Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:16])[CH:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[NH2:7])[CH3:3].[CH:17](=O)[CH3:18].C([BH3-])#N.[Na+]>>[CH2:17]([NH:7][CH:6]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)[C:5]([O:4][CH2:2][CH3:3])=[O:16])[CH3:18]
Reactant: CCOC(=O)C(N)Cc1ccc(O)cc1
Reactant: CC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCNC(Cc1ccc(O)cc1)C(=O)OCC

Procedure:
Reaction and post-treatment were carried out according to Reference example 9 using 983 mg of DL-tyrosine ethyl ester hydrochloride, 0.26 ml of acetaldehyde and 100 mg of sodium cyanoborohydride to obtain 515 mg of the desired compound as a syrup which soon crystallized.
Reaction SMILES: [Na][Na].[OH:3][C:4]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].S(OC)(O[CH3:19])(=O)=O.[OH-].[Na+].C>O>[CH3:19][O:3][C:4]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Cc1cc(C)c(O)c(C(=O)O)c1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [Na][Na]
Agent: [OH-]
Solvent: O
Product: COc1c(C)cc(C)cc1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The disodium salt of 2-hydroxy-3,5-dimethylbenzoic acid (21 g.) and dimethyl sulphate (92 ml.) were stirred together at 140°-150° C. for 2.5 hours. After standing overnight, the mixture was added to a solution of sodium hydroxide (40 g.) in water (250 ml.), and the mixture stirred and heated on the steam-bath for 1 hour. Charcoal was added, the mixture was filtered and the filtrate was cooled, acidified with concentrated hydrochloric acid, and maintained at 0° C. The solid which separated was filtered off and recrystallised from aqueous ethanol to give 2-methoxy-3,5-dimethylbenzoic acid (14.7 g.), m.p. 97°-98° C.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][N:7]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[C@H:6]([C:15]([OH:17])=O)[CH2:5]1)(=[O:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:30][NH:31][CH3:32].C(N=C=NCCCN(C)C)C>O1CCCC1.O.C(OCC)(=O)C>[C:1]([CH:4]1[CH2:8][N:7]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[C@H:6]([C:15](=[O:17])[N:31]([CH3:32])[CH3:30])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: C=CCOC(=O)N1CC(C(C)=O)C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)N1CC(C(C)=O)C[C@H]1C(=O)N(C)C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
To a solution of (2S)-4-acetyl-1-allyloxycarbonylpyrrolidine-2-carboxylic acid (23.27 g) in tetrahydrofuran (230 ml) were added in turn 1-hydroxybenzotriazole hydrate (13.7 g), dimethylamine hydrochloride (8.27 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (18.5 ml) at 0° C. After 2 hours, the reaction mixture was poured into a mixture of ethyl acetate and water, the organic layer was separated, washed twice with saturated aqueous layer hydrogen carbonate and brine in turn. The solvent was dried over magnesium sulfate and removed in vacuo. The residue was chromatographed on silica gel (600 ml) eluting with a mixture of dichloromethane and acetone (6:1→4:1) to give (2S)-4-acetyl-1-allyloxycarbonyl-2-dimethylcarbamoylpyrrolidine (11 g).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[C:13]=1[C:14]#[N:15]>C(Cl)Cl.N1C=CC=CC=1>[Br:20][C:16]1[C:13]([C:14]#[N:15])=[C:12]([NH:11][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:19]=[CH:18][CH:17]=1
Reactant: N#Cc1c(N)cccc1Br
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1c(Br)cccc1NS(=O)(=O)c1ccccc1
Reaction time: 2 h
Yield: 28 %

