Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11](=O)[C:10]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]3[C:8]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Zn].C(O)(=O)C>[CH2:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:17])[C:9]2[C:10]1=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: O=C1c2ccccc2C(=O)N1c1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1c2ccccc2CN1c1ccccc1
Yield: 76.8 %

Procedure:
A mixture of N-phenylphthalimide (100 g), zinc powder (147 g) and acetic acid (700 ml) is heated under reflux for 5.5 hours with stirring. After cooling, the mixture is filtered and the insoluble solid is washed with hot acetic acid (100 ml). The combined filtrate and washings are concentrated to give crystal (72 g, 78%). Recrystallization from benzene gives colorless scales. Melting point: 166° to 167° C.
Reaction SMILES: [CH2:1]([N+:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]=1[CH3:12])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.[Cl:24][C:25]([Cl:46])([Cl:45])[C:26]1[N:31]=[C:30]([C:32]([Cl:35])([Cl:34])[Cl:33])[N:29]=[C:28]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39](Cl)=[O:40])[N:27]=1.C1(C)C=CC=CC=1>C(N(CC)CC)C>[Cl:35][C:32]([Cl:33])([Cl:34])[C:30]1[N:31]=[C:26]([C:25]([Cl:46])([Cl:24])[Cl:45])[N:27]=[C:28]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39]([CH:12]=[C:4]2[N:3]([CH2:1][CH3:2])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[S:5]2)=[O:40])[N:29]=1
Reactant: CC[n+]1c(C)sc2ccccc21
Reactant: O=C(Cl)c1cccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN1C(=CC(=O)c2cccc(-c3nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n3)c2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Ethyl-2-methyl-benzothiazolium-p-toluenesulfonate (5.0 pbw) and 3-(4,6-bis-trichloromethyl-s-triazin-2-yl) benzoylchloride (7.4 pbw) are successively suspended or dissolved, respectively, in 50 pbw of toluene. The mixture is cooled to 15° C. and, at this temperature, 6.0 pbw of triethylamine are added dropwise with the exclusion of moisture. The mixture discolors towards dark brown and is stirred for 3 hours at room temperature. The precipitate that forms is removed by filtration with suction and washed with cold toluene. The residue is digested in 200 pbw of methanol and stirred for about 60 minutes, filtered again and dried. The product is recrystallized from 2-methoxy-ethanol, giving orange-colored crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].I[CH3:14]>CN(C=O)C>[F:1][C:2]1[CH:9]=[C:6]([CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH3:14])[CH:7]=[O:8]
Reactant: CI
Reactant: COc1cc(C=O)cc(F)c1O
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(F)c1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
To a stirred solution prepared from 100 mL of DMF and 5-fluorovanillin (lit 1.0 g, 5.88 mmol). After 15 minutes, iodomethane was added, and stirring at room temperature continued for 16 hours. The reaction was terminated by the addition of water, the mixture was extracted with hexane (3×100 ML), and solvents were removed in vacuo. Purification by flash chromatography on a column of silica gel using hexane-ethyl acetate (4:1) as eluent afforded a colorless solid (1 g, 93% yield); mp 51–53° C. (Lit17 mp 52–53° C.) 1H-NMR (300 MHz, CDCl3) δ 3.94 (s, 3H), 4.05 (s, 3H), 7.24 (s, 1H), 7.26 (s, 1H), 9.82 (s, 1H).
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=[C:22]2[C:28]3[CH:29]=[C:30]([CH2:33][NH2:34])[CH:31]=[CH:32][C:27]=3[CH:26]=[CH:25][C:24]3[CH:35]=[CH:36][CH:37]=[CH:38][C:23]2=3)[CH2:18][CH2:17]1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:47]=[C:48]([O:52][CH3:53])[C:49]=1[O:50][CH3:51])[C:44](Cl)=[O:45].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:53][O:52][C:48]1[CH:47]=[C:43]([CH:42]=[C:41]([O:40][CH3:39])[C:49]=1[O:50][CH3:51])[C:44]([NH:34][CH2:33][C:30]1[CH:31]=[CH:32][C:27]2[CH:26]=[CH:25][C:24]3[CH:35]=[CH:36][CH:37]=[CH:38][C:23]=3[C:22](=[C:19]3[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]3)[C:28]=2[CH:29]=1)=[O:45]
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccc(CN)cc32)CC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)NCc2ccc3c(c2)C(=C2CCN(C)CC2)c2ccccc2C=C3)cc(OC)c1OC
Reaction time: 0.08 h

