Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][N:8]([C:14](=[O:22])[CH:15]([CH3:21])[CH2:16][S:17]C(=O)C)[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6](=[O:23])[CH2:7][N:8]([C:14](=[O:22])[CH:15]([CH3:21])[CH2:16][SH:17])[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Solvent: CO
Product: CC(CS)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
Into a solution containing 50 g (0.14 mol) of N-(3-acetylthio-2-methylpropanoyl)-N-cyclopentylglycine t-butyl ester in 700 ml of methanol was bubbled nitrogen gas for 10 minutes followed by ammonia gas for 30 minutes. After 30 minutes the mixture was concentrated in vacuo and the residue taken up in ethyl acetate. It was washed once with 3% aqueous HCl and once with water, dried over MgSO4, filtered, and concentrated in vacuo to yield an oily product. Purification via HPLC [15% ethyl acetate in hexanes] afforded 30 g (70%) of N-(3-mercapto-2-methyl-propanoyl)-N-cyclopentylglycine t-butyl ester as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3][CH2:2]1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:5][CH2:6]1)=[O:36])[CH3:39]
Reactant: O=C(NCC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-4-ylmethyl)-amide (example A144) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])([O-])=O.[C:18]1([O-:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Na+].Cl>CN(C)C=O>[O:24]([C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [O-]c1ccccc1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C(=O)OC
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccccc2)cc1C(=O)OC

Procedure:
0.1 Mole of dimethyl 4-nitrophthalate and 0.1 mole of sodium phenolate were reacted with each other in a solvent of dimethylformamide at 100° C. over a 3-hour period under a stream of nitrogen. After being allowed to stand at room temperature and thereby cooled, the reaction mixture was poured into a dilute aqueous solution of hydrochloric acid, and extracted with ethyl acetate. The solvent was distilled away from the extract to yield dimethyl 4-phenoxyphthalate. Then, dimethyl 4-phenoxyphthalate thus-obtained was refluxed in a mixture of ethanol and an aqueous solution of potassium hydroxide to result in conversion into 4-phenoxyphthalic acid. Thereafter, the acid underwent reaction in an acetic acid/acetic anhydride mixture at a temperature of 100° C., and the solvent was distilled away from the reaction solution to yield 4-phenoxyphthalic anhydride. Subsequently, equimolar amounts of 4-phenoxyphthalic anhydride. Subsequently, equimolar amounts of 4-phenoxyphthalic anhydride and m-diethylaminophenol were refluxed in toluene to yield a 2-(2-hydroxy-4-diethylaminobenzoyl)-4- or -5-aryloxybenzoic acid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[NH2:18]>>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[S:10]([NH:18][C:17]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:15]([F:14])[CH:16]=1)(=[O:12])=[O:11]
Reactant: COc1ccc(N)cc1F
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1F
Product: COc1ccc(NS(=O)(=O)c2ccc(F)c(F)c2F)cc1F

Procedure:
The title compound was prepared in a manner similar to that described in Example 1, by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with 2,3,4-trifluorophenylsulfonyl chloride and replacing p-anisidine with 3-fluoro-4-methoxyaniline. 1H-NMR (CDCl3): δ 7.52 (1H, m), 7.00 (1H, m), 6.93 (1H, m), 6.80 (2H, m), 6.70 (1H, br s), 3.80 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][C:9]=2[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1.OP([O-])([O-])=O.[K+].[K+].[F:23][C:24]([F:30])([F:29])S(Cl)(=O)=O>CC#N.C1C=NC2C3N=CC=CC=3C=CC=2C=1.C1C=NC2C3N=CC=CC=3C=CC=2C=1.C1C=NC2C3N=CC=CC=3C=CC=2C=1.O.[Cl-].[Cl-].[Ru+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:24]([F:30])([F:29])[F:23])[NH:10][C:9]=2[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)c1[nH]ccc1-c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: [Ru+2]
Agent: O=P([O-])([O-])O
Agent: [Cl-]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1[nH]c(C(F)(F)F)cc1-c1ccc(Cl)cc1
Reaction time: 24 h
Yield: 104.9 %

