Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1.[NH2:19][C:20]1[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=1[C:22]([NH:24][CH2:25][CH:26]1[CH2:28][CH2:27]1)=[O:23].CCN(CC)CC>CC(O)C>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[N:3]=[C:2]2[NH:19][C:20]1[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=1[C:22]([NH:24][CH2:25][CH:26]1[CH2:28][CH2:27]1)=[O:23]
Reactant: Clc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Reactant: Nc1ccccc1C(=O)NCC1CC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=C(NCC1CC1)c1ccccc1Nc1nc(-c2cccnc2)nc2ccc(Cl)cc12
Temperature: 25 °C

Procedure:
A 100 mL round bottom flask was charged with 4,6-dichloro-2-(pyridin-3-yl)quinazoline (synthesized as described in Scheme 1 and 4, substituting 5-chloro-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid) (150 mg, 0.54 mmol) and 2-amino-N-(cyclopropylmethyl)benzamide) (310 mg, 1.63 mmol) and anhydrous i-PrOH (20 mL) was added and refluxed for 3 h. The reaction mixture was cooled to room temperature and Et3N (3 eq) was added. The solvent was removed in vacuo. To the crude product was added a water-methanol mixture (5:1, 50 mL), and then sonicated for 5 min. The solidified compound was collected by filtration, and the solid was recrystallized from hot methanol and washed with water. The product was dried at 50° C. to give 2-(6-chloro-2-(pyridin-3-yl)quinazolin-4-ylamino)-N-(cyclopropylmethyl)benzamide as a colorless cotton (220 mg, 94%). The structure was confirmed by NMR and elemental analysis. 1H NMR (Bruker 300 MHz, DMSO-d6) ppm 0.20-0.98 (m, 5H), 3.07-3.21 (m, 2H), 7.24-8.26 (m, 7H), 8.68-9.55 (m, 5H), 12.22 (s, 1H). CHN Calcd. C, 67.05; H, 4.69; N, 16.29. Found C, 67.15; H, 4.89; N, 16.25
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH:9]=[O:10].[CH3:11][Mg]Cl.Cl.[Mg]>C1COCC1.O>[CH3:11][CH:9]([OH:10])[CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: C[Mg]Cl
Reactant: O=CCCc1ccccn1
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)CCc1ccccn1
Reaction time: 1 h

Procedure:
Dimethyl sulphoxide (3.3 ml) was added dropwise to a solution of oxalyl chloride (3.9 ml) in dichloromethane (25 ml) at -78° under nitrogen. After gas evolution had ceased (5 min) a solution of 2-pyridinepropanol (4.0 g) in dichloromethane (20 ml) was added over 5 min and the solution stirred at -78° for 20 min. Triethylamine (5 ml) was added dropwise to the solution, then the resulting dark green mixture warmed to 20° and washed with 2M sodium carbonate solution (20 ml). The organic phase was dried and evaporated in vacuo to give 2-pyridinepropanal. This aldehyde was immediately dissolved in THF (30 ml) and added dropwise to a 3M solution of methylmagnesium chloride in THF (20 ml) at 0°-5° under nitrogen. After 1 h, water (10 ml) was cautiously added followed by sufficient 2M hydrochloric acid to dissolve all the magnesium residues (resulting pH~7 ). The solution was extracted with dichloromethane (3×30 ml) and the organic extracts dried and evaporated in vacuo to a dark oil. Kugelrohr bulb to bulb distillation (b.p. 130°-135°/0.7 mm) afforded the title compound as a pale yellow oil (0.91 g), t.l.c. ethyl acetate Rf 0.17.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([C:7]1[CH:8]=[C:9]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[CH:10]=[CH:11][C:12]([NH:14][NH2:15])=[O:13])([CH3:6])[CH3:5].[C:24](=S)=[S:25]>C(O)C>[CH3:21][C:20]([C:17]1[CH:16]=[C:9]([CH:10]=[CH:11][C:12]2[O:13][C:24](=[S:25])[NH:15][N:14]=2)[CH:8]=[C:7]([C:4]([CH3:3])([CH3:5])[CH3:6])[C:18]=1[OH:19])([CH3:23])[CH3:22]
Reactant: S=C=S
