Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH:11]([NH:24][OH:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>[OH-].[Na+]>[CH:11]([N:24]([OH:25])[CH:1]=[O:3])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CO
Reactant: ONC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: O=CN(O)C(c1ccccc1)c1ccccc1
Temperature: 55 °C
Reaction time: 0.08 h
Yield: 65.8 %

Procedure:
Formic acid (0.53 mL, 14.1 mmol) was added dropwise to acetic anhydride (1.07 mL, 11.3 mmol) at 0° C., stirred for 5 mins. and then warmed to 55° C. for 5 mins prior to cooling back down to room temperature. N-benzhydrylhydroxylamine 41 (225 mg, 1.13 mmol) was added, and stirred at room temperature for 3 days. The reaction mixture was diluted with aqueous NaOH solution (to pH=7), the solution was stirred for 5 mins, and then acidified with aqueous HCl solution (to pH=4). Following extraction with ethyl acetate, the combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated. The crude material was concentrated and purified by silica gel column chromatography with gradient of ethyl acetate (0-75%) in hexane to afford compound 42 as a tan solid (169 mg, 66%). 1H NMR: (DMSO-d6) 8.41 (br s, 1H), 7.44-7.28 (m, 11H). LRMS (ESI): (calc.) 227.3 (found) 228.2 (MH)+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:7]([O-])(=O)C(C)O.[NH4+].C(O)(=O)C=C.P([O-])([O-])([O-])=O.[Al+3].C(=O)C.C(O)(=O)CC.C(=O)=O.C(OC)(=O)C(C)O>>[C:1]([OH:6])(=[O:5])[CH:2]=[CH2:4].[C:1]([O:6][CH3:7])(=[O:5])[CH:2]=[CH2:4].[CH:2](=[O:3])[CH3:1]
Reactant: CC(O)C(=O)[O-]
Reactant: CC(O)C(=O)O
Agent: C=CC(=O)O
Agent: CC=O
Agent: COC(=O)C(C)O
Solvent: CCC(=O)O
Product: C=CC(=O)OC
Yield: 5 %

Procedure:
For example, in U.S. Pat. No. 4,786,756 (issued in 1988), the inventors claim the vapor phase dehydration of lactic acid or ammonium lactate to acrylic acid using aluminum phosphate (AlPO4) treated with an aqueous inorganic base as a catalyst. As examples, the '756 patent discloses a maximum yield of acrylic acid of 43.3% when lactic acid was fed into the reactor at approximately atmospheric pressure, and a respective yield of 61.1% when ammonium lactate was fed into the reactor. In both examples, acetaldehyde was produced at yields of 34.7% and 11.9%, respectively, and other side products were also present in large quantities, such as, propionic acid, CO, and CO2. Omission of the base treatment caused increased amounts of the side products. Another example is Hong et al. (2011) Appl. Catal. A: General 396:194-200, who developed and tested composite catalysts made with Ca3(PO4)2 and Ca2(P2O7) salts with a slurry-mixing method. The catalyst with the highest yield of acrylic acid from methyl lactate was the 50%-50% (by weight) catalyst. It yielded 68% acrylic acid, about 5% methyl acrylate, and about 14% acetaldehyde at 390° C. The same catalyst achieved 54% yield of acrylic acid, 14% yield of acetaldehyde, and 14% yield of propionic acid from lactic acid.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.B1(B2OCC(C)(C)CO2)OCC(C)(C)CO1.C([O-])(=O)C.[K+].Cl[C:57]1[CH:62]=[C:61]([CH3:63])[CH:60]=[CH:59][N:58]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[CH2:15]([NH:14][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([C:57]3[CH:62]=[C:61]([CH3:63])[CH:60]=[CH:59][N:58]=3)=[CH:3][C:4]([C:17]3[CH:22]=[N:21][C:20]([N:23]4[CH2:24][CH2:25][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:28]4)=[N:19][CH:18]=3)=[CH:5][C:6]=2[N:7]=1)=[O:13])[CH3:16]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Reactant: Cc1ccnc(Cl)c1
Agent: CC(=O)[O-]
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(-c3cc(C)ccn3)c2s1
Temperature: 80 °C
Yield: 3.1 %