Procedure:
To a mixture of 0.50 g (1.26 mmol) of the dihydrochloride salt of 1-methyl-4-(3-aminomethyl-5H-dibenzo[a,d]cycloheptene-5-ylidene)piperidine and 0.25 g (1.08 mmol) 3,4,5-trimethoxybenzoyl chloride in 25 ml of toluene was added 1 ml of 10% aqueous sodium hydroxide. The mixture was shaken vigorously for 5 minutes. The toluene was removed by evaporation under reduced pressure and the residual gum was redissolved in chloroform. This chloroform phase was separated, dried over magnesium sulfate, filtered, and the chloroform was removed by evaporation. The crystalline residue was recrystallized from acetonitrile to give 3,4,5-trimethoxy-N-((5-(1-methyl-4-piperidinylidene)-5H-dibenzo[a,d]cyclohepten-3-yl)methyl)benzamide, mp 200°-202° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C1C=NC(C2C=CC(O)=CC=2)=NC=1)CCCCCCCCCC.[CH2:56]([C:58]1[O:62][C:61]([C:63]([O:65][C:66]2[CH:71]=[CH:70][C:69]([C:72]3[N:77]=[CH:76][C:75]([CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])=[CH:74][N:73]=3)=[CH:68][CH:67]=2)=O)=[CH:60][CH:59]=1)[CH3:57]>C1COCC1>[CH2:78]([C:75]1[CH:74]=[N:73][C:72]([C:69]2[CH:70]=[CH:71][C:66]([O:65][CH2:63][C:61]3[O:62][C:58]([CH2:56][CH3:57])=[CH:59][CH:60]=3)=[CH:67][CH:68]=2)=[N:77][CH:76]=1)[CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88]
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(OC(=O)c3ccc(CC)o3)cc2)nc1
Agent: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCc1cnc(-c2ccc(OCc3ccc(CC)o3)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A fully reacted mixture of equimolar amounts of diethyl azodicarboxylate and triphenylphosphine in THF is admixed with equimolar amounts of 4.9 g of 4-(5-undecyl-pyrimidin-2-yl)phenol and 5-ethyl-furan-2-yl-methanol (prepared by LiAlH4 reduction of methyl 5-ethyl-furan-2-carboxylate, which in turn can be obtained by esterification of 5-ethyl-furan-2-carboxylic acid from Example 1). The mixture is stirred for 24 h at room temperature and then evaporated to dryness under reduced pressure. Purification by chromatography (silica gel, dichloromethane) and recrystallization affords the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:14](=[O:16])[CH3:15])=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([CH3:13])[C:11]=2[CH:12]=1.[CH3:17][Mg]Br>C1COCC1>[CH3:1][O:2][C:3]1[C:4]([C:14]([OH:16])([CH3:17])[CH3:15])=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([CH3:13])[C:11]=2[CH:12]=1
Reactant: C[Mg]Br
Reactant: COc1cc2c(cc1C(C)=O)CCCC2C
Solvent: C1CCOC1
Product: COc1cc2c(cc1C(C)(C)O)CCCC2C
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
1-(3-Methoxy-5-methyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone (5.1 g, 23.37 mmol) was dissolved in 50 mL dry THF under nitrogen atmosphere, and the resulting solution was cooled in an ice bath. Methyl magnesium bromide (11.69 mL, 35.1 mmol in diethyl ether) was added dropwise, and the solution was stirred for one hour at 0° C., then for four hours at room temperature. The reaction mixture was poured into ice water and extracted with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide 5.38 g of 2-(3-methoxy-5-methyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-propan-2-ol as an oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[C:7]([N:9]([CH3:11])[NH2:10])[CH:6]=[CH:5][CH:4]=1.[CH3:14][CH:15]([CH3:19])[C:16](=O)[CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:13][C:2]([F:1])([F:12])[C:3]1[N:8]=[C:7]([N:9]([CH3:11])[N:10]=[C:16]([CH:15]([CH3:19])[CH3:14])[CH3:17])[CH:6]=[CH:5][CH:4]=1
Reactant: CN(N)c1cccc(C(F)(F)F)n1
Reactant: CC(=O)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=NN(C)c1cccc(C(F)(F)F)n1)C(C)C