Reactant: CC(C)(C)c1cc(C=CC(=O)NN)cc(C(C)(C)C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1cc(C=Cc2n[nH]c(=S)o2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Potassium hydroxide (0.5 g, 0.0096 mole) is added in one portion to a stirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxycinnamic acid hydrazide (2.8 g, 0.0096 mole) and carbon disulfide (1.7 g, 0.022 mole) in absolute ethanol (15.0 ml). The resulting mixture is stirred 1.5 hours at 0° C. before heating to reflux for four hours. The solution is cooled and the solvent is removed in vacuo. The residue is dissolved in water (50 ml) and washed with ether (20 ml). The aqueous layer is made acidic with aqueous 2M HCl and the product extracted with a 1:1 mixture of ethyl acetate/ether. The combined organic extracts are washed with saturated aqueous NaCl and dried over MgSO4. Filtration and concentration gives a solid which is recrystallized from ethyl acetate/hexane to give 1.4 g (3.2 g theor., 44%) desired product, mp 209.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]([CH3:26])=[CH2:25])[C:5]2=[CH:4][CH:3]=1.O.[CH:29]1(B(O)O)[CH2:31][CH2:30]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.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>[Cl:22][C:18]1[CH:17]=[C:16]([CH:15]2[CH2:14][C:13](=[O:23])[NH:12][CH:11]([C:24]([CH3:26])=[CH2:25])[C:10]32[C:5]2[C:6](=[CH:7][C:2]([CH:29]4[CH2:31][CH2:30]4)=[CH:3][CH:4]=2)[NH:8][C:9]3=[O:27])[CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)C1CC1
Reactant: C=C(C)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(C3CC3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
Under nitrogen atmosphere, to a solution of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxyl acid tert-butyl ester (0.050 g) prepared in Example 172b in toluene (5 mL) was added water (0.1 mL), cyclopropyl boronic acid (0.020 g, 0.23 mmol), K3PO4 (0.098 g, 0.46 mmol), and Pd(PPh3)4 (0.018 g, 0.016 mmol). The mixture was irradiated at 130° C. by microwave for 0.5 h. Then cooled to room temperature and filtered through a short pad of silica gel, the silica gel was washed with ethyl acetate. The filtrate was concentrated. To the residue was added trifluoroacetic acid (5 mL). The solution was stirred at room temperature for 0.5 h, then partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with NaHCO3 aqueous solution, dried over MgSO4 and concentrated. The residue was purified with Prep.LC to give title compound as a white solid (Yield: 8 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:46]1N=N[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.NC1C=CC=CC=1>CN(C=O)C>[CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)Nc3ccccc3)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (30 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and aniline (8.21 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (17.2 mg, 49%). LC-MS m/z 583 (M+H)+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[C:3]([C:12]#N)=[CH:2]1.[PH2]([O-])=[O:15].[Na+].O.N1C=CC=CC=1>C(O)(=O)C.[Ni]>[CH:12]([C:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:1][CH:2]=1)=[O:15]
Reactant: O=[PH2][O-]
Reactant: N#Cc1c[nH]c2ccccc2c1=O
Agent: [Ni]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1c[nH]c2ccccc2c1=O
Temperature: 60 °C

Procedure:
The 4-(1H)-quinolone-3-nitrile (12 g) and sodium hypophosphite (16.12 g) were dissolved in a mixture of acetic acid:water:pyridine=125 ml: 125 ml:250 ml and 4 g of Raney Nickel (W2 grade) added (Backeberg and Staskim, J.C.S. 1962, 3691). The reaction mixture was heated at 60° C. for four hours, then the hot suspension was filtered and the catalyst cake washed with warm ethanol into the filtrates. The combined filtrates and washings were evaporated to one-third of the original volume and on equal volume of water added. The precipitated solid was filtered off, washed with water and dried to give the required 3-formyl compound as a light-brown solid, m.p. 268°-270° C. (3-formyl-4(1H)-quinolone).