Procedure:
To a solution of ethyl 1-(5-(7-bromo-2-(3-ethylureido)benzothiazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylate (Intermediate 4) (0.5 g, 0.91 mmol) in DMSO (5 mL) was added bis(neopentylglycolato)diboron (0.41 g, 1.82 mmol) and potassium acetate (0.18 g, 1.82 mmol). The reaction was degassed by purging N2 for 15 min followed by addition of dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (II) (0.07 g, 0.091 mmol) and again degassed for 10-15 min then heated up to 80° C. for 2 h. After completion of reaction (TLC as well as MS monitoring), the reaction was cooled to rt followed by addition of 2-chloro-4-methylpyridine (0.23 g, 1.37 mmol) and an aqueous solution of Cs2CO3 (0.45 g, 1.37 mmol, dissolved in minimum amount of water). The reaction was degassed by purging N2 for 15 min followed by addition of tetrakis (triphenylphosphine)palladium(0) (0.11 g, 0.091 mmol) and again degassed for 10-15 min then heated up to 80° C. for 16 h. After reaction completion, 100 mL of ice-cold water was added then extracted with EtOAc (3×150 mL) and the combined organic layer was washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 1.50% MeOH: DCM to obtain a beige solid, which was further purified through preperative-HPLC to obtain the desired product as an off-white solid (0.016 g, 3%).
Reaction SMILES: [Br-:1].Cl[CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=1[CH2:10][P+:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:6].[CH:34]1[CH:35]=[CH:36][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:38][CH:39]=1>C(#N)C>[Br-:1].[C:37]1([N:40]2[CH2:45][CH2:44][N:43]([CH2:3][CH2:4][C:5]([NH:7][C:8]3[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=3[CH2:10][P+:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:6])[CH2:42][CH2:41]2)[CH:38]=[CH:39][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(CCCl)Nc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: [Br-]
Solvent: CC#N
Product: O=C(CCN1CCN(c2ccccc2)CC1)Nc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A mixture of 2-(3-chloropropionylamino)benzyltriphenylphosphonium bromide (2.70 g, 5 mmol) and phenylpiperazine (1.70 g, 10 mmol) in acetonitrile (85 ml) was heated at reflux for 2.5 h. The mixture was cooled to room temperature and filtered and the filtrate evaporated in vacuo to give 2-(3-[4-phenylpiperazin-1-yl]propionylamino) benzyltriphenylphosphonium bromide as a white solid (3.1 g, 93%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])C=O.[CH3:13][O:14][CH:15](OC)[O:16][CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO>[CH3:13][O:14][CH:15]([O:16][CH3:17])[C:4]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([F:1])[CH:3]=1
Reactant: COC(OC)OC
Reactant: O=Cc1ccc([N+](=O)[O-])c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(OC)c1ccc([N+](=O)[O-])c(F)c1

Procedure:
A mixture of 0.5 g (2.96 mmole) of 3-fluoro-4-nitrobenzaldehyde, 1 mL of trimethylorthoformate, 0.020 g of p-toluenesulfonic acid monohydrate and 2 mL of methanol was heated at reflux for 1 hour. The mixture was cooled, and 1 mL of saturated aqueous sodium bicarbonate solution was added. The mixture was concentrated under reduced pressure, and the residue was partitioned between 30 mL of ethyl acetate and 30 mL of saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.64 g of 4-dimethoxymethyl-2-fluoro-1-nitro-benzene (IV.2a) as a pale yellow oil. This material was used without further purification.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=O.[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[C:15]([C:23]([NH2:25])=[O:24])[C:16]([NH2:22])=[N:17]2>CCCCCC>[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[C:15]1[C:23](=[O:24])[NH:25][C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[N:22][C:16]1=[N:17]2
Reactant: NC(=O)c1cc2c(Cl)cccc2nc1N
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCCCCC
Product: CCOC(=O)c1nc2nc3cccc(Cl)c3cc2c(=O)[nH]1

