Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14]C=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[Cl:17]N1C(=O)CCC1=O.[C:25]([Cl:29])(Cl)(Cl)Cl>>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:15]([Cl:17])=[CH:14][C:25]([Cl:29])=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C1CCC(=O)N1Cl
Product: CCOC(=O)c1oc2c(Cl)cc(Cl)c(O)c2c1C
Temperature: -10 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (0.5 g, 2.27 mmol) was added 5 mL of carbon tetrachloride, carbon tetrachloride, and the mixture was cooled with an ethanol/ice bath while 1 equivalent of N-chlorosuccinimide was added in small portions. After stirring at −10° C. for 3 h, the reaction mixture was filtered and the filtrate was loaded onto a silica gel column. Chromatography gave 190 mg (30% yield) of 5,7-dichloro-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as an off-white solid.
Reaction SMILES: [Br-].[CH2:2]([Zn+])[CH:3]([CH3:5])[CH3:4].Br[C:8]1[CH:9]=[C:10]([C@:15]([C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([F:34])[CH:25]=2)([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:12][C:13]=1[F:14]>CN1C(=O)CCC1.C1COCC1.CCOC(C)=O.C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[F:14][C:13]1[CH:12]=[CH:11][C:10]([C@:15]([C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([F:34])[CH:25]=2)([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:9][C:8]=1[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)c(Br)c1
Reactant: CC(C)C[Zn+]
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Cc1cc([C@](N)(Cc2ccccc2)c2cc(F)cc(C(F)(F)F)c2)ccc1F
Temperature: 75 °C
Yield: 18 %

Procedure:
To a solution of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride (8 mg, 0.01 mmol) in NMP (0.5 mL) was added isobutylzinc(II) bromide in THF (0.5 M, 0.7 mL, 0.35 mmol) followed by (S)-1-(3-bromo-4-fluorophenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine, prepared as described Procedure 62, 5 and 6, (50 mg, 0.11 mmol) in anhydrous THF. The reaction mixture was heated at 75° C. overnight. The reaction mixture was diluted with EtOAc and the organic layer was washed with sat. NH4Cl, dried over Na2SO4 and concentrated to yield (R)-1-(4-fluoro-3-isobutylphenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine. LCMS: RT=3.62 min [M−NH2] 417 (Waters Sunfire-S5-C18 4.6×50 mm, eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH2:17][NH:18][CH:19]3[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]3)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[Cl:34][C:35]1[C:36]2[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40](Cl)=[O:41]>>[Cl:34][C:35]1[C:36]2[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40]([N:18]([CH2:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[CH:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH2:20]1)=[O:41]
Reactant: COc1ccc(-c2ccc(C#N)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2cccc(F)c2c1Cl
Product: COc1ccc(-c2ccc(C#N)cc2)cc1CN(C(=O)c1sc2cccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 13 (87 mg, 0.19 mmol) is treated with acid chloride 6 (58 mg, 0.23 mmol) using Method D to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].[H-].[Na+].[NH2:13][C:14]1[CH:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1.C(OCC)C>CS(C)=O>[NH2:13][C:14]1[CH:19]=[C:18]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([O:9][CH3:10])[CH:4]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: COc1cc(O)ccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: COc1cc(Oc2ccnc(N)c2)ccc1N
Temperature: 25 °C
Yield: 31.5 %

Procedure:
4-Amino-3-methoxyphenol (5.88 g) was dissolved in dimethyl sulfoxide (80 ml) while stirring, and then 60% sodium hydride (1.6 g) was added thereto gradually under a nitrogen stream, followed by stirring for 20 min. 2-amino-4-chloropyridine (2.75 g) was then added thereto, followed by stirring at 160° C. for 8 hrs. The reaction mixture was cooled down to room temperature, and partitioned between ethyl acetate and water. The organic layer was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; ethyl acetate, then ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether was then added to precipitate crystals. The crystals were filtered and dried under aeration to provide the titled compound (1.56 g, 34%) as pale brown crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.Br[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1COCC1.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>[Cl:30][C:24]1[CH:23]=[C:22]([C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=[CH:9][CH:10]=2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: N#Cc1ccc(Br)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2ccnn2C2CCCCO2)cc1Cl
Temperature: 35 °C
Reaction time: 2.5 h
Yield: 69.6 %

