Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[CH:5][N:4]=1)[NH2:2].[CH3:14][C:15](OC(C)=O)=[O:16]>O1CCOCC1>[CH3:10][O:9][C:8]1[C:3]([NH:1][NH:2][C:15](=[O:16])[CH3:14])=[N:4][CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc([N+](=O)[O-])cnc1NN
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])cnc1NNC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a suspension of 2-hydrazinyl-3-methoxy-5-nitropyridine (Step 84.1) (20 g, 106 mmol) in dioxane (170 mL) was added at RT Ac2O (13.1 mL, 138 mmol) and the reaction mixture was stirred for 1 hr at RT. The reaction mixture was poured onto ice-water (700 mL) and stirred for 1 hr at 0° C. The precipitate was collected by filtration, washed with H2O and Et2O, and dried under reduced pressure at 50° C. to afford the title product (23.3 g, 101 mmol, 95% yield) as a yellow solid. tR: 0.45 min (LC-MS 2); ESI-MS: 227 [M+H]+ (LC-MS 2); ESI-MS: 225 [M−H]− (LC-MS 2).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:9]=1[NH2:10].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O>[F:7][C:8]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:9]=1[NH:10][S:19]([CH3:18])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 72.8 %

Procedure:
To 334 ml of a pyridine solution containing 52.1 g of 2-fluoro-5-nitroaniline was added 42.1 g of methanesulfonyl chloride under ice cooling, followed by stirring at room temperature for 7 hours. Water was added to the reaction solution, the precipitate was collected by filtration, and the crude crystals were recrystallized from ethanol to give 56.9 g of N-(2-fluoro-5-nitrophenyl)methanesulfonamide as pale yellow needles.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]2([CH3:16])[CH3:15])#[CH:2].[CH2:17]([O:19][C:20](=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][C:23]=1[F:29])[CH3:18].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:17]([O:19][C:20](=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[O:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]3([CH3:16])[CH3:15])=[CH:24][C:23]=1[F:29])[CH3:18]
Reactant: CCOC(=O)Cc1ccc(I)cc1F
Reactant: C#Cc1ccc2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)O3)cc1F

Procedure:
Following general procedure F and using 6-ethynyl-2,2,4,4-tetramethylchroman (0.204 g, 0.95 mmol), ethyl-2-fluoro-4-iodo phenyl acetate (Reagent C, 0.263 g, 0.86 mmol), triethyl amine, tetrahydrofiran, copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent, the title compound was obtained (0.21 g, 62%).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Si]([N:14]=[N+:15]=[N-:16])(C)(C)C>CCOCC>[CH2:7]([C:8]1[N:14]=[N:15][NH:16][CH:9]=1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C#CCCCCCCC
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CCOCC
Product: CCCCCCCc1c[nH]nn1
Temperature: 150 °C

Procedure:
##STR8## 1-Nonyne (5.0 g) and Me3SiN3 (6.2 g) were sealed into a heavy-walled glass reactor at -70° C. and 0.6 mm Hg. The mixture was heated at 150° C. for 34 hours, cooled and dissolved in Et2O. The Et2O solution was washed successively with 5 percent aq. HCl, 7 percent aq. NaHCO3, saturated aq. NaCl, dried over MgSO4, filtered and distilled to give 3.89 g (58%) pale yellow oil, bp 110-130/0.05 mm whose NMR spectrum and elemental analysis confirm its structure.
Reaction SMILES: CC1(C)[O:19][CH:5]2[CH:6]3[CH2:11][O:10][C:9](=[O:12])[CH:8]=[C:7]3[CH2:13][CH:14]([O:15]COC)[CH:4]2[O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CO.O>[OH:15][CH:14]1[CH2:13][C:7]2=[CH:8][C:9](=[O:12])[O:10][CH2:11][CH:6]2[CH:5]([OH:19])[CH:4]1[OH:3]
Reactant: COCOC1CC2=CC(=O)OCC2C2OC(C)(C)OC12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1C=C2CC(O)C(O)C(O)C2CO1
Yield: 57 %