Procedure:
Benzenesulfonyl chloride (0.53 g) was added to a solution of 2-amino-6-bromobenzonitrile (Intermediate 22, 0.5 g) in DCM (15 mL) and pyridine (1 mL). The mixture was stirred for 2 hours, then a further aliquot of benzenesulfonyl chloride (0.53 g) was added and the mixture was stirred overnight. The reaction mixture was diluted with DCM, washed with 1N hydrochloric acid, and the organic solution was dried with sodium sulfate and filtered. The filtrate was evaporated under vacuum and the residue was purified by flash chromatography on silica, eluting with a mixture of DCM and methanol. The fractions containing the desired product were combined and evaporated to give the title compound as a white powder (0.24 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]([CH2:17][C:18]1[N:28]=[CH:27][C:26]([I:29])=[CH:25][C:19]=1[C:20](OCC)=[O:21])S(C1C=CC(C)=CC=1)(=O)=O)[CH3:2].[O-]CC.[Na+].O.Cl>C(O)C>[OH:21][C:20]1[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:30])=[N:6][CH:17]=[C:18]2[C:19]=1[CH:25]=[C:26]([I:29])[CH:27]=[N:28]2
Reactant: CCOC(=O)CN(Cc1ncc(I)cc1C(=O)OCC)S(=O)(=O)c1ccc(C)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ncc2ncc(I)cc2c1O
Reaction time: 5 h

Procedure:
A mixture of ethyl 2-(((2-ethoxy-2-oxoethyl)((4-methylphenyl)sulfonyl)amino)methyl)-5-iodonicotinate (Preparation 11, 8.20 g) and sodium ethoxide (2.6 g) in anhydrous ethanol (60 mL) is stirred for 5 h. The mixture is then poured into water and neutralized with 3 N aqueous hydrochloric acid. The resulting precipitate is filtered and dried.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[H+].[B-](F)(F)(F)F.CCOCC.[Br:24]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([Br:24])[CH:6]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)c1ccc(O)c(Br)c1
Temperature: -15 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
This procedure is modified from the work of Oberhauser (J. Org. Chem, 1997, 62, 4504). To a solution of 4-hydroxybenzoic acid ethyl ester (57.8 g, 348 mmol) in 480 mL of dry acetonitrile was added HBF4 Et2O (54% in Et2O, 32.9 mL). The solution was cooled to −15° C. with an ice/methanol bath. N-bromosuccinimide (67.2 g, 378 mmol) was added portionwise at a rate where the temperature would not rise above −10° C. After addition was complete, the cooling bath was removed and the reaction mixture was allowed to stir overnight at room temperature. Worked up by pouring the reaction mixture into aqueous sodium bisulfite (38%, 200 mL) and extracting four times with ethyl acetate. The organic layers were combined, washed with water, saturated brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to give a white solid. Recrystallization from ethyl acetate/hexane gave 3-bromo-4-hydroxybenzoic acid ethyl ester (70.7 g, 83%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.39 (t, J=6.7 Hz, 3H, —CO2CH2CH3), 4.34 (t, J=6.7 Hz, 2H, —CO2CH2CH3), 7.02 (d, 1H, arom), 7.91 (dd, 1H, arom), 8.19 (d, 1H, arom).
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH:7][C@H:8]([C:10]1[C:11]([CH3:15])=[N:12][NH:13][CH:14]=1)[CH3:9])=[O:6])([CH3:4])[CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=N1>CN(C=O)C.CCOC(C)=O.CCOC(C)=O.CCCCCCC>[CH2:22]([N:13]1[CH:14]=[C:10]([C@@H:8]([NH:7][S@@:5]([C:2]([CH3:3])([CH3:4])[CH3:1])=[O:6])[CH3:9])[C:11]([CH3:15])=[N:12]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: Cc1n[nH]cc1[C@H](C)N[S@](=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cn[nH]c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1nn(Cc2ccccc2)cc1[C@H](C)N[S@](=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
(R)-2-methyl-N—((S)-1-(3-methyl-1H-pyrazol-4-yl)ethyl)propane-2-sulfinamide (290 mg, 1.26 mmol) was dissolved in DMF (5 ml) and added dropwise to a solution of Cs2CO3 (458 mg, 1.41 mmol) in DMF (4 ml). The resulting reaction mixture was stirred at room temperature for 15 min. benzylbromide (216 mg, 1.26 mmol) was added and the reaction was stirred at room temperature for 2 h. LCMS shows mostly product with some starting pyrazole. Added another 0.1 ml of BnBr and 135 mg of Cs2CO3. Stirred another 24H at 50° C. The reaction mixture was diluted with EtOAc (300 mL), washed with 4% aqueous NaCl (2×150, 2×50 mL). The combined aq. layers were back extracted with EtOAc (100 ml). The combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered and concentrated. Silica gel chromatography, EtOAc/heptane 20-80% to give title compound (mix of regioisomers, 150 mg, 0.470 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=3)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>[Pd].C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:35]=4)=[CH:23][CH:22]=3)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(C3CCCCC3)c(-c3ccc(I)cc3)cnc12
Reactant: COc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn2c(C3CCCCC3)c(-c3ccc(-c4cccc(OC)c4)cc3)cnc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 81.9 %

