Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8]C1>CCCCCC.C(OCC)C.CCCCCC>[C:10]1([C:9](=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:8])[OH:6].[CH3:4][CH2:3][CH2:2][CH2:1][CH2:11][CH2:10][CH2:9][CH2:14][CH3:13]
Reactant: c1ccc2c(c1)OCO2
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCCCCC
Product: Oc1ccccc1O

Procedure:
In J. Org. Chem., Vol. 37, page 673 (1972), E. L. Stogryn describes the preparation of 2,2-difluorobenzo-1,3-dioxole-5-carbaldehyde by formylation of 2,2-difluorobenzo-1,3-dioxol-5-yllithium with dimethylformamide. The lithium compound is obtained by reaction of 1 mole 5-bromo-2,2-difluorobenzo-1,3-dioxole with 1.3 mole butyllithium. Ortho-metallation is not mentioned by Stogryn, although butyllithium was applied in 30% excess. S. Cabiddu et al. describe in Journal of Organometallic Chemistry 136 139-146 (1977) two competitive reactions which occur by the treatment of 1,3-benzodioxole in hexane with n-butyllithium in diethyl ether/hexane at -10° C. After carbonation of the reaction mixture the authors detected the formation of 1,3-benzodioxole-4-carbonic acid, originated from the 4-lithium compound with a yield of 41% and in addition thereto pyrocatechol and n-nonane, as a result of cleavage of the ether bond with a yield of each 45% of theory.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([O:15][CH3:16])=[O:14])[C:9]([OH:11])=[O:10].N[CH:18](C1C=CC=CC=1C)C(O)=O>>[CH3:16][O:15][C:13]([NH:12][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:18])[C:9]([OH:11])=[O:10])=[O:14]
Reactant: Cc1ccccc1C(N)C(=O)O
Reactant: COC(=O)NC(C(=O)O)c1ccccc1F
Product: COC(=O)NC(C(=O)O)c1ccccc1C

Procedure:
Methoxycarbonylamino-o-tolyl-acetic acid was prepared using the procedure used to prepare (2-Fluoro-phenyl)-methoxycarbonylamino-acetic acid using Amino-o-tolyl-acetic acid. LCMS-ESI+: calc'd for C11H13NO4: 223.08 (M+); Found: 223.94 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[C:12]=1[Cl:13])[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[CH3:17]O>>[Cl:13][C:12]1[C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]([C:7]([O:9][CH3:17])=[O:8])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CO
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reaction time: 15 h

Procedure:
2.96 ml of SOC12 is added at 0° C., under an inert atmosphere and dropwise to 10 g of 3,5-dinitro-4-chlorobenzoic acid (JANSSEN) in 150 ml of methanol and agitation is carried out under reflux of methanol for 2 hours then for 15 hours at ambient temperature. The reaction medium is poured into ice and precipitation of the product is observed. After drying, 10.3 g of expected product is obtained.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].Br[CH2:8][CH2:9][CH2:10][CH3:11].Cl>C(O)(C)C>[CH2:8]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCBr
Reactant: CC(C)(N)CO
Agent: Cl
Solvent: CC(C)O
Product: CCCCNC(C)(C)CO
Yield: 26.8 %

Procedure:
A solution of 2-amino-2-methylpropan-1-ol (14 g, 157 mmol) in isopropanol (100 ml) was treated with 1-bromobutane (37 g, 272 mmol). The mixture was refluxed for 12 hrs, treated with 8 ml of concentrated HCl, then distilled to remove volatiles. The remaining residue was basified with 20% of NaOH, and extracted with Et2O (2×). The Et2O layers were combined and distilled to afford 6.1 g (27%) of the title compound (124-126° C. @54-56 Torr). 1H NMR (400 MHz, CDCl3) δ ppm 0.92 (t, J=7.36 Hz, 3H) 1.06 (s, 6H) 1.10 (s, 1H) 1.29-1.50 (m, 4H) 2.49 (t, J=6.75 Hz, 2H) 3.28 (s, 2H).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=O)C.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([CH2:16][C:17]#[N:18])=[O:15].C1(=O)CCCC1.N1CCOCC1.[S]>>[NH2:18][C:17]1[S:5][C:6]2[CH2:1][CH2:4][CH2:8][C:7]=2[C:16]=1[C:14]([C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)=[O:15]
Reactant: N#CCC(=O)c1cccs1
Reactant: CC(=O)c1cccs1
Agent: [S]
Solvent: O=C1CCCC1
Solvent: C1COCCN1
Product: Nc1sc2c(c1C(=O)c1cccs1)CCC2
Yield: 67 %