Reaction SMILES: [CH2:1]([C@H:8]1[C@@H:12]([CH2:13][O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[O:11][C:10](=[O:27])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([NH:32][C:33]([C@@H:35]1[CH2:44][C@H:43]2[C@H:38]([CH2:39][CH2:40][CH2:41][CH2:42]2)[CH2:37][NH:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C.Cl>[N+:24]([C:21]1[CH:20]=[CH:19][C:18]([S:15]([OH:17])(=[O:14])=[O:16])=[CH:23][CH:22]=1)([O-:26])=[O:25].[CH2:1]([C@H:8]1[C@@H:12]([CH2:13][N:36]2[C@H:35]([C:33]([NH:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:44][C@H:43]3[C@H:38]([CH2:39][CH2:40][CH2:41][CH2:42]3)[CH2:37]2)[O:11][C:10](=[O:27])[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Reactant: O=C1N[C@@H](Cc2ccccc2)[C@@H](COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@H]1OC(=O)N[C@H]1Cc1ccccc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)O)cc1
Temperature: 80 °C
Yield: 88.4 %

Procedure:
A suspension of 24.69 g of p-nitrobenzenesulphonic acid (4S, 5S)-4-benzyl-2-oxo-oxazolidin-5-ylmethyl ester (Example 12), 15.0 g of N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide and 10.0 g of sodium carbonate in 76 ml of 4-methyl-2-pentanone is heated under reflux for 10 hours while stirring. The suspension is cooled to 80° C., diluted with 176 ml of 4-methyl-2-pentanone and 54 ml of 3N hydrochloric acid, cooled to 40° C. and filtered. The residue is washed with water and 4-methyl-2-pentanone and dried to give 35.1 g (88%) of (3S,4aS,8aS)-2-[(4S,5R)-4-benzyl-2-oxo-oxazolidin-5-ylmethyl]-N-tert.butyl-decahydro-isoquinoline-3-carboxamide p-nitrobenzenesulphonate, [α]D20 =-31.2° (1% in DMF).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[C:13]([CH:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14].CC(O)=O.[BH3-]C#N.[Na+]>CO>[C:13]([CH:17]1[CH2:18][CH2:19][CH:20]([NH:23][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:12])=[CH:5][CH:6]=2)[CH2:21][CH2:22]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNC2CCC(C(C)(C)C)CC2)cc1
Temperature: 25 °C

Procedure:
To a solution of methyl-4-formylbenzoate (73 mmol, 12 g) in 200 mL of MeOH was added 4-tert-butylcyclohexylamine (74 mmol, 13.2 mL) via syringe. The reaction mixture was heated to reflux for 0.75 h, then was cooled in an ice bath. The resulting precipitate was filtered and the filter cake was washed with 2×20 mL of cold MeOH. The solid was dried under reduced pressure, then suspended in 224 mL of MeOH. HOAc (652 mmol, 37.4 mL) was added to the solution, followed by NaBH3CN (42.7 mmol, 2.68 g) in several portions. The reaction mixture was stirred at ambient temperature for 1.5 b, then concentrated under reduced pressure to ca. 25% of the initial volume. 400 mL of EtOAc was added to the solution and the mixture was washed with 3×200 mL of 5% NaHCO3 followed by brine. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 1:1 EtOAc/hexanes to afford the trans isomer as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.00 (d, 2H), 7.40 (d, 2H), 3.92 (s, 3H), 3.88 (s, 2H), 2.40 (m, 1H), 2.01 (m, 2H), 1.79 (m, 2H), 0.95-1.15 (overlapping m, 5H), 0.85 (s, 9H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[C:10]([C:12]2[S:13][C:14]([O:18][CH3:19])=[C:15]([CH3:17])[N:16]=2)[CH:9]=[CH:8][C:6]=1[NH2:7])(=[O:4])=[O:3].[H-].[Na+].Cl[S:23]([C:26]1[S:30][C:29]2[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:28]=2[C:27]=1[CH3:36])(=[O:25])=[O:24].Cl>CC(N(C)C)=O.C1COCC1>[F:35][C:33]1[CH:32]=[CH:31][C:29]2[S:30][C:26]([S:23]([NH:7][C:6]3[CH:8]=[CH:9][C:10]([C:12]4[S:13][C:14]([O:18][CH3:19])=[C:15]([CH3:17])[N:16]=4)=[CH:11][C:5]=3[S:2]([CH3:1])(=[O:3])=[O:4])(=[O:24])=[O:25])=[C:27]([CH3:36])[C:28]=2[CH:34]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Reactant: COc1sc(-c2ccc(N)c(S(C)(=O)=O)c2)nc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: COc1sc(-c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(S(C)(=O)=O)c2)nc1C
Temperature: -25 °C
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