Procedure:
1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.5 g; 23.28 mmol) and 4-bromo-2-chlorobenzonitrile (4 g; 18.48 mmol) were dissolved in THF (65 ml). To this mixture bis(triphenylphosphine)-palladium(II) chloride (0.65 g; 0.92 mmol), sodium carbonate (4.7 g; 44.3 mmol) and 18 ml of water were added and the reaction mixture was stirred at 35° C. for 2.5 h. The solvents were distilled to almost dryness and water (48 ml) was added. After 30 min of stirring the precipitated product was filtered and 32 ml of ethanol was added to the precipitation. The suspension was stirred for 15 min at RT and 30 min at −10° C. before filtering to give 3.7 g of the product. 1H-NMR (400 MHz; d6-DMSO): δ 1.63-1.54 (m, 3H), 1.84-1.80 (m, 1H), 1.97-1.94 (m, 1H), 2.39-2.35 (m, 1H), 3.63-3.57 (m, 1H), 3.99 (m, 1H), 5.32-5.27 (m, 1H), 6.72 (d, 1H), 7.65 (d, 1H), 7.72 (m, 1H), 7.92 (d, 1H), 8.14 (d, 1H).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][C:18](=[O:22])[CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:23])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[BH4-].[Na+].[Cl-].[Na+].CCOCC>CO>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH:18]([OH:22])[CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:23])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)(C)c1ccc(C2=CCCC(=O)C2)c(O)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1ccc(C2=CCCC(O)C2)c(O)c1
Reaction time: 0.5 h

Procedure:
To a -18° C. solution of 17.5 g (50 mmol) of 3-[4-(1,1-dimethylheptyl)-2hydroxyphenyl]-cyclohex-3-enone in 50 ml of methanol is added 1.9 g (50 mmol) of sodium borohydride. The reaction mixture is stirred for 30 minutes and then added to 250 ml of saturated sodium chloride-250 ml of ether. The ether extract is washed once with 250 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue is purified via column chromatography on 400 g of silica gel eluted with 50% ether-pentane to yield the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C.Cl>O1CCCC1.C(OCC)(=O)C>[CH3:1][S:2]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCO)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccc(OCCOS(C)(=O)=O)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.13 mL) was added to an ice-cooled mixture of ethyl 4′-(2-hydroxyethoxy)biphenyl-4-carboxylate (0.41 g) and triethylamine (0.30 mL) in tetra hydrofuran (8 mL) with stirring. The mixture was stirred at that temperature for 30 min, at room temperature for 45 min, and at 45° C. for 1 hr. Methanesulfonyl chloride (0.13 mL) and triethylamine (0.30 mL) were added every an hour to the reaction mixture for 3 times at 45° C., and the mixture was stirred at 70° C. for 3 hrs. 1 mol/L hydrochloric acid and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over an hydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford ethyl 4′-(2-methanesulfonyloxyethoxy)biphenyl-4-carboxylate (0.32 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:22]([NH:25][C:26]1[CH:34]=[C:33]2[C:29]([CH2:30][C:31](=[O:35])[NH:32]2)=[CH:28][CH:27]=1)(=[O:24])[CH3:23].N1CCCCC1.C(OCC)(=O)C>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[CH:8]=[C:30]1[C:29]2[C:33](=[CH:34][C:26]([NH:25][C:22](=[O:24])[CH3:23])=[CH:27][CH:28]=2)[NH:32][C:31]1=[O:35])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)ccc1OCCN1CCOCC1
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)Nc1ccc2c(c1)NC(=O)C2=Cc1ccc(OCCN2CCOCC2)c(C(C)(C)C)c1
Reaction time: 12 h
Yield: 25.6 %

Procedure:
A mixture of 3-tert-butyl-4-(2-morpholin-4-ylethoxy)-benzaldehyde (0.25 g), 6-acetamido-2-oxindole (0.16 g) and piperidine (0.43 ml) in ethanol (3 ml) was held in a sealed tube at 100° C. for 12 hours. The reaction was cooled, added to ethyl acetate (250 ml), washed with 1N hydrochloric acid (100 ml) and brine (100 ml), dried with magnesium sulfate and concentrated. Some product went into the acid wash, so this was basified with solid sodium bicarbonate to pH 9 and extracted with ethyl acetate (2×150 ml). The organic layers were dried over magnesium sulfate, combined with the oil from the first crop of product and concentrated. Chromatography (silica, 40% ethyl acetate followed by 5-10% methanol/methylene chloride) afforded 100 mg (27%) of N-{3-[3-tert-butyl-4-(2-morpholin-4-ylethoxy) benzylidene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-acetamide as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[CH:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([CH3:17])[CH3:16]>>[ClH:1].[ClH:1].[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:21]3[CH2:22][CH2:23][N:18]([CH:15]([CH3:17])[CH3:16])[CH2:19][CH2:20]3)=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: CC(C)N1CCNCC1
Reactant: Fc1ccc(-c2ccc(Cl)nc2)cc1
Product: CC(C)N1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 2-chloro-5-(4-fluorophenyl)pyridine and 1-isopropylpiperazine.
Reaction SMILES: [NH3:1].O=O.[CH3:4][CH2:5][CH3:6].[CH3:7][CH:8]([CH3:10])[CH3:9]>>[C:4](#[N:1])[CH:5]=[CH2:6].[C:7](#[N:1])[C:8]([CH3:10])=[CH2:9]
Reactant: CC(C)C
Reactant: CCC
Reactant: N
Agent: O=O
Product: C=C(C)C#N
Product: C=CC#N