Procedure:
A mixture of 60 mg (0.126 mmol) of 7-cyclohexyl-6-(4-iodo-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, 29 mg (0.19 mmol, 1.5 equiv) of 3-methoxyphenylboronic acid, 5 mg (0.0063 mmol, 5 mol %) of Pd catalyst, and 80 mg (0.378 mmol, 3 equiv) of potassium phosphate was placed into a carousel tube. After a vacuum and argon cycle, 1,4-dioxane (3 mL) was added, and the resulting mixture was heated at 80° C. under argon for 14 h. Since analysis by LC-MS revealed unreacted starting material still present, 29 mg (0.19 mmol, 1.5 equiv) of 3-methoxyphenylboronic acid, 10 mg (0.012 mmol, 10 mol %) of Pd catalyst, and 80 mg (0.378 mmol, 3 equiv) of potassium phosphate was added and heating was continued for 24 h. The reaction mixture was then diluted with ethyl acetate, filtered through a small pad of Celite, dried over sodium sulfate and evaporated to give a brown residue (crude coupling product), which was chromatographed on silica gel (Biotage; gradient elution 2% to 5% ethyl acetate in dichloromethane) to afford 47 mg (82% yield) of desired 7-cyclohexyl-6-(3′-methoxy-biphenyl-4-yl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester as indicated by 1H NMR; LC-MS—calcd for C28H29N3O3 [M++H]+: 456.22, found: 456.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[N:15]=[C:14]([NH:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH3:18])[C:13]([F:26])=[CH:12][N:11]=1>>[F:26][C:13]1[C:14]([NH:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH3:18])=[N:15][C:10]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)=[N:11][CH:12]=1
Reactant: Nc1cccc(O)c1
Reactant: CC(Nc1nc(Cl)ncc1F)c1ccc(F)cc1
Product: CC(Nc1nc(Nc2cccc(O)c2)ncc1F)c1ccc(F)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine, 3-aminophenol and (±)-N-(2-chloro-5-fluoropyrimidinyl)-1-(4-fluorophenyl)ethylamine were reacted to produce the desired (±)-5-fluoro-N4-[1-(4-fluorophenyl)ethyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.79 (d, 1H, J=3.3 Hz), 7.38-7.34 (dd, 2H, J=5.2 and 8.5 Hz), 7.14 (t, 1H, J=4.5 Hz), 7.09 (d, 1H, J=8.5 Hz), 7.03 (d, 1H, J=8.5 Hz), 6.84 (br s, 1H), 6.84-6.78 (ddd, 1H, J=0.8, 2.0, and 8.2 Hz), 6.46-6.42 (ddd, 1H, J=0.8, 2.0 and 8.2 Hz), 5.26 (overlapped dq, 1H, J=7.1 and 7.9 Hz), 5.18 (d, 1H, J=7.1 Hz), 1.59 (d, 3H, J=7.1 Hz); LCMS: ret. time: 21.52 min.; purity: 92%; MS (m/e): 343 (MH+).
Reaction SMILES: [ClH:1].[F:2][C:3]([F:31])([F:30])[C:4]1([C:26]([F:29])([F:28])[F:27])[CH:8]([N:9]([CH3:18])[C:10](=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[NH:7][C:6]([C:19]2[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=2)=[N:5]1.[C:32](=O)([O-])[O-].[K+].[K+].[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.O>CS(C)=O>[ClH:1].[F:2][C:3]([F:30])([F:31])[C:4]1([C:26]([F:29])([F:28])[F:27])[CH:8]([N:9]([CH3:18])[C:10](=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:7]([CH3:32])[C:6]([C:19]2[CH:20]=[CH:21][C:22]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:23][CH:24]=2)=[N:5]1
Reactant: C1CCNCC1
Reactant: O=C([O-])[O-]
Reactant: CCCCCCC(=O)N(C)C1NC(c2ccc(F)cc2)=NC1(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCC(=O)N(C)C1N(C)C(c2ccc(N3CCCCC3)cc2)=NC1(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Yield: 22.4 %