Procedure:
In 6 separate tubes, 3-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid (1 g, 4.51 mmol) and K2HPO4 (2.36 g, 13.54 mmol) were combined in dry MeCN (40 mL) and degassed with Ar for 10 min. Dichlorotris(1,10-phenanthroline)ruthenium(II) hydrate (0.130 g, 0.180 mmol) was added, followed by trifluoromethanesulfonyl chloride (0.53 mL, 4.96 mmol) and the suspension was irradiated with a fluorescent light bulb (E27-32W, 4000K, 65 mA) at 40° C. for 20 h. More trifluoromethanesulfonyl chloride (0.24 mL, 2.250 mmol) was added and the irradiation was continued for 24 h. More trifluoromethanesulfonyl chloride (0.24 mL, 2.250 mmol) was added and the irradiation was continued for 48 h. More trifluoromethanesulfonyl chloride (0.24 mL, 2.250 mmol) was added and the irradiation was continued for 72 h. More degassed dry MeCN (5-10 mL per vial) was added to fill up the vials and more trifluoromethanesulfonyl chloride (0.5 mL, 4.69 mmol) was added. The irradiation was continued for 20 h. More trifluoromethanesulfonyl chloride (0.5 mL, 4.69 mmol) was added and the irradiation was continued for 24 h. The reaction mixtures were combined and filtered over a short plug of silica (eluent EtOAc). The filtrate was concentrated in vacuo and stirred with i-Pr2O (100 mL) to give a brown suspension. The solids were filtered off and the filtrate was concentrated in vacuo. The residue was absorbed on hydromatrix and purified using column chromatography (silica, gradient heptane/EtOAc 2:1−>1:2) to give a brown oil which solidified upon standing. The solid was treated with MeCN (5 mL), filtered off and washed with MeCN (3×5 mL) to give the desired product (1.37 g, 17%) as a white solid. The mother liquor was concentrated in vacuo and the residue was triturated with DCM to give the starting material (156 mg, 2%) as a light yellow solid. The mother liquor (4.9 g) was absorbed on hydromatrix and purified using column chromatography (silica, gradient heptane/EtOAc 7:3−>2:3) to give impure fractions which were combined and crystallised from MeCN. The product was filtered off and washed with a mixture of heptane and MeCN (˜1:1, 2×3 mL) and dried to give another batch of the desired product (468 mg, 6%) as a white solid. The mother liquor was concentrated in vacuo to give the desired product (1.23 g, 78% pure) as a brown oil. From the column more impure product was retrieved to give the title compound (1.86 g, 51% pure) as a brown oil.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][C:10]2[C:12]([N+:18]([O-:20])=[O:19])=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:9]=2[O:8][CH2:7]1)=[O:5])C>C(O)C.[OH-].[Na+]>[CH3:17][O:16][C:15]1[C:9]2[O:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][C:10]=2[C:12]([N+:18]([O-:20])=[O:19])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C1COc2c(OC)ccc([N+](=O)[O-])c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c2c1OCC(C(=O)O)C2
Yield: 92.2 %

Procedure:
A mixture of 8-methoxy-5-nitro-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid ethyl ester (5.8 g, 21 mmol) in ethanol (150 mL) and 2 M NaOH (15 mL) was heated to reflux for 30 min. The solvent was evaporated in vacuo the residue dissolved in water. Acidification to pH 2 and extraction with ethyl acetate followed by evaporation of the solvent in vacuo gave 4.9 g (94% yield) of the title compound: mp 181-183° C.; EIMS (70 eV) m/z (relative intensity) 253 (55, M+).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[N:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[N:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:26]([F:29])([F:27])[F:28])[CH:3]=1
Reactant: CCOC(=O)c1cnn(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(n2ncc(C(=O)O)n2)CC1
Reaction time: 8 h
Yield: 85.2 %