Under an argon atmosphere, 41 mg of 2-methanesulfonyl-4-(5-methoxy-4-methylthiazol-2-yl)aniline was dissolved into a mixed solution of 3 mL of THF and 3 mL of dimethylacetamide. The solution was cooled to −25° C. and 15 mg of sodium hydride (oily, 60%) was added thereto, followed by 10 minutes of stirring at the same temperature. Further, 44 mg of 2-chlorosulfonyl-5-fluoro-3-methylbenzo[b]thiophene was added and the whole was stirred for 2 hours at the same temperature, followed by termination of the reaction with 1 mol/L hydrochloric acid. After the reaction mixture was warmed to room temperature, the mixture was extracted with ethyl acetate-toluene (2/1) and the organic layer was washed with water and saturated brine, successively. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by evaporation under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to obtain 51 mg of the title compound as light yellow powder.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10]>CO.O.CC(O)=O>[CH2:12]([O:11][C:9]([N:6]1[CH2:5][CH2:4][NH:3][CH:2]([CH3:1])[CH2:7]1)=[O:10])[CH3:13]
Reactant: CC1CNCCN1
Reactant: CCOC(=O)Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCOC(=O)N1CCNC(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methylpiperazine (10.0 g) in MeOH (120 mL), H2O (40 mL) and AcOH was added at −5° C. dropwise during 25 min ethyl chloroformate (10 mL) and the reaction mixture was stirred overnight at RT. Then, H2O (100 mL) was added and the MeOH evaporated in vacuo. The aq. phase was diluted with toluene (70 mL), the layers were separated and the org. layer was washed with water (50 mL). The aq. phase was then basified with NaOH (2M, 80 mL) and extracted with toluene (100 mL). The combined org. phases were washed with brine (50 mL), dried over MgSO4 and evaporated in vacuo to give the desired compound (8.5 g).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[C:10]([C:11](=O)[CH:12]([CH3:14])[CH3:13])=[C:9](Cl)[CH:8]=[CH:7][N:6]=1>C1COCC1>[Cl:4][C:5]1[C:10]2[C:11]([CH:12]([CH3:14])[CH3:13])=[N:2][NH:3][C:9]=2[CH:8]=[CH:7][N:6]=1
Reactant: CC(C)C(=O)c1c(Cl)ccnc1Cl
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1n[nH]c2ccnc(Cl)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
Normal-butyllithium (a 1.6 M solution in hexane, 8.13 mL) was dropwise added to a solution of N,N-diisopropylamine (1.99 mL) in THF (30 mL) at −78° C. under a nitrogen atmosphere, followed by increasing the temperature to 0° C. Then, the solution was cooled to −78° C., and a solution of 2,4-dichloropyridine (1.0 g) in THF (3 mL) wad dropwise added thereto at −78° C., followed by stirring for 1.5 hr. Then, a solution of isobutylaldehyde (1.85 mL) in THF (3 mL) was dropwise added to the reaction solution at −78° C., followed by stirring at the same temperature for 30 min. Then, the reaction solution was poured into ice water and was extracted with ethyl acetate. The organic layer was washed with saturated saline, and the organic layer after the washing was dried over anhydrous sodium sulfate. Then, the solvent was distilled away, and the residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain 1-(2,4-dichloropyridin-3-yl)-2-methylpropan-1-ol (1.48 g, 99%) as a colorless oily substance. A solution of DMSO (0.9 mL) in dichloromethane (5 mL) and a solution of 1-(2,4-dichloropyridin-3-yl)-2-methylpropan-1-ol (1.39 g) in dichloromethane (5 mL) were sequentially added to a solution of oxalyl chloride (0.8 mL) in dichloromethane (30 mL) at −78° C., followed by stirring for 30 min. Then, triethylamine (3.52 mL) was added to the reaction solution at 0° C., followed by stirring for 1 hr. The reaction solution was poured into ice water and was extracted with chloroform. The organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain 1-(2,4-dichloropyridin-3-yl)-2-methylpropan-1-one (1.18 g, 86%) as a colorless oily substance. Hydrazine monohydrate (1.3 mL) was added to a solution of 1-(2,4-dichloropyridin-3-yl)-2-methylpropan-1-one (0.93 g) in THF (13 mL), followed by stirring at room temperature for 12 hr and then at 50° C. for 25 hr. The reaction solvent was distilled away under reduced pressure, and the residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain compound (4a) (0.55 g, 66%) as a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[Br-].