Procedure:
To a solution of N-[4,4-bis(trifluoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-1H-imidazol-5-yl]-N-methylheptanamide hydrochloride (0.20 g, 0.4 mmole) in dimethyl sulfoxide (5 mL) was added potassium carbonate (0.29 g, 1.2 mmole) and piperidine (0.10 g, 1.2 mmole). The reaction mixture was heated at 145° overnight under nitrogen. The solution was cooled to room temperature, poured into water and extracted with ether. The ether layer was washed with 1N HCL to give unreacted starting material. The aqueous layer was made basic and it was extracted with ether. The organic layer was washed with water and saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under vacuum. The residue was treated with HCl in ether to give the title compound (50 mg, 22%) as a semi solid: MS m/e 521 (M+ +H); 1H NMR (CDCl3 /TMS) δ 0.90(m,3H,CH3), 1.30(m,8H,(CH2)4), 1.67(m,6H,(CH2)3), 2.40(t,2H,CH2), 2.90(s,3H,NCH3), 2.97(s,3H,NCH3), 3.30(m,4H,2CH2), 6.53(s,1H,CH), 6.90(d,2H,Harom), 7.53(d,2H,Harom).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:23]=[CH:22][C:14]([CH2:15][NH:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1>CCCCCC>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])=[CH:22][CH:23]=1
Reactant: O=C=Nc1ccccc1
Reactant: Clc1ccc(CNC2CCCC2)cc1
Solvent: CCCCCC
Product: O=C(Nc1ccccc1)N(Cc1ccc(Cl)cc1)C1CCCC1
Yield: 94.3 %

Procedure:
A solution of 12 grams (0.1 mole) of phenylisocyanate in 50 ml of hexane was added dropwise to 21 grams (0.1 mole) of N-4-chlorobenzyl-N-cyclopentylamine in 400 ml of hexane under cooling and stirring conditions. After the addition, the temperature of the reaction mixture was gradually raised, and the solution was then stirred at 50° C. for about 7 hours. The mixture was cooled and filtered. The residue was recrystallized from a mixed solvent of hexane-ethyl alcohol. 31 grams of N-4-chlorobenzyl-N-cyclopentyl-N'-phenylurea were obtained. Yield: 95%. Melting point: 129°-134° C.
Reaction SMILES: [O:1]=[C:2]([Cl:8])OC(Cl)(Cl)Cl.[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C>ClCCl>[N:9]1([C:2]([Cl:8])=[O:1])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: c1ccc2c(c1)CCN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cl)N1CCc2ccccc21
Temperature: 0 °C
Reaction time: 12 h

Procedure:
22.5 mmol of diphosgene dissolved in 90 ml of dichloromethane are cooled to 0° C.; there are then added 45 mmol of indoline, and then 67.5 mmol of triethylamine, while maintaining the temperature at 0° C. After 12 hours at ambient temperature, the mixture is filtered and the filtrate is concentrated under reduced pressure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:15]([CH2:18][C:19]([N:21]([CH:31]1[CH2:33][CH2:32]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[Cl:30])=[O:20])[CH2:16][OH:17])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[I-].[Na+].[CH3:45][O:46][CH2:47]Cl>COCCOC>[C:1]([O:5][C:6]([N:8]([C@@H:15]([CH2:18][C:19]([N:21]([CH:31]1[CH2:32][CH2:33]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[Cl:30])=[O:20])[CH2:16][O:17][CH2:45][O:46][CH3:47])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCN(C(=O)OC(C)(C)C)[C@H](CO)CC(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Reactant: COCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: COCOC[C@H](CC(=O)N(Cc1cccc(Cl)c1Cl)C1CC1)N(CCC(=O)OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 53.1 %