Procedure:
It is the primary object of the present invention to provide the process for the recovery or regeneration of ammonia contained in the effluent from a reactor zone where an ammonia, oxygen and propane/isobutane are reacted to produce acrylonitrile/methacrylonitrile.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1.C([Li])CCC.[CH3:25][O:26][C:27](=[O:38])[C:28]1[CH:37]=[CH:36][CH:35]=[C:30]([C:31](OC)=[O:32])[CH:29]=1>O1CCCC1>[CH3:25][O:26][C:27]([C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=1)[C:31]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1)=[O:32])=[O:38]
Reactant: CCCCCCCCC(O)/C=C/c1cccc(Br)n1
Reactant: COC(=O)c1cccc(C(=O)OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC(O)/C=C/c1cccc(C(=O)c2cccc(C(=O)OC)c2)n1
Yield: 15.9 %

Procedure:
Under the conditions of example 1B, 652 mg of 2-bromo-6-[(1E)-(3RS)-3-hydroxy-1-undecenyl]-pyridine in 3 ml of tetrahydrofuran is mixed with 2.75 ml of n-butyllithium (1.6 molar in hexane) and 427 mg of isophthalic acid dimethyl ester in 3 ml of tetrahydrofuran, worked up and chromatographed on silica gel with hexane/ethyl acetate=95/5 to 75/25. 130 mg of an oily crude product is obtained, which is subjected to complete purification of the high-pressure liquid chromatography on silanized silica gel (RP18 material) with methanol/H2O=85/15. 58 mg of the title compound is thus obtained as colorless oil.
Reaction SMILES: [CH:1]1([C:4]2[S:5][C:6]3[C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=[C:9]([O:16][CH3:17])[C:7]=3[N:8]=2)[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:24][C:25]1[C:29]([NH2:30])=[C:28]([CH3:31])[O:27][N:26]=1>CN(C)C=O.ClCCl.C(N(CC)CC)C>[CH3:24][C:25]1[C:29]([NH:30][C:13]([C:12]2[C:6]3[S:5][C:4]([CH:1]4[CH2:2][CH2:3]4)=[N:8][C:7]=3[C:9]([O:16][CH3:17])=[CH:10][CH:11]=2)=[O:15])=[C:28]([CH3:31])[O:27][N:26]=1
Reactant: Cc1noc(C)c1N
Reactant: COc1ccc(C(=O)O)c2sc(C3CC3)nc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2c(C)noc2C)c2sc(C3CC3)nc12
Yield: 24.3 %

Procedure:
Starting from 2-cyclopropyl-4-methoxybenzothiazole-7-carboxylic acid (0.20 g), oxalyl chloride (0.11 ml), dichloromethane (30 ml) and dimethylformamide (1 drop), followed by 3,5-dimethylisoxazol-4-amine (0.20 g), triethylamine (0.22 ml) and dichloromethane (30 ml). Purification by flash chromatography (eluent 50% ethyl acetate/heptane) yielded the title compound as a white solid (0.067 g). TLC Rf 0.33 (ethyl acetate); Mpt 196-197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH:9]=[CH:10]N(C)C)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[Cl:31][C:32]1[CH:37]=[C:36]([NH:38][C:39]([NH2:41])=[NH:40])[CH:35]=[CH:34][N:33]=1>CC(O)C>[Cl:31][C:32]1[CH:37]=[C:36]([NH:38][C:39]2[N:41]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[CH:9]=[CH:10][N:40]=2)[CH:35]=[CH:34][N:33]=1
Reactant: N=C(N)Nc1ccnc(Cl)c1
Reactant: CN(C)C=CC(=O)c1ccnc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc(Nc2nccc(-c3ccnc(Cl)c3)n2)ccn1
Reaction time: 20 h
Yield: 49.1 %