Procedure:
The procedure of Example 1 was followed except that 2-acetylthiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(thiophene-2-carbonyl)acetonitrile (Steps A and B). Cyclopentanone (Aldrich), 2-(thiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 67%; IR (KBr) cm−1: 3344, 3242, 3130, 1566, 1435, 1264, 1031, 771, 747; 1H NMR (CDCl3):δ 2.27 (m, 2H), 2.47 (t, 2H, J=7.4 Hz), 2.70 (t, 2H, J=7 Hz), 6.65 (bs, 2H), 7.06 (dd, 1H, J=3.8 and 4.8 Hz), 7.37 (dd, 1H, J=1.0 and 4.6 Hz), 7.53 (dd, 1H, J=5.0 and 1.2 Hz); yellow solid, mp: 133–134° C. (petroleum ether).
Reaction SMILES: O.[NH2:2]N.Cl.[C:5]([NH2:8])(=[NH:7])[CH3:6].C([O:11][C:12](=O)[C:13](=O)[CH:14]([NH:16][C:17](=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH3:15])C>C(O)C>[C:17]([NH:16][CH:14]([C:13]1[C:12](=[O:11])[NH:7][C:5]([CH3:6])=[N:8][N:2]=1)[CH3:15])(=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC(=N)N
Reactant: NN
Reactant: CCOC(=O)C(=O)C(C)NC(=O)CC(C)C
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1nnc(C(C)NC(=O)CC(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Hydrazine hydrate (100%, 78 ml, 80 g) in absolute ethanol (40 ml) was added with stirring over a period of 15 minutes to a solution of acetamidine hydrochloride (151 g) in absolute ethanol (1200 ml) cooled to 5°. The mixture was stirred for a further 10 minutes, then ethyl-3-isovaleramido-2-oxobutyrate [prepared by hydrolysis of the enol esters (535 g) as in Example 1(i)] in absolute ethanol (200 ml) was added and heated at 70°-80° with stirring for 20 hours. After cooling the mixture to room temperature, ammonium chloride was removed by filtration and the filtrate concentrated and diluted with ethyl acetate (250 ml) to precipitate the triazinone (94.0 g). The filtrate on standing deposited a second crop (6.7 g). Two recrystallisations from ethanol gave a sample of m.p. 224°-226°.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:13]=[C:14]2[S:18][CH2:17][NH:16][C:15]2=[O:19])[CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])([CH3:4])[CH3:3]>O1CCCC1.[Pd]>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH2:13][CH:14]2[S:18][CH2:17][NH:16][C:15]2=[O:19])[CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: Cc1cc(C=C2SCNC2=O)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(CC2SCNC2=O)cc(C(C)(C)C)c1O
Yield: 17.7 %

Procedure:
A solution of 0.28 g of the compound of Example 61 in 30 ml of tetrahydrofuran was hydrogenated at 60 pounds per square inch in the presence of 1.12 g of 5% palladium on carbon overnight at 60° C. The reaction mixture was filtered and evaporated to dryness. The resulting residue was dissolved in 3.5 ml of a 1:1.5 ethyl acetate/hexane solution and loaded onto a silica gel chromatography column. Elution with 40% ethyl acetate in hexane produced fractions which, upon evaporation to dryness, provided 0.05 g of title compound. m.p. 64-68° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:24][CH2:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=2)=[N:5][C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1)#[N:2].Cl.CN.C(Cl)CCl.[CH3:42][N:43]1CCOCC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([C:3]1[C:4]([O:24][CH2:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([NH:43][CH3:42])=[O:32])=[CH:28][CH:27]=2)=[N:5][C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH:8]=1)#[N:2]
Reactant: CN1CCOCC1
Reactant: Cc1ccc(-c2cc(C#N)c(OCc3ccc(C(=O)O)cc3)nc2-c2ccc(Cl)cc2Cl)cc1
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CNC(=O)c1ccc(COc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(C)cc3)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dried round bottom flask was added the product of Example 122 (0.030 g; 0.0613 mmol), methylamine hydrochloride (0.005 g; 0.0675 mmol), EDC (0.018 g; 0.0919 mmol), DMAP (0.007 g; 0.0613 mmol), N-methylmorpholine (0.028 mL; 0.251 mmol), and methylene chloride (0.5 mL). The reaction mixture was stirred at room temperature overnight. The volatiles were removed, and the residue was taken up in ethyl acetate, washed with saturated NaHCO3 (2×), water, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification was done by MPLC (silica gel; 0-50% ethyl acetate:hexane) to afford the desired product: m/e=502 (M+1); Rt=4.2 min on LCMS. HPLC/MS: 502 (M+1); Rt=4.20 min
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Cl:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Cl:15][CH2:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: Cc1cccc(C)c1C(=O)OC(C)C
Reactant: O=C1CCC(=O)N1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(CCl)c1C(=O)OC(C)C
Yield: 96.5 %