Procedure:
1,5,6,7,8,8a-Hexahydro-7,8-(dimethylmethylenedioxy)-6-methoxymethoxy-3H-2-benzopyran-3-one (284 mg) was dissolved in 50 ml of methanol and 5 ml of water, and a catalytic amount of p-toluenesulfonic acid was added. The mixture was refluxed for 1 hour. After cooling, the reaction mixture was poured into a sodium hydrogen carbonate aqueous solution and extracted with diethyl ether. The extract was washed with a sodium chloride aqueous solution, dried, and concentrated under reduced pressure. The product was purified by silica gel column chromatography to obtain 114 mg of 1,5,6,7,8,8a-hexahydro-6,7,8-trihydroxy-3H-2-benzopyran-3-one having the following property (yield 57%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[CH:7][N:8]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([C:21]3[N:22]=[N:23][N:24]([CH3:26])[N:25]=3)=[CH:16][C:15]=2[CH3:27])[N:9]=1)(OC)=[O:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].C(OCC)(=O)C>C1COCC1>[OH:2][CH2:1][C:5]1[N:6]=[CH:7][N:8]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([CH3:27])=[CH:16][C:17]([C:21]3[N:22]=[N:23][N:24]([CH3:26])[N:25]=3)=[CH:18][C:19]=2[CH3:20])[N:9]=1
Reactant: COC(=O)c1ncn(CCCOc2c(C)cc(-c3nnn(C)n3)cc2C)n1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCn1cnc(CO)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
To a solution of 5-carbomethoxy-2-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propyl]-1,2,4-triazole (37.1 mg, 0.1 mmol) in 1 ml of THF was added at 0° C. a solution of 1M LAH in THF (65 μl, 1M in THF, 0.065 mmol). The mixture was stirred for 10 min at 0° C. and then stirred at 20° C. for 24 h. Rochelle salt solution was added to the mixture and the solution was stirred at 20° C. for 10 min. Ethyl acetate was added to the above mixture, the aqueous layer was extracted with methylene chloride (3×), and the combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (10 cm column, ethyl acetate/hexane, 1/1 - 1/0; methylene chloride/acetone, 2/1 - 1/2) to afford 27 mg (79%) of 5-hydroxymethyl-2-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propyl]-1,2,4-triazole, as a white solid.
Reaction SMILES: [CH3:1][O-].[Na+].[C:4]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][O:19]S(C)(=O)=O)[CH2:14][CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CO.C1COCC1>[C:4]([O:8][C:9](=[O:10])[NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][O:19][CH3:1])[CH2:14][CH2:13]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
A solution of sodium methoxide in methanol (6.0 mL of a 25% solution, ˜27.0 mmol) was added to a solution of trans methanesulfonic acid 4-tert-butoxycarbonylamino-cyclohexylmethyl ester (1.50 g, 4.88 mmol) in THF (15 mL) and methanol (15 mL). The mixture was heated at reflux for 6.75 hours. The cold mixture was concentrated under vacuum to remove most of the solvent then diluted with water (10 mL). The mixture was then cautiously neutralised with 1M hydrochloric acid then extracted with DCM (3×20 mL). The combined organic phase was dried over magnesium sulphate and concentrated under vacuum. The residue was purified by chromatography on silica gel (eluting with 9:1 cyclohexane:ethyl acetate) to afford 1.07 g (90%) of trans (4-methoxymethyl-cyclohexyl)-carbamic acid tert-butyl ester as a white solid. 1H NMR (400 MHz, CDCl3): δ 4.36 (br s, 1H), 3.37 (br s, 1H), 3.32 (s, 3H), 3.18 (d, 2H), 2.07-1.97 (m, 2H), 1.84-1.75 (m, 2H), 1.56-1.45 (m, 1H), 1.44 (s, 9H), 1.16-0.96 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:10](Br)[NH:11]2)=[CH:7][CH:6]=1)=[O:4].N1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30](OC)=[O:31])[CH:28]=2)C=C1.OCC1C=CC=CC=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH:15]1([C:9]2[C:8]3[C:12](=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[NH:11][C:10]=2[C:26]2[CH:25]=[CH:24][CH:29]=[CH:28][C:27]=2[CH2:30][OH:31])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: OCc1ccccc1B(O)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO)[nH]c2c1
Temperature: 110 °C
Yield: 95 %

Procedure:
2-bromo-3-cyclohexyl indole-6-carboxylic acid methyl ester (1 eq., prepared as described in WO2004/087714 from commercially available methyl indole-6-carboxylate) was mixed with [2-(hydroxymethyl)phenyl]boronic acid (1.5 eq.) and bis(triphenylphosphine)palladium dichloride (0.2 eq.) was added. The mixture was degassed and dioxane and 2M aq. Na2CO3 solution (2 eq.) were added. The mixture was heated under N2-atmosphere to 110° C. for 1 h then diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The residual material was subjected to flash chromatography (PE:EtOAc, 4:1). After evaporation of the solvents the product was obtained as orange solid (95%). MS (ES+): 364.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.CCO.[OH-].[Na+]>COC(C)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH:9]=[CH:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=2)[CH:7]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: COC(C)(C)C
Product: O=C(C=Cc1cccc(Cl)c1)c1cc(Br)ccc1O
Reaction time: 0.5 h
Yield: 347.6 %