Procedure:
Diethyl oxalate (350 ml.) and 5-chloro-2-aminoquinoline-3-carboxamide (5.9 g., 0.0267 mole) are heated together at 170° C. for four hours. By-product water and ethanol are distilled from the reaction mixture. The dark reaction mixture is cooled, treated with hexane (300 ml.) and filtered. The brown solid is dissolved in methylene chloride:ethanol (1:1), decolorized with charcoal and concentrated to give a tan solid. The solid is recrystallized from methylene chloride-hexane. It is purified further by chromatography on silica gel using methylene chloride:ethanol (9:1) as eluant. The product, recovered by evaporation of the eluate, is recrystallized from methylene chloride-ethanol. Yield = 0.756 g. (9.3%). M.P. 278°-279° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:14]=[C:15](I)[C:16]3[C:21]([CH3:23])([CH3:22])[C:20](=[O:24])[NH:19][C:17]=3[N:18]=2)=[N:6]1>CN(C=O)C.[Pd]>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:14]=[CH:15][C:16]3[C:21]([CH3:23])([CH3:22])[C:20](=[O:24])[NH:19][C:17]=3[N:18]=2)=[N:6]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4c3CCC4)nc(I)c21
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4c3CCC4)ncc21
Yield: 82.8 %

Procedure:
45 mg (0.08 mmol) of 2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one were dissolved in 5 ml of absolute DMF, 18 mg (0.02 mmol) of 10% palladium on charcoal were added and hydrogenation was effected under standard hydrogen pressure overnight. The reaction mixture was filtered through Celite and concentrated, and the residue was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 20:80→100:0). 25 mg of the target compound were obtained (80% of theory).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C1C(=O)N([I:30])C(=O)C1.C(O)(=O)C>>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:14][CH2:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]2)=[CH:11][C:12]=1[I:30]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)[C@H]1CC[C@H](c2ccc(Cl)c(I)c2)CC1
Temperature: 25 °C

Procedure:
Sulfuric acid (0.708 mL, 13.29 mmol) was added into a cold (ice bath) mixture of methyl trans-4-(4-chlorophenyl)cyclohexanecarboxylate (3.3588 g, 13.29 mmol) and n-iodosuccinimide (2.99 g, 13.29 mmol) in acetic acid (0.798 g, 13.29 mmol). The reaction mixture was stirred in an ice bath and was allowed to warm to ambient temperature overnight. The reaction crude was poured into an ice water and extracted with EtOAc. The separated organic phase was dried over Na2SO4, filtered and evaporated to afford a dark mixture. The resulting crude mixture was purified by flash chromatography (SiO2, Biotage 65i cartridge). The column was eluted by a EtOAc/hexanes mixture (0% to 10%). Related fractions were pooled and evaporated to afford a crystalline solid as the titled compound. LCMS calc.=377.99. found=379.00 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([CH3:14])[C:8]([CH3:16])([CH3:15])[CH2:7]1)(=[O:4])[NH:2][NH2:3].[CH3:17][C:18]1([CH3:34])[CH2:23][CH:22]([NH:24][C:25](=[O:31])[C:26](OCC)=[O:27])[CH2:21][C:20]([CH3:33])([CH3:32])[NH:19]1>CO>[CH3:17][C:18]1([CH3:34])[CH2:23][CH:22]([NH:24][C:25](=[O:31])[C:26]([NH:3][NH:2][C:1]([O:5][CH:6]2[CH2:11][C:10]([CH3:12])([CH3:13])[N:9]([CH3:14])[C:8]([CH3:16])([CH3:15])[CH2:7]2)=[O:4])=[O:27])[CH2:21][C:20]([CH3:33])([CH3:32])[NH:19]1
Reactant: CN1C(C)(C)CC(OC(=O)NN)CC1(C)C
Reactant: CCOC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Solvent: CO
Product: CN1C(C)(C)CC(OC(=O)NNC(=O)C(=O)NC2CC(C)(C)NC(C)(C)C2)CC1(C)C
Temperature: 50 °C