Procedure:
19.2 g of isopropyl 2,6-dimethylbenzoate are initially charged in 100 ml of carbon tetrachloride admixed at room temperature with 13.3 g of N-chlorosuccinimide and 200 mg of AIBN. The mixture is heated to reflux for 3 h. After the mixture has been cooled, it is filtered with suction, and the succinimide is washed with 20 ml of carbon tetrachloride. The filtrates are combined, and carbon tetrachloride is distilled off in vacuo. 21.8 g of colorless liquid are obtained. The product is distilled under high vacuum (0.05 mbar, 94–97° C.). Yield: 13.9 g (61% of theory; 93.6 area %).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:27][CH:28]([CH2:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1)[C:29]#[N:30].C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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.O>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH:34]=[N:33][N:32]([CH2:31][CH:28]([CH3:27])[C:29]#[N:30])[CH:36]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CC(C#N)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
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: CO
Solvent: C1COCCO1
Solvent: O
Product: CC(C#N)Cn1cc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)cn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2 (1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 2-methyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile (7.5 mg, 0.029 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling it was diluted with methanol. After filtration the filtrate was purified with RP-HPLC (pH=10) to afford the desired product (2.9 mg). LCMS (M+H)+: m/z=472.3.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([CH2:12][Cl:13])=[N:9]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.P(Cl)(Cl)([Cl:25])=O>COCCOC>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:25])=[N:7][C:8]([CH2:12][Cl:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(CCl)nc2cc(Br)ccc12
Solvent: Cc1cccc(C)n1
Solvent: COCCOC
Product: ClCc1nc(Cl)c2ccc(Br)cc2n1
Temperature: 25 °C

Procedure:
Heat a mixture of 7-bromo-2-chloromethyl-3H-quinazolin-4-one (5 g, 18.2 mmol), 2,6-lutidine (5 g), and phosphorus oxychloride (5 mL) in 1,2-dimethoxyethane (500 mL) at 80° C. for 16 hours. Cool the mixture to room temperature and fully evaporate the mixture, then dilute with ether and wash with water. Dry the solvent (Na2SO4) and evaporate the ether to obtain 7-bromo-4-chloro-2-chloromethylquinazoline (3.5 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH3:9].[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:17][S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])[CH3:9]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccccc1F
Solvent: C1CCOC1
Product: CC(=N[S@](=O)C(C)(C)C)c1ccccc1F
Temperature: 25 °C
Yield: 78.3 %

Procedure:
1-(2-Fluorophenyl)ethanone (15 g, 109 mmol) and (R)-2-methylpropane-2-sulfinamide (15.79 g, 130 mmol) were placed in a round bottom flask fitted with a reflux condenser. Tetrahydrofuran (90 ml) (dried over 4 Å MS) was added followed by Ti(OEt)4 (49.5 g, 217 mmol) and the resulting yellow solution was stirred at gentle reflux overnight. The reaction was allowed to cool to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and brine (100 mL) was added dropwise while stirring vigorously. The addition of brine resulted in immediate formation of copious amounts of a white precipitate. After 10 min stirring at room temperature the suspension was filtered through a plug of celite using ethyl acetate for elution. The filtrate was transferred to a separation funnel, the layers were separated, and the organic layer was washed with brine (150 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure and was purified using a CombiFlash system (330 g SiO2, gradient elution; heptanes:ethyl acetate 100:0→70:30) to afford (R)—N-(1-(2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (20.6 g, 70.8% yield) 1H NMR (600 MHz, CDCl3) δ 7.69 (t, J=7.1 Hz, 1H), 7.43 (dd, J=13.0, 6.0 Hz, 1H), 7.18 (td, J=7.7, 1.0 Hz, 1H), 7.11 (ddd, J=11.3, 8.3, 0.8 Hz, 1H), 2.78 (d, J=3.4 Hz, 3H), 1.32 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:30]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:30][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)c1ccc(Br)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1