Procedure:
In a bottle 1-(5-bromo-2-hydroxyphenyl)ethanone (25 g, 0.02 mol), 3-chlorobenzaldehyde (16.35 g, 0.12 mol), EtOH (96%, 144 mL), and NaOH (42.1 g, 1.06 mol) were combined. The mixture was stirred vigorously for 0.5 h. 2-Methoxy-2-methylpropane was added and the mixture was filtered. The filtrate was poured into HCl (1 N, 800 mL) and filtered. The combined solid was dried to give 1-(5-bromo-2-hydroxyphenyl)-3-(3-chlorophenyl)prop-2-en-1-one (23.47 g, 60%). 1H-NMR (CDCl3): 6.88 (d, 1H), 4.35 (m, 2H), 7.49 (m, 3H), 7.61 (s, 1H), 7.80 (m, 1H), 7.93 (m, 1H), 12.56 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1.I[CH3:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([N:22]([CH3:35])[CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4cccc5ccccc45)cc3)c2)o1
Reactant: CI
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)Cc4cccc5ccccc45)cc3)c2)o1

Procedure:
2′-Methyl-N-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(naphth-1-ylmethyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(naphth-1-ylmethyl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 8.17,(1H, d), 7.99-7.40,(13H, m), 5.19-5.05,(2H, m), 3.03,(1H, s), 2.85,(2H, s), 2.55,(3H, s), 2.32-2.23,(3H, m). LCMS; retention time 3.66 min, MH+ 448.
Reaction SMILES: [H-].[Na+].[C:3]([O:9]C)(=O)[C:4]([CH3:7])([CH3:6])[CH3:5].[C:11](#[N:13])[CH3:12]>O1CCCC1>[C:3]([CH2:12][C:11]#[N:13])(=[O:9])[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)C
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CC#N

Procedure:
In a 1 l. flask under an atmosphere of dry nitrogen there was placed 26.4 g. of a 50% oil dispersion of sodium hydride together with 240 ml. of dry tetrahydrofuran. While this mixture was refluxed there was added thereto dropwise over a period of about 1 hour a mixture of 40.6 g. of methyl pivalate and 22.6 g. of acetonitrile in 40 ml. of dry tetrahydrofuran. When addition was complete, the mixture was refluxed overnight. The reaction mixture was worked up by evaporating part of the tetrahydrofuran in vacuo and dissolving the remaining solution in about 300 ml. of water. This aqueous mixture was acidified to about pH 4 using concentrated aqueous hydrochloric acid. The remainder of the tetrahydrofuran was then removed using a rotovapor. The solid which was formed was filtered and slurried with 150 ml. of hexane to remove mineral oil. The crystals were filtered and dried. The crystals had a melting point of about 57°-59° C. and were identified as pivalyl acetonitrile. Yield: 36.3 g. (83%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[CH2:7][CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[CH2:7][CH2:8][N+:9]([O-:29])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: O=C1CCN=C(c2ccccc2F)c2cc(Cl)ccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1CC[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6.4 g (22 mmol) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one and 6.4 g (34 mmole) of m-chloroperbenzoic acid in 350 ml of methylene chloride was stirred at room temperature for 2 hr. The methylene chloride solution was washed with saturated aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow oil. The oil was crystallized from a mixture of ether and petroleum ether to give off-white prisms, mp 166°-168° C. Recrystallization from a mixture of ether and methylene chloride gave colorless prisms, mp 168°-170° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[CH2:5][CH:6]=[CH2:7])C=C>ClC1C=CC=CC=1>[N:4]1([CH2:8][P:9](=[O:16])([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])[CH:1]=[CH:7][CH:6]=[CH:5]1
Reactant: C=CCN(CC=C)CP(=O)(OCC)OCC
Solvent: Clc1ccccc1
Product: CCOP(=O)(Cn1cccc1)OCC
Temperature: 60 °C
Reaction time: 16 h
Yield: 43.9 %