Procedure:
Ethyl 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-2H-1,2,3-triazole-4-carboxylate (0.35 g, 0.82 mmol) (i.e. the product of Example 32, Step B) was dissolved in a mixture of methanol (5 mL) and tetrahydrofuran (2 mL). A 1 N aqueous solution of sodium hydroxide (1.6 mL, 1.6 mmol) was added to the reaction mixture and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in water. The aqueous layer was washed with diethyl ether and the aqueous layer was acidified with concentrated hydrochloric acid to pH 1, and extracted with dichloromethane and then chloroform. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford 0.27 g of the title compound as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH:17]([C:20]1[CH:24]=[C:23]([NH2:25])[NH:22][N:21]=1)([CH3:19])[CH3:18].CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+].N#N>C1(C)C=CC=CC=1.[Cu]I>[CH:17]([C:20]1[CH:24]=[C:23]([NH2:25])[N:22]([C:2]2[CH:16]=[CH:15][CH:14]=[C:4]([O:5][CH2:6][CH2:7][N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH:3]=2)[N:21]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1cc(N)[nH]n1
Reactant: Ic1cccc(OCCN2CCOCC2)c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: N#N
Solvent: Cc1ccccc1
Product: CC(C)c1cc(N)n(-c2cccc(OCCN3CCOCC3)c2)n1
Temperature: 25 °C

Procedure:
To a solution of 4-(2-(3-iodophenoxyl)ethyl)morpholine (1.0 g, 2.9 mmol) in anhydrous toluene (20 mL) was added 3-isopropyl-1H-pyrazol-5-amine (397 mg, 3.17 mmol) followed by (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (227 μL, 1.44 mmol) and potassium carbonate (1.99 g, 14.4 mmol). The mixture was purged with N2, copper(I) iodide (82 mg, 0.43 mmol) was added and the reaction mixture was heated at reflux under N2 for 64 hr. The resulting mixture was cooled to RT and was partitioned between EtOAc and water (100 mL). The organic layer was separated and washed with brine (2×100 mL) and was then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, 0-20% MeOH in DCM, gradient elution) to afford the title compound, Intermediate A13, as a brown oil (325 mg, 33%); Rt 1.66 min (Method 2, basic); m/z 329 (M+H)+ (ES+).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1(=[O:17])[NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[C:1]([CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1CCCCCN1
Product: O=C1NCCCCC1C(=O)c1ccccc1
Yield: 95 %

Procedure:
The title compound is prepared in a yield of 95% from benzoyl chloride and caprolactam as in Example 1. The purity of the product is 98%.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[CH3:23])[C:6]=2[CH:5]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:3]=1.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[C:14]=3[CH3:23])[C:6]=2[CH:5]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:3]=1
Reactant: Cc1c(Cn2c(C)nc3c(Br)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Reactant: OB(O)c1ccco1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: Cc1c(Cn2c(C)nc3c(-c4ccco4)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Yield: 24.43 %