Procedure:
A mixture J.6 (S)-tert-butyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-pyrrolidine-1-carboxylate (12.8 g, 31.12 mmol) and ammonium acetate (12.0 g, 155.7 mmol) in xylenes (155 mL) was heated in a sealed tube at 140° C. for 2 hours. The volatile component was removed in vacuo, and the residue was partitioned carefully between ethyl acetate and water, whereby enough saturated NaHCO3 solution was added so as to make the pH of the aqueous phase slightly basic after the shaking of the biphasic system. The layers were separated, and the aqueous layer was extracted with an additional ethyl acetate. The combined organic phase was washed with brine, dried (MgSO4), filtered, and concentrated. The resulting material was recrystallized from ethyl acetate/hexanes to provide two crops of J.7 (S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate, 5.85 g. The mother liquor was concentrated in vacuo and submitted to a flash chromatography (silica gel; 30% ethyl acetate/hexanes) to provide an additional 2.23 g. 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): δ 12.17/11.92/11.86 (m, 1H), 7.72-7.46/7.28 (m, 5H), 4.86-4.70 (m, 1H), 3.52 (app br s, 1H), 3.36 (m, 1H), 2.30-1.75 (m, 4H), 1.40/1.15 (app br s, 9H). LC (Cond.-J1): RT=1.71 min; LC/MS: Anal. Calcd. For [M+H]+ C18H23BrN3O2: 392.10; found 391.96. HRMS: Anal. Calcd. For [M+H]+ C18H23BrN3O2: 392.0974; found 392.0959.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]#[N:14])=[C:11]([Cl:15])[S:10][N:9]=2)=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[N:24]=[C:25]=[O:26]>C1COCC1>[Cl:15][C:11]1[S:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:25]([NH:24][C:18]3[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=3[F:16])=[O:26])=[CH:3][CH:4]=2)[C:12]=1[C:13]#[N:14]
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: N#Cc1c(-c2ccc(N)cc2)nsc1Cl
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3nsc(Cl)c3C#N)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.3 %

Procedure:
A solution of 3-(4-amino-phenyl)-5-chloro-isothiazole-4-carbonitrile (4.565 g, 19.4 mmol) and 2-fluoro-5-methylphenyl isocyanate (5.85 g, 38.7 mmol) in 100 mL of dry THF was heated to reflux overnight. TLC indicated presence of considerable amount of starting material. Additional 2 g of 2-fluoro-5-methylphenyl isocyanate was added and the reaction was continued for another 24 h. The reaction was cooled to room temperature. THF was removed in vacuo and the resulting solid was stirred in 200 mL of Et2O for 1 h. Product was collected by filtration and washed with Et2O/hexanes to afford the title compound as a light yellow solid (6.78 g, 90%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH3:40])=[C:10]([CH2:12][O:13][C:14]3[CH:39]=[CH:38][C:17]([CH2:18][O:19][C:20]4[C:24](/[CH:25]=[CH:26]/[C:27]([O:29]CC)=[O:28])=[CH:23][N:22]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[N:21]=4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[C:1]1([C:7]2[O:8][C:9]([CH3:40])=[C:10]([CH2:12][O:13][C:14]3[CH:39]=[CH:38][C:17]([CH2:18][O:19][C:20]4[C:24](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:23][N:22]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[N:21]=4)=[CH:16][CH:15]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)O)cc1
Yield: 86.6 %

Procedure:
To a mixture of ethyl (2E)-3-[3-({4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]-2-propenoate (0.39 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was heated under reflux for 2 hrs. The reaction mixture was neutralized by adding 1N hydrochloric acid and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give (2E)-3-[3-({4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]-2-propenoic acid as colorless crystals (0.32 g, yield 86%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 186-187° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:21][CH2:20]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>C(O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:20][CH2:21][CH:22]([C:25]([N:27]3[CH2:28][CH2:29][N:30]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[N:7]=4)[CH2:31][CH2:32]3)=[O:26])[CH2:23][CH2:24]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1nccc(Cl)n1
Reactant: O=C(C1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1)N1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nccc(N2CCN(C(=O)C3CCN(S(=O)(=O)c4ccc(Br)cc4)CC3)CC2)n1
Yield: 67.1 %