Procedure:
To a solution of 6.32 g of 1-(2-chloropyridin-4-yl)-3-(dimethylamino)prop-2-en-1-one (30 mmol) in 60 ml of 2-Propanol was added 2.52 g of sodium hydroxide (63 mmol) and 11.96 g of 1-(2-chloropyridin-4-yl)guanidine bis(trifluoroacetate) (30 mmol). The reaction mixture was heated to reflux under stirring for 20 h. After filtration, the precipitate was washed with 100 ml of n-butanol and 120 ml of iPr2O and then air-dried to yield 4.69 g of N,4-bis(2-chloropyridin-4-yl)pyrimidin-2-amine (yield=37%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:4]=2[S:5][CH:6]=1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.O>CN1CCCC1=O>[ClH:11].[Cl:11][C:8]1[CH:9]=[CH:10][C:3]2[C:2]([NH:1][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:6][S:5][C:4]=2[CH:7]=1
Reactant: Clc1ccncc1
Reactant: Nc1csc2cc(Cl)ccc12
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1ccc2c(Nc3ccncc3)csc2c1
Yield: 174.5 %

Procedure:
A solution of 3-amino-6-chlorobenzo[b]thiophene (5 g, 27 mmol) and 4-chloropyridine hydrochloride (6 g, 40 mmol) in 75 mL of 1-methyl-2-pyrrolidinone was stirred at 80° for 1.5 h, and then was cooled, stirred with water and extracted with ether. The aqueous layer was basified with sodium carbonate and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution and then was dried (anhydrous magnesium sulfate), filtered and concentrated to a dark oil. Elution through silica with ethyl acetate via flash column chromatography yielded 7 g of an amber oil. Conversion to the hydrochloride salt in 20% methanol in ether yielded 4.2 g of yellow crystals, mp 264-266° (dec.).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][CH2:6][CH2:7][CH:8]([OH:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11](I)[CH:10]=1)=[O:4].[CH2:19]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH2:20][C:21]#[CH:22]>>[F:1][C:2]([F:18])([F:17])[C:3]([NH:5][CH2:6][CH2:7][CH:8]([OH:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:22]#[C:21][CH2:20][CH2:19][C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[CH:10]=1)=[O:4]
Reactant: C#CCCc1ccc(C)cc1
Reactant: O=C(NCCC(O)c1cccc(I)c1)C(F)(F)F
Product: Cc1ccc(CCC#Cc2cccc(C(O)CCNC(=O)C(F)(F)F)c2)cc1

Procedure:
Sonogashira reaction of (2,2,2-trifluoro-N-(3-hydroxy-3-(3-iodophenyl)propyl)acetamide) with 1-(but-3-ynyl)-4-methylbenzene yielded 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(4-p-tolylbut-1-ynyl)phenyl)propyl)acetamide as yellow oil. Yield (0.310 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.29-7.51 (m, 4H), 7.17 (d, J=8.0 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 4.84-4.86 (m, 1H), 3.66-3.70 (m, 1H), 3.38-3.43 (m, 1H), 2.89 (t, J=7.6 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 2.33 (s, 3H), 2.25 (bs, 1H), 1.92-1.97 (m, 2H).
Reaction SMILES: [OH:1]N1[C:6](=O)[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[O-]O.[C:15]1([CH:21](C)[CH3:22])C=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:24]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.O=O>>[CH:3]1([OH:12])[CH2:4][CH2:11][CH2:10][CH2:9][CH2:8][CH2:5][CH2:6][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:21][CH2:22]1.[C:24]1(=[O:1])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[CH2:24]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)c1ccccc1
Agent: C1CCCCCCCCCCCCCC1
Agent: O=O
Agent: [O-]O
Product: O=C1CCCCCCCCCCCCCC1
Product: OC1CCCCCCCCCCCCCC1

Procedure:
2 mmol of N-hydroxyphthalimide and 4 mmol of cumene hydroperoxide are added at a temperature of 130° C. to 200 mmol of cyclopentadecane in a round-bottomed flask having an attached reflux condenser. Oxygen at approximately 15 l/h is passed through the reaction mixture for 8 hours at said temperature. Cyclopentadecanol is obtained at a selectivity of 20% and cyclopentadecanone at a selectivity of 46%, at a cyclopentadecane conversion rate of 44%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:15][NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]#[CH:26])=[CH:19][C:18]=3[C:27]([C:29]3[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=3)=O)[CH:9]=2)[N:4]=1.[O-:38][C:39]#[N:40].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:15][N:16]3[C:17]4[C:18](=[CH:19][C:20]([O:23][CH2:24][C:25]#[CH:26])=[CH:21][CH:22]=4)[C:27]([C:29]4[CH:34]=[CH:33][C:32]([CH:35]([CH3:36])[CH3:37])=[CH:31][CH:30]=4)=[N:40][C:39]3=[O:38])[CH:9]=2)[N:4]=1
Reactant: C#CCOc1ccc(NCc2ccc3nc(OC)c(OC)nc3c2)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1ccc2nc(OC)c(OC)nc2c1
Reaction time: 2 h