Procedure:
A mixture of 4-bromo-2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole, prepared as described in Example 62 (200 mg, 0.427 mmol), 2-furanyl-boronic acid (71.7 mg, 0.641 mmol), PdCl2(dppf)-CH2Cl2 adduct (34.9 mg, 0.043 mmol) and sodium carbonate (91 mg, 0.854 mmol) in 1,2-Dimethoxyethane (DME) (2.5 mL) and Water (0.5 mL) was irradiated in a microwave reactor for 1 h at 100° C. The mixture was poured into water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by RP-HPLC (Gilson, 25-65% Acetonitrile in water plus 0.1% TFA) to give the desired product (48.5 mg, 0.104 mmol, 24.43% yield) as a white powder (separation from impurity was difficult. The head of the peak was discarded decreasing the overall yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.51-7.63 (m, 3H), 7.42 (d, J=2.02 Hz, 1H), 7.12 (t, J=7.83 Hz, 1H), 6.60 (dd, J=3.28, 1.77 Hz, 1H), 6.51 (d, J=7.83 Hz, 1H), 6.49 (d, J=2.02 Hz, 1H), 5.28 (s, 2H), 3.80-3.94 (m, 4H), 3.12-3.22 (m, 4H), 2.56 (s, 3H), 2.53 (s, 3H). MS (ES+) m/e 456.0 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C@H:4]([OH:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC.C(OCC)(=O)C.O1CCCC1>[CH2:14]([O:13][C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[CH3:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: C=CCCCCCC[C@H](C)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCCCCCC[C@H](C)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a suspension of 3.2 g (133 mmol) sodium hydride (freed from paraffin) in 105 ml ice cold abs. tetrahydrofuran was added 6.2 g (39.5 mmol) (S)-dec-9-ene-2-ol under argon. After stirring for 2 h, 470 mg (1.3 mmol) tetra-n-butyl ammonium iodide were added, followed by dropwise addition of 13.5 g (9.4 ml, 78.9 mmol) benzyl bromide, while stirring was continued for 12 h. Subsequently, 50 ml saturated aqueous ammonium chloride solution were added at 0° C. followed by 50 ml hexane. The aqueous layer was separated and extracted four times with 100 ml of a 1:4 mixture of ethyl acetate/hexane. The combined organic layers were dried over magnesium sulphate and concentrated in vacuo. Flash chromatography (5% ethyl acetate in hexane furnished 9.7 g (39.4 mmol, 100%) (S)-2-benzyloxydec-9-ene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4O[CH:17]=[N:18][N:19]=4)[S:8][C:7]=3[C:6]=2[CH:20]=1.[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=1[NH2:24].C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:24]([C:23]5[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]=5[Cl:21])[CH:17]=[N:18][N:19]=4)[S:8][C:7]=3[C:6]=2[CH:20]=1
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: Brc1ccc2c(c1)-c1sc(-c3nnco3)cc1CCO2
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1ccc(-n2cnnc2-c2cc3c(s2)-c2cc(Br)ccc2OCC3)c(Cl)c1
Temperature: 160 °C
Yield: 45.9 %

Procedure:
A microwave tube charged with 2-(9-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-[1,3,4]oxadiazole (200 mg; 0.57 mmol), 2,4-dichloroaniline (139 mg; 0.86 mmol), TFA (64 μl; 0.86 mmol) and toluene (1.5 ml) was heated in a microwave at 160° C. for 30 min. The reaction mixture was basified with DIPEA (0.2 ml), volatiles removed in vacuo and the residue purified by prep. LCMS to give 532 as a pale yellow solid (129 mg; 46%). δH (400 MHz, CDCl3) 3.14 (t, J=5.2, 2H), 4.29 (t, J=5.2, 2H), 6.89-6.92 (m, 2H), 7.25-7.28 (m, 1H), 7.42 (d, J=8.4, 1H), 7.52 (dd, J=8.4 and 2.4, 1H), 7.66 (d, J=2.4, 1H), 7.71 (d, J=2.0, 1H), 8.22 (s, 1H). [M+H]+: 493
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[C:16](=O)[C:15]3[C:14]([C:18]([O:20]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][CH:8]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:5][CH:4]=[N:3]1.O.[NH2:30][NH2:31]>CO>[CH3:1][N:2]1[C:6]([CH:7]2[C:16]3=[N:30][NH:31][C:18](=[O:20])[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([C:15]=43)[NH:9][CH:8]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:5][CH:4]=[N:3]1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ncnn1C)C(c1ccccc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: Cn1ncnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 30 %

