:6])[CH:8]=[CH:9][C:10]=2[O:15][C:14]([CH2:18][F:19])([CH2:16][F:17])[CH:13]=1)=[N:21][CH3:22])#[N:31]
Reactant: N#CN
Reactant: CNC(=S)C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCI
Product: CN=C(NC#N)C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21
Yield: 49 %

Procedure:
A mixture of 0.14 g of 6-pentafluoroethyl-2,2-bis(fluoromethyl)-N-methyl-2H-1-benzopyran-4-carbothioamide, 0.31 g of ethyl iodide, 0.017 g of sodium hydride and 5 ml of tetrahydrofuran was refluxed with heating for 45 minutes. To the reaction mixture were added 0.081 g of cyanamide and 0.017 g of sodium hydride and the resultant mixture was refluxed with heating for 22 hours. To the reaction mixture was added a small amount of hydrochloric acid and the mixture was concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (developing solution, ethyl acetate:hexane=1:1) to obtain 0.07 g of N-cyano-6-pentafluoroethyl-2,2-bis(fluoromethyl)-N'-methyl-2H-1-benzopyran-4-amidine with a melting point of 178°-179° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].[CH3:22]/[C:23](/[CH:31]=[O:32])=[CH:24]/[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H][H]>C(O)(C)C>[CH3:22]/[C:23](/[CH2:31][OH:32])=[CH:24]\[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: [H][H]
Reactant: C/C(C=O)=C/c1ccccc1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)O
Product: C/C(=C\c1ccccc1)CO
Yield: 84.9 %

Procedure:
Into a stainless steel autoclave equipped with a glass inner tube, Cu(NO3)(PPh3)2 (11.7 mg, 0.018 mmol) and triphenylphosphine (28.3 mg, 0.108 mmol) were introduced. The inside of the autoclave was then replaced with nitrogen. To the autoclave, an isopropyl alcohol solution of sodium hydroxide (0.03 M) (6.0 mL, 0.18 mmol), and α-methyl cinnamic aldehyde (0.50 mL, 3.6 mmol) were added, and stirring was performed at a hydrogen pressure of 5 MPa at 50° C. for 16 hours. The hydrogen was released with great care, and the conversion was analyzed by GC (>99%). The contents were concentrated, and then purified by silica gel chromatography. Thus, 453 mg of the α-methyl cinnamic alcohol was obtained (yield: 85%).