Procedure:
0.1 g (0.41 mmole) of the diethyl diallylaminomethylphosphonate prepared in example 25 was dissolved in 2 ml chlorobenzene, then 0.014 g (0.02 mmole) of the bimetallic ruthenium complex 3.e prepared in example 24 was added and the mixture was stirred for 16 hours at 60° C. The catalyst was removed after evaporation of the chlorobenzene by column chromatography, yielding 0.04 g (0.18 mmole, yield 45%) diethyl 1H-pyrrole-1-ylmethylphosphonate. This product was further characterised by the following spectra:
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH2:12]([O:19][C:20]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:21]=1[C:22]([OH:24])=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:35][C:36]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:37]=1[C:38]#[N:39]>C(Cl)Cl.N1C=CC=CC=1>[CH2:12]([O:19][C:20]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:21]=1[C:22]([NH:35][C:36]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:37]=1[C:38]#[N:39])=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Reactant: N#Cc1ccc(Cl)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N#Cc1ccc(Cl)cc1NC(=O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N,N-Dimethylformamide (0.010 mL) and oxalyl chloride (0.21 mL) were sequentially added to a methylene chloride (3.0 mL) suspension of 2-(benzyloxy)-5-(piperidin-1-yl)benzoic acid (0.56 g), followed by stirring at room temperature for 1 hour and 20 minutes. Under ice-cooling, the reaction mixture was added to a solution mixture of 2-amino-4-chlorobenzonitrile (0.23 g) in methylene chloride (3.0 mL) and pyridine (0.30 mL), followed by stirring at room temperature for 2 hours and 30 minutes. The solvent was evaporated under reduced pressure, and a 10% aqueous solution of citric acid and chloroform were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-85% hexane/ethyl acetate] to obtain 2-(benzyloxy)-N-(5-chloro-2-cyanophenyl)-5-(piperidin-1-yl)benzamide as a yellow solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([OH:15])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=1>>[S:1]1[C:5]2[CH:6]=[C:7]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:29])[CH3:30])=[CH:24][CH:23]=3)=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(O)c1ccc(CN)cc1
Reactant: O=C(O)c1cccnc1Oc1ccc2ncsc2c1
Product: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2ccc3ncsc3c2)cc1

Procedure:
Prepared from 2-(Benzothiazol-6-yloxy)-nicotinic acid and 2-(4-aminomethyl-phenyl)-propan-2-ol. mp195-7° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].[H-].[Na+].[CH2:31](Br)[CH2:32][CH:33]([CH3:35])[CH3:34].[Cl-].[NH4+]>CN(C)C=O>[F:28][C:3]1[CH:4]=[C:5]([F:27])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:2]=1[NH:1][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)CCBr
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)CCNc1c(F)cc(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
510 mg (1.32 mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one obtained in Example 66 was dissolved in 15 ml of dimethylformamide under argon atmosphere, 160 mg of sodium hydride (60% oil dispersion) and 0.35 ml of isoamyl bromide were added under ice-cooling and the mixture was stirred at room temperature for 1.5 hours. 0.16 ml of isoamyl bromide was added and the mixture was stirred for additional 1 hour. An aqueous saturated solution of ammonium chloride was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to give 310 mg (51%) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-isopentylamino-4H-1-benzopyran-4-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]([O:27][C:28]([N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[C:38]([CH2:39]Br)[C:33]=2[N:32]=[CH:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>CC#N>[C:23]([O:27][C:28]([N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[C:38]([CH2:39][N:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[CH2:15][C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[C:33]=2[N:32]=[CH:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Reactant: Cc1cccnc1CNC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccnc1CN(Cc1cccc2c1ncn2C(=O)OC(C)(C)C)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure A: Reaction of 4-[(3-Methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester in dry CH3CN with 4-Bromomethyl-benzoimidazole-1-carboxylic acid tert-butyl ester, DIPEA and KI gave 4-{[(1-tert-Butoxycarbonyl-piperidin-4-yl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester as a white foam. Deprotection with TFA using General Procedure F gave (1H-Benzoimidazol-4-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([OH:17])([CH3:16])[CH3:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][OH:29])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([OH:17])([CH3:16])[CH3:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:24]4[CH:31]=[CH:30][C:27]([CH2:28][OH:29])=[CH:26][CH:25]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(C)(C)O)cc(-c3ccc(Cl)cc3)nc12
Product: CC(C)(O)c1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3ccc(CO)cc3)cnn12

Procedure:
The title compound was prepared from 2-[5-(4-chloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidin-7-yl]-propan-2-ol (example C.13) (78 mg, 0.25 mmol) and 4-bromobenzyl alcohol (47 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (16 mg, 15%). MS (ISP) 418.1 [(M+H)+].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([SH:15])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][CH2:22][CH:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])(=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:28]([CH:23]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22][O:21][C:17](=[O:20])[CH2:18][CH2:19][S:15][C:7]1[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]=1[OH:16])[CH3:29]
Reactant: CC(C)(C)c1cc(S)c(O)c(C(C)(C)C)c1
Reactant: C=CC(=O)OCC(CC)CCCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCC(CC)COC(=O)CCSc1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Yield: 35 %

Procedure:
The procedure of Example 1 was repeated using 20.0 grams of 2,4-di-tert-butyl-6-mercaptophenol, 15.5 grams of 2-ethylhexyl acrylate, 0.25 ml of triethylamine and 150 mls of toluene. The residue was purified by chromatography on silica gel using toluene/heptane eluent to give 12.4 g (35% yield) of a colorless oil.