Procedure:
Into a 250 mL round bottom flask was added 4D (12.42 g, 24.7 mmol) and DME (137 mL). Di-isopropylethylamine (DIEA) or Hunig's base (23.6 mL, 135.7 mmol, 5.5 eq) and sodium iodide (14.79 g, 98.7 mmol, 4.0 eq) was added to the solution and cooled with an ice bath. Methoxymethyl chloride (MOMCl) (10.7 mL, 127.1 mmol, 5.15 eq) was added slowly at 0° C. The reaction was allowed to warm to room temperature overnight. Solvent was removed under vacuum and the residue was portioned between water (150 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layers were combined and washed once with brine (100 mL). The organic phase was dried over sodium sulfate and filtered. Solvent was removed under vacuum and the residue was purified by column chromatography (30% ethyl acetate/hexanes) to give 4E (7.18 g, 53%) as a viscous oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.87 (m, 4H) 1.46 (br. s., 9H) 2.63 (br. s., 4H) 3.36 (s, 3H) 3.66 (s, 8H) 4.06-4.30 (m, 1H) 4.62 (m, 3H) 4.79 (m, 1H) 6.94 (d, J=7.83 Hz, 1H) 7.11-7.17 (m, 1H) 7.36 (dd, J=8.08, 1.26 Hz, 1H). ESI-MS:m/z 547.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:33])[CH:10]([C:31]#[N:32])[C:11]([C:13]2[C:14]3[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:15]=3[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].N1C=CC=CC=1>CN(C)C=O>[C:34]([NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:33])[CH:10]([C:31]#[N:32])[C:11]([C:13]2[C:14]3[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:15]=3[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1)(=[O:36])[CH3:35]
Reactant: N#CC(C(=O)Nc1cccc(N)c1)C(=O)c1nn(-c2ccccc2)c2c1Cc1ccccc1-2
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(NC(=O)C(C#N)C(=O)c2nn(-c3ccccc3)c3c2Cc2ccccc2-3)c1
Temperature: 0 °C

Procedure:
N-(3-Amino-phenyl)-2-cyano-3-(1,4-dihydro-1-phenyl-indeno [1,2-c]pyrazol-3-yl)-3-oxo-propanamide (1.8 g) dissolved in dimethylformamide (30 ml) is reacted with acetic anhydride (5 ml) in the presence of pyridine (5 ml) at 40° C. for 8 hours. The reaction mixture is diluted with ice water and the precipitate is filtered and washed with water crystallization from dimethylformamide gives 1.2 g of N-(3-acetylamino-phenyl) -2-cyano-3-(1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-3-yl)-3-oxo-propanamide.
Reaction SMILES: [I:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@H:4]1[OH:17].[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:17][C@H:4]1[C@@H:3]([CH2:2][I:1])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5]1)(=[O:20])[CH3:19]
Reactant: Cc1cn([C@H]2C[C@@H](O)[C@@H](CI)O2)c(=O)[nH]c1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CI
Temperature: 25 °C
Reaction time: 17 h
Yield: 77 %