Procedure:
Into a 100 ml 3-neck flask was added 7.3 grams (0.0318 mole) of 1,2,2,6,6-pentamethyl-4-piperidinyl carbazate, 12.9 grams (0.032 mole) of a 60% solution of ethyl N-(2,2,6,6-tetramethyl-4-piperidinyl)oxamate in methanol and 15 ml of methanol. The flask was equipped with a magnetic stirrer, thermometer and a Dean Stark trap with reflux condenser. The flask was placed in a hot oil bath and heated to reflux. The methanol was distilled off through the Dean Stark trap and the residue was heated for 4 hours at 75°-80° C. Liquid chromatography of the residue indicated that the reaction had proceeded to 85-90% of completion. The reaction was cooled to 50° C. and 50 ml of methanol was added to dissolve the product. The methanol solution was cooled in the freezer (-10° C.) overnight and the next day the crystals that formed were filtered off and air dried. The dry crystals weighed 3.1 grams and melted at 165°-170° C. A liquid chromatography scan indicated the presence of only one component. The infrared spectrum of the product contained a weak carbonyl peak at 1740 cm-1 and strong, sharp carbonyl peaks at 1600 and 1685 cm-1. A second crop of 4.5 grams was obtained by concentrating the filtrate to about 25 ml, cooling and filtering off the solids that formed. The filtrate was stripped to dryness, leaving 7.0 grams of product which was contaminated with small amounts of the starting materials.
Reaction SMILES: [C:1]1(=[O:12])[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][C:3](=[O:11])[CH2:2]1.C(N(CC)CC)C.C1(C)C=CC(S([N:29]=[N+:30]=[N-])(=O)=O)=CC=1>C(O)C>[N+:29](=[C:2]1[C:3](=[O:11])[CH2:4][C@H:5]2[C@@H:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[C:1]1=[O:12])=[N-:30]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: O=C1CC(=O)C2CCCCC2C1
Solvent: CCN(CC)CC
Solvent: CCO
Product: [N-]=[N+]=C1C(=O)C[C@@H]2CCCC[C@H]2C1=O
Temperature: 0 °C

Procedure:
A solution of 1.06 gm (6.38 nmole) of decalin-1,3-dione in 3 mL of dry ethanol was cooled in an ice bath and treated with 0.89 mL of (6.4 mmole) triethylamine followed by 1.128 gm (6.50 mmole) of p-toluenesulfonyl azide. The mixture was stirred in the ice bath for 4 hours, then concentrated in vacuo (less than 40° C.). The residue was dissolved in 45 mL of ether and the ether washed with a solution of 0.42 gm KOH in 30 mL of water, dried (Na2SO4), filtered, and concentrated to 1.22 gm of an orange oil. This was chromatographed on 40-micron silica giving 0.45 gm of trans-2-diazodecalin-1,3-dione, mp 81°-3° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH:19]1[CH2:23][CH2:22][O:21][CH2:20]1>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:18][CH:19]2[CH2:23][CH2:22][O:21][CH2:20]2)=[CH:4][C:3]=1[CH3:10]
Reactant: BrCC1CCOC1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC2CCOC2)cc(C)c1Br
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (1.5 g) and K2CO3 (3.2 g) in N,N-dimethylformamide (12 mL) is added 3-(bromomethyl)tetrahydrofuran (3.6 g). The mixture is stirred for 16 hours at 80° C. and then partitioned between water and ethyl acetate. The organic phase is washed with brine and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. Yield: 1.72 g; LC (method 1): tR=1.37 min; Mass spectrum (ESI+): m/z=285 [M+H]+.
Reaction SMILES: [N:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([C:11]1[N:12]=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:34])[CH2:23][N:24]3[C:28]([CH3:29])=[CH:27][C:26]([C:30]([F:33])([F:32])[F:31])=[N:25]3)[CH2:18][CH2:17]2)[S:14][CH:15]=1)(=O)[CH3:9]>[Cl-].[NH4+]>[CH3:29][C:28]1[N:24]([CH2:23][C:22]([N:19]2[CH2:20][CH2:21][CH:16]([C:13]3[S:14][CH:15]=[C:11]([C:8](=[N:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH3:9])[N:12]=3)[CH2:17][CH2:18]2)=[O:34])[N:25]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:27]=1
Reactant: CC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Reactant: NN1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Product: CC(=NN1CCCCC1)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Reaction time: 2 h

Procedure:
At 80° C., piperidine-1-amine (104 mg) is added to a solution of 1-[4-(4-acetyl-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (46 mg). The reaction mixture is stirred at this temperature for a further 2 hours. Aqueous ammonium chloride solution (10 ml) is then added to the reaction mixture. After phase separation, the aqueous phase is extracted three times with methyl tert-butyl ether (20 ml). All the organic phases are dried over Na2SO4. The mixture is then filtered and concentrated under reduced pressure. This gives 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[N-(piperidin-1-yl)ethanimidoyl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (55 mg, 99%), (log P(pH2.7)=3.69).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.C1COCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:17]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CCC(=O)c1ccc(NC(=O)c2ccc(C)cc2)cc1
Yield: 40.4 %