Procedure:
To a solution of 52 mg (0.105 mmol) {2-[(2,3-dimethoxy-quinoxalin-6-ylmethyl)-amino]-5-prop-2-ynyloxy-phenyl}-(4isopropyl-phenyl)-methanone in 1 ml acetic acid is added 14 mg (0.210 mmol) sodium cyanate. After stirring for 2 h the solvent is removed in vacuo and the residue is partitioned between CH2Cl2 and water. The organic layer is extracted with 2 M sodium hydroxide and evaporated. Purification of the crude product by flash-chromatography (ethyl acetate/hexanes 9:1) affords a yellow oil.
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([OH:11])=O>>[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([NH:4][CH2:2][CH3:3])=[O:11]
Reactant: CCN
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Agent: Cl
Product: CCNC(=O)c1ccc(F)c(Cl)c1
Yield: 77 %

Procedure:
Using ethanamine hydrochloride and 3-chloro-4-fluorobenzoic acid in the general procedure for coupling of amines to carboxylic acids, the title compound was obtained (77% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.20 Hz, 3 H) 3.28 (qd, J=7.16, 5.56 Hz, 2 H) 7.53 (t, J=8.84 Hz, 1 H) 7.87 (ddd, J=8.72, 4.80, 2.15 Hz, 1 H) 8.06 (dd, J=7.33, 2.27 Hz, 1 H) 8.61 (t, J=4.67 Hz, 1 H). ESI-MS: m/z 202.0 (M+H)+. mp=101.7-101.8° C.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:29][F:30])[O:8][CH2:7][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18][C:19]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]=3)[C:12]=2[CH3:28])[CH2:5][O:4]1.ClC1C=CC=C(C(OO)=[O:39])C=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CO>[F:1][CH2:2][C:3]1([CH2:29][F:30])[O:4][CH2:5][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:19]3[NH:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[O:39])[C:12]=2[CH3:28])[CH2:7][O:8]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OCC2COC(CF)(CF)OC2)ccnc1CSc1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1c(OCC2COC(CF)(CF)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reaction time: 2 h
Yield: 68 %

Procedure:
To a toluene/methanol (10:1) (20 ml) solution of the 2-(((4-((2,2-bis(fluoromethyl)-1,3-dioxan-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (305 mg, 700 μmol) obtained in the step (7d), a toluene/methanol (10:1) (5 ml) solution of 3-chloroperbenzoic acid (167 mg, 630 μmol as the content was regarded as 65%) was added dropwise at −50° C. to −60° C. for 5 minutes in a nitrogen atmosphere. The mixture was stirred for 2 hours in the same conditions. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was added and the resultant mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate/methanol) to obtain the title compound (215 mg, yield: 68%) as a light yellow foam.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[C:12](/[C:15](=O)[CH3:16])\[C:13]#[N:14])[CH:9]=2)[NH:4][N:3]=1.[CH3:18][C:19]1([CH3:27])[CH2:24][O:23][C:22](=[O:25])[CH2:21][C:20]1=O.C([O-])(=O)C.[NH4+:32]>>[CH3:16][C:15]1[NH:32][C:20]2[C:19]([CH3:27])([CH3:18])[CH2:24][O:23][C:22](=[O:25])[C:21]=2[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])[C:12]=1[C:13]#[N:14]
Reactant: [NH4+]
Reactant: CC(=O)/C(C#N)=C/c1ccc2[nH]nc(C)c2c1
Reactant: CC1(C)COC(=O)CC1=O
Agent: CC(=O)[O-]
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C2=C(N1)C(C)(C)COC2=O

Procedure:
The title compound was prepared from 200 mg (0.888 mmol) (2E)-2-[(3-methyl-1H-indazol-5-yl)-methylidene]-3-oxobutanenitrile (Example 2A), 126 mg (0.888 mmol) 5,5-dimethyldihydro-2H-pyran-2,4(3H)-dione [preparation: US 2006/0014826-A1 (Intermediate 6)] and 102 mg (1.332 mmol) ammonium acetate in analogy to the procedure described in Example 1 yielding 51 mg (16% of th.) after purification by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) followed by flash chromatography (silica gel; ethyl acetate/cyclohexane gradient, final mixture 5:1 v/v).