Procedure:
To a stirred solution of 1-(2,5-dideoxy-5-iodo-β-D-threo-pentofuranosyl)thymine (for preparation see ref. J. Org. Chem. 1964, 29, 2076) (5.1 g, 14.5 mmol) in anhydrous pyridine (50 mL) at 0° C. under argon was added acetic anhydride (7.0 ml, 75.4 mmol). The reaction mixture was stirred at room temperature for 17 h. The reaction mixture was cooled with ice bath and quenched by slow addition of water (15 mL). The reaction mixture was stirred for 30 min and concentrated to dryness, and co-evaporated with anhydrous toluene three times. The residue was re-dissolved in dichloromethane and chromatographed on silica gel with 1-3% methanol in ethyl acetate gave 4.4 g of 1-(3-O-acetyl-2,5-dideoxy-5-iodo-β-D-threo-pentofuranosyl)thymine (49).
Reaction SMILES: [NH2:1][CH2:2][C:3]1(N(C)C)[CH2:8][CH2:7][C:6](F)(F)[CH2:5][CH2:4]1.C([O:21]C1(OC)C=CC(C(O)=O)=CC1OC)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:2]([NH2:1])(=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC1C=C(C(=O)O)C=CC1(OC)OCc1ccccc1
Reactant: CN(C)C1(CN)CCC(F)(F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
1-(aminomethyl)-4,4-difluoro-N,N-dimethylcyclohexanamine represented by Formula 105 (190 mg, 0.99 mmol) was slowly added to a solution of 4-benzyloxy-3,4-dimethoxybenzoic acid represented by Formula 89 (327.66 mg, 1.14 mmol) and diisopropylethylamine (0.70 mL, 3.95 mmol) in DMF (7 mL) at room temperature. The reaction mixture was cooled to 0° C. and, after adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU, 375.75 mg, 0.99 mmol) thereto, agitated at room temperature for 24 hours. The reaction solvent was removed under reduced pressure and chloroform (20 mL) was added to the remaining concentrate to prepare a solution. The solution was washed with a potassium carbonate solution, followed by separation to form an organic layer. After drying the organic layer with sodium sulfate (Na2SO4), the solvent was removed again under reduced pressure. The obtained vacuum-concentrated mixture was subjected to separation and purification through column chromatography (ethyl acetate/hexane/triethylamine, 2:1:0.1, v/v/v) using silica gel (SiO2), resulting in an alkalinized benzamide compound represented by Formula 11. HCl in MeOH (1.25 M, 0.75 mL, 0.93 mmol) was added to the alkalinized benzamide compound (360 mg, 0.78 mmol) in MeOH (5 mL) at room temperature. The reaction mixture was agitated at room temperature for 3 hours, the reaction solvent was removed under reduced pressure, and the remaining solids were filtered and washed with hexane to produce a benzamide salt compound represented by Formula 15 as a desired product (VVZ-016; 370 mg, 75% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][NH:15][N:14]=1)=O>C(O)(=O)C>[CH3:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]2[NH:1][C:11]([C:13]3[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][NH:15][N:14]=3)=[N:10][C:3]=2[CH:4]=1
Reactant: Cc1cc(N)c(NC(=O)c2n[nH]cc2[N+](=O)[O-])cc1C
Solvent: CC(=O)O
Product: Cc1cc2nc(-c3n[nH]cc3[N+](=O)[O-])[nH]c2cc1C
Temperature: 25 °C
Yield: 107 %

Procedure:
A stirred solution of 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4,5-dimethylphenyl)amide [5.7 g, Reference Example 36(a)] in acetic acid (100 mL) was heated at 120° C. for 1 hour, then cooled to ambient temperature and then evaporated. The oily residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and then evaporated to give 5,6-dimethyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole (5.70 g) as an orange solid. LC-MS (METHOD B): RT=2.30 minutes, 258.11 (M+H)+. (b) 5-Ethyl-6-methyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[C:20]2[Cl:23])=[N:15]1)[CH2:11][C:12]#[CH:13]>>[Cl:23][C:20]1[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=1)=[N:15][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1)[CH:22]=2
Reactant: C#CCCn1cc2c(Cl)cccc2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCn2cc3c(Cl)cccc3n2)n1
Yield: 70.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (51 mg, 0.27 mmol) and 2-but-3-ynyl-4-chloro-2H-indazole (50 mg, 0.24 mmol, Example 150(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 54 mg (0.17 mmol, 70%) of 4-chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown solid.