Procedure:
A mixture of 4-methyl-benzoyl chloride (0.74 mL, 0.0056 mol) and 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.93 g, 0.0045 mol) in toluene (22 mL) was refluxed under nitrogen for 17 hours and allowed to cool. The mixture was diluted with THF (20 mL), and washed with 0.1 M aqueous sodium hydroxide. The solids that remained undisolved were filtered, washed with water, and dried in house vacuum (40° C., air bleed) to give 0.592 g of 4-[4-(4-methyl-benzoylamino)-phenyl]-4-oxo-butyric acid, methyl ester as an off-white solid; mp 192-195° C.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[S:7][C:8]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)=[CH:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[C:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)([OH:26])=[O:25]>>[CH:19]([N:18]1[C:14]([C:8]2[S:7][C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:31]5[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=5)[C:24]([OH:26])=[O:25])=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][C:10]=3[CH:9]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: O=C(O)c1cccc(B(O)O)c1
Product: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(-c3cccc(C(=O)O)c3)cc1OCC2

Procedure:
Following the procedure for 114, 5 5-(8-Bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazole was reacted with 3-carboxyphenylboronic acid to give 147. MS (ESI+) 432.1
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[F:30][C:31]1[CH:32]=[C:33]([C:43](=[O:45])[CH3:44])[CH:34]=[CH:35][C:36]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([N:40]1[CH2:39][CH2:38][N:37]([C:36]2[CH:35]=[CH:34][C:33]([C:43](=[O:45])[CH3:44])=[CH:32][C:31]=2[F:30])[CH2:42][CH2:41]1)=[O:6]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3Cl)CC2)c(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
To a solution of 2-Chloro-5-methanesulfonyl-benzoic acid (200 mg, 0.852 mmol) in DMF (3 ml) was added dropwise 1,1′-Carbonyldiimidazole (142 mg, 0.852 mmol). When the CO2 evolution ceased, the mixture was heated to 50° C. for 15 minutes. The mixture was cooled to room temperature. 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone (189 mg, 0.852 mmol) was added portionwise. The mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The solution was washed twice with water, dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was purified on silica gel (Heptane/AcOEt 0%-50% (15 minutes) to provide the title compound (185 mg, 49%) as a white solid, MS (m/e): 439.1 (M+H+, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=3)[C:15]=2[CH3:16])=[O:10])=[CH:4][C:3]=1[C:27]#[N:28].CC1(C)C(C)(C)OB([C:37]2[CH2:42][CH2:41][CH:40]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[CH2:39][CH:38]=2)O1>O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+].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:27]([C:3]1[CH:4]=[C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][N:18]=3)[C:15]=2[CH3:16])=[O:10])[CH:6]=[N:7][C:2]=1[C:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH2:44][CH2:45][O:46][CH2:47][CH2:48]2)[CH2:39][CH:38]=1)#[N:28]
Reactant: Cc1c(C(=O)Nc2cnc(Cl)c(C#N)c2)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: CC1(C)OB(C2=CCC(N3CCOCC3)CC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2cnc(C3=CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 90 °C
Yield: 54.1 %

Procedure:
N-(6-Chloro-5-cyanopyridin-3-yl)-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (200 mg), 4-[4-(4,4,5,5-tetramethyl-[1,3,2] dioxaborolan-2-yl)cyclohex-3-en-1-yl]morpholine (159 mg) described in Reference Example 166 and tetrakis(triphenylphosphine)palladium (57 mg) were dissolved in a mixture of tetrahydrofuran (1 ml) and 1M aqueous solution of sodium carbonate (0.54 ml), and stirred at 90° C. After completion of the reaction, the reaction solution was left stand, filtered through Celite, washed with chloroform and the filtrate was concentrated. Water was added to the resulting residue and the precipitate was filtered. The obtained solid was refluxed in ethanol, the resulting solution was left stand, the precipitated solid was collected by filtration and dried in vacuo to give the titled compound (143 mg) as a pale yellow solid.