[CH2:15]([Zn+])[CH:16]([CH3:18])[CH3:17].C1C[O:23]CC1>>[CH3:15][CH:16]([CH3:18])[CH2:17][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH2:7])=[O:23])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: N#Cc1ccc(Br)c(C(F)(F)F)c1
Reactant: C1CCOC1
Reactant: CC(C)C[Zn+]
Agent: [Br-]
Product: CC(C)Cc1ccc(C(N)=O)cc1C(F)(F)F

Procedure:
To a solution of 4-bromo-3-trifluoromethylbenzonitrile (1.25 g, 5.0 mmol) and isobutylzinc bromide (25 mmol) in THF (50 mL, 25 mmol) under argon was added 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (612 mg, 0.75 mmol) and the reaction heated at reflux for 5 h. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (80 mL) and water (80 mL). A solid formed and was filtered off and discarded. The organic layer was washed with water (80 mL) before it was dried (phase separator) and concentrated in vacuo to give the crude title compound as a black oil. This was used directly in the next step (1.35 g).
Reaction SMILES: CN[C:3]([NH:10][CH3:11])=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:12](N(CC)C(C)C)(C)C.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>C1(C)C=CC=CC=1>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](=[O:25])[C:4](=[CH:3][N:10]([CH3:11])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)C=C(NC)NC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1Cl
Temperature: 25 °C

Procedure:
A mixture of ethyl 3,3-dimethylaminoacrylate (4.68 g, 32.7 mmol) and N,N-diisopropylethylamine (12 mL, 8.9 g, 69 mmol) was stirred at rt and a solution of 2-chlorobenzoyl chloride (5.72 g, 32.7 mmol) in 30 mL of toluene was added over 5 mins.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6](/[CH:8]=[CH:9]\[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]CC)=[O:43])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[N:4]1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([N:3]1[CH:7]=[C:6](/[CH:8]=[CH:9]\[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C\c4cnn(CC)c4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCn1cc(/C=C\c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccc(CC(=O)O)cc4)oc3C)c(OC)c2)cn1
Yield: 89.4 %

Procedure:
A mixture of ethyl {4-[4-({4-[({4-[(Z)-2-(1-ethyl-1H-pyrazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (350 mg), 1N aqueous sodium hydroxide solution (10 mL), tetrahydrofuran (20 mL) and ethanol (20 mL) was heated under reflux for 30 min. After cooling, the reaction mixture was acidified by adding 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the obtained crystal from tetrahydrofuran-hexane gave {4-[4-({4-[({4-[(Z)-2-(1-ethyl-1H-pyrazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as colorless crystals (300 mg, yield 89%). melting point: 146-147° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][OH:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl.O>[CH3:23][S:24]([O:15][CH2:14][CH2:13][C:12]#[C:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCC#CCCO
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCC#CCCOS(C)(=O)=O
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A solution of 3.9 g of 3-hexyn-1,6-diol mono-t-butyl-dimethylsilyl ether in 50 ml of methylene chloride was cooled to -20° C. and treated with 4.18 ml of triethyl amine and then 1.77 ml of methane sulfonyl chloride. After stirring 15 minutes at -20° C. the reaction mixture was diluted with water and extracted twice with 50 ml of methylene chloride. The organic layers were washed with brine, dried over sodium sulfate and evaported in vacuo to give the 3-hexyn-1,6-diol t-butyldimethylsilyl ether methyl sulfonate.