Procedure:
To a solution of ethyl 3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (400 mg, 1.06 mmol) in methanol (8 mL) was added hydrazine monohydrate (0.5 mL), and the mixture was then stirred at 25° C. for 10 hr. The mixture was filtered to obtain a white solid (110 mg, yield 30%). LC-MS (ESI) m/z: 345 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.77 (s, 3H), 4.48-4.49 (d, J=6.4 Hz, 1H), 5.16-5.19 (d, J=6.4 Hz, 1H), 7.40-7.42 (m, 2H), 7.54-7.58 (t, 1H), 7.74 (s, 1H), 12.23 (s, 1H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=O)[NH:16][N:15]=2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[Cl:3][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([C:11]2[CH:12]=[N:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)=[N:15][N:16]=1
Reactant: COc1ccc(-c2n[nH]c(=O)c3ccccc23)cn1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2nnc(Cl)c3ccccc23)cn1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
932 μl (10 mmol) of phosphorus oxychloride was added to a pyridine solution (5 ml) of 507 mg (2 mmol) of 4-(6-methoxypyridin-3-yl)-2H-phthalazin-1-on, and the reaction liquid was stirred at 120° C. for 30 minutes. This was concentrated under reduced pressure, aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 300 mg (yield: 55%) of 1-chloro-4-(6-methoxypyridin-3-yl)-phthalazine as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([CH:22]=O)[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:24]OC(C)(C)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:22]([C@H:19]1[CH2:20][CH2:21][C@H:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[CH2:17][CH2:18]1)=[CH2:24]
Reactant: COC(C)(C)C
Reactant: O=C[C@H]1CC[C@H](C#Cc2ccc(-c3ccc(F)cc3)cc2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=C[C@H]1CC[C@H](C#Cc2ccc(-c3ccc(F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.73 g of potassium t-butylate was added to a suspension of 2.3 g of methyltriphenylphosphonium bromide in 25 ml of t-butyl methyl ether in a nitrogen atmosphere and the mixture was stirred at room temperature for 0.5 hour. Then, a solution of 0.8 g of trans-4-[(4'-fluoro-4-biphenylyl)ethynyl]cyclohexanecarboxaldehyde in 25 ml of t-butyl methyl ether was added dropwise at 0° C. and the reaction mixture was stirred at 0° C. for a further 0.5 hour and at room temperature for 2.5 hours, thereafter washed with 50 ml of saturated sodium hydrogen carbonate solution and with 50 ml of saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was chromatographed on silica gel with hexane. The 4-[(trans-4-vinylcyclohexyl)ethynyl]-4'-fluorobiphenyl obtained was purified by recrystallization from hexane; m.p. (C-N) 133.9° C., cI.p. (N-I) 170° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31]O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.CCOC(C)=O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:31][CH:28]3[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:26][CH2:27]3)=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
A solution of 4′-(methylsulfonyl)-4-biphenylol (0.15 g, 0.60 mmol), N-Boc-4-piperidinemethanol (0.14 g, 0.60 mmol) and Ph3P (0.16 g, 0.66 mmol) in THF (4 mL) was cooled to −20° C. Diisopropyl azodicarboxylate (0.13 g, 94%, 0.60 mmol) in THF (1 mL) was added dropwise. The reaction mixture was kept between −20° C. and 0° C. for 3 h, then allowed to warm up to ambient temperature, and stirred at ambient temperature overnight. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a yellow oil. The crude product was purified by chromatography on a silica gel column eluted with 40% EtOAc/hexane to give 0.20 g (74%) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.97 (d, 2H, J=7.6 Hz), 7.83 (d, 2H, J=7.3 Hz), 7.64 (d, 2H, J=7.6 Hz), 7.03 (d, 2H, J=7.8 Hz), 4.15-4.05 (m, 2H), 3.90 (d, 2H, J=6.4 Hz), 3.13 (s, 3H), 2.90-2.70 (bs, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 446 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[NH:8][C:7](=[O:14])[C:6]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH3:4].[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38].C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([C:33]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:31]([F:30])[CH:32]=2)[C:7](=[O:14])[C:6]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: COc1ccc(B(O)O)cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC)c(F)c2)c2ncnn12
Reaction time: 16 h
Yield: 117.9 %

Procedure:
To a suspension (15 mL) of 4′-[(7-butyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), (3-fluoro-4-methoxyphenyl)boronic acid (0.44 g), triethylamine (0.5 mL), pyridine (1 mL) and molecular sieves 4A (1 g) in dichloromethane was added copper(II) acetate (0.47 g), and the mixture was stirred for 16 hr. The reaction mixture was diluted with ethyl acetate, insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.78 g, 100%).