Procedure:
2-Methyl-4-chloro-pyrimidine (0.34 g) was added to a suspension of 1-(4-bromophenylsulphonyl)-4-(1-piperazinylcarbonyl)piperidine (1.0 g) in ethanol (10 ml) and 1(triethylamine (0.5 ml). The reaction was heated under reflux for 2 hours, cooled and the solvent removed by evaporation. The reaction mixture was purified by filtration column chromatography (silica, gradient elution dichloromethane to 10% methanol in dichloromethane) to give 1-(4-bromophenylsulphonyl)-4-[1-(2-methylpyrimidin-4-yl)piperazin-4-ylcarbonyl]piperidine as a solid (0.82 g) mpt 239-240° C.; NMR (CDCl3) 1.75-2.0 (m, 5H), 2.5 (m, 2H), 3.45-3.8 (m, 10H), 6.3 (m, 1H), 7.65 (m, 4H), 8.2 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].C(Cl)(Cl)(Cl)Cl.[C:17](Cl)(=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:26])[C:5]([OH:7])=[O:6]
Reactant: CCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1Cl

Procedure:
Four point five grams of 3-chloro-4-hydroxybenzoic acid were dispersed in a mixed solvent of 30 ml of carbon tetrachloride and 5 ml of pyridine and then heated. 3.7 g of nonanic acid chloride was dropped into the mixture with refluxing. After heating 3 hours the solvent was removed from the mixture. After decomposing unreacted nonanic acid chloride by adding a small amount of water, the residue was washed with methanol to obtain 3-chloro-4-octylcarbonyloxybenzoic acid (AE). After dispersing the compound (AE) into 20 ml of carbon tetrachloride, (AE) was reacted with 5 ml of thionyl chloride with refluxing for 3 hours. 6.5 g of 3-chloro-4-octylcarbonyloxybenzoic acid chloride (AF) was obtained after removing solvent.
Reaction SMILES: Br[C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[C:4]([CH2:8]CN)[CH:5]=[CH:6][CH:7]=1.[Cu]C#[N:24].O.C[N:27]1CC[CH2:29][C:28]1=O>>[NH2:27][CH2:28][CH2:29][C:6]1[CH:7]=[CH:2][C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][N:13]=2)=[C:4]([CH:5]=1)[C:8]#[N:24]
Reactant: NCCc1cccc(Br)c1Oc1ccc(C(F)(F)F)cn1
Reactant: N#C[Cu]
Reactant: CN1CCCC1=O
Solvent: O
Product: N#Cc1cc(CCN)ccc1Oc1ccc(C(F)(F)F)cn1

Procedure:
A mixture of 2-[3-bromo-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethylamine (950 mg, 2.059 mmol) and copper(I)cyanide (239.78 mg, 2.677 mmol, 1.3 eq) were suspended in N-methylpyrrolidone (2.1 ml) was irradiated in microwave Biotage Initiator at 200° C. for 20 min. After cooling, water (20 ml) was added and extraction with EtOAc (3×15 ml) followed. Organic layers were combined, dried over Na2SO4/MgSO4, filtered off and evaporated in vacuo to give crude 5-(2-amino-ethyl)-2-(5-trifluoromethyl-pyridin-2-yloxy)-benzonitrile. Crude product was put on a previously conditioned SCX column (5 g). The column was washed with MeOH (2×10 ml) and then with 2N NH3/MeOH (2×10 ml) to retrieve the product 5-(2-amino-ethyl)-2-(5-trifluoromethyl-pyridin-2-yloxy)-benzonitrile (245 mg, 0.797 mmol, yield=38%, purity=91%). [M+H]=308.23 H NMR (300 MHz, CDCl3) δ/ppm 2.79 (br. s., 2H), 2.94-3.07 (m, 2H), 7.21 (br. s., 2H), 7.49 (d, J=8.9 Hz, 1H), 7.54 (br. s., 1H), 7.90-8.05 (m, 1H), 8.38 (br. s., 1H)
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([Cl:18])[CH:12]=1>CC(C)=O>[Cl:18][C:13]1[CH:12]=[C:11]([NH:10][C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)[CH:16]=[CH:15][C:14]=1[OH:17]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CC(C)=O
Product: Oc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1Cl
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Cyanuric chloride (12.95 g, 70.0 mmol) was dissolved in acetone (200 mL), the solution was cooled to 0-5° C. with an ice bath, and 4-amino-2-chlorophenol (10.09 g, 70.0 mmol) in acetone (100 mL) was added. The mixture was stirred at 0-5° C. for 1 hour under nitrogen. The reaction mixture was extracted three times using dichloromethane; the combined organic layer were washed with brine and dried over sodium sulfate. The sample was concentrated in vacuo, and the resulting solid was dried overnight under vacuum to yield E6 (20.2 g, 99%); mp 180° C.; HPLC: Inertsil ODS 3V C18, 40:30:30 v:v:v [KH2PO4 (0.01 M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 11.6 min, 99.4% purity; MS (TOF ES+) m/z 293 (97.5), 291 (M+H, 100).