Procedure:
A solution of 1-[6-trifluoromethylpyrid-2-yl]-1-methyl hydrazine (12.12 g; 0.069 mol), 3-methyl-2-butanone (5.96 g; 0.069 mol) and p-toluenesulphonic acid (0.13 g) in toluene (70 ml) was heated under reflux, with water removal (azeotrope), for 24 h. The solution was concentrated to yield an oil which was purified by flash-chromatography over silica (eluent: 20% diethyl ether in hexane) to yield 3-methyl-2-butanone 1-[6-trifluoromethylpyrid-2-yl]-1-methyl hydrazone as an orange oil (11.6 g; 71%). ##STR22##
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:28])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23](I)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.[Cl:30][C:31]1[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][C:32]=1[OH:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][C:2]1([CH3:29])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:28])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:41][C:32]4[CH:33]=[CH:34][CH:35]=[C:36]([C:37]([F:38])([F:39])[F:40])[C:31]=4[Cl:30])[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1
Reactant: Oc1cccc(C(F)(F)F)c1Cl
Reactant: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(I)cc1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(Oc2cccc(C(F)(F)F)c2Cl)cc1=O
Temperature: 25 °C

Procedure:
A solution of 2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (Intermediate 94, 51.5 mg, 0.10 mmol) in N,N-dimethylformamide (2 mL) at 25° C. was treated with 2-chloro-3-trifluoromethyl-phenol (23.6 mg, 0.12 mmol) and cesium carbonate (65.2 mg, 0.20 mmol). The reaction was stirred at 25° C. over 3 nights. At this time, the reaction was warmed to 80° C. overnight. At this time, the reaction was filtered, rinsed with dimethylsulfoxide (1 mL) and then purified by HPLC chromatography (50-100% acetonitrile/water, C18 Pursuit Agilient, 20×150 mm, 30 ml/min) to afford 2-[4-(2-chloro-3-trifluoromethyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide as a white solid as a mixture of diastereomers (39 mg, 67%); ES+-HRMS m/e calcd for C26H29N5O5F3Cl [M+H+] 584.1882 found 584.1885. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.79-0.95 (m, 6H), 1.24 (s, 3H), 1.29, 1.30 (2×s, 3H), 1.45 (br. s., 1H), 1.69-1.87 (m, 1H), 1.99-2.32 (m, 1H), 3.73 (dd, J=8.4, 5.7 Hz, 1H), 4.00 (dd, J=8.4, 6.2 Hz, 1H), 4.04-4.22 (m, 2H), 4.27-4.43 (m, 1H), 5.53 (dd, J=11.2, 4.2 Hz, 1H), 5.95 (d, J=2.7 Hz, 1H), 6.38 (d, J=2.4 Hz, 1H), 7.59 (s, 1H), 7.70 (t, J=8.2 Hz, 1H), 7.87 (t, J=7.5 Hz, 2H), 8.25 (d, J=2.7 Hz, 1H), 10.85 (s, 1H)
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[N+:11]([O-])([OH:13])=[O:12].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1
Reactant: Cc1n[nH]c2ncccc12
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1n[nH]c2ncc([N+](=O)[O-])cc12
Temperature: 25 °C

Procedure:
3-Methyl-pyrazolo[3,4-b]pyridine (1 mmol, 1 eq.) was suspended into a mixture of 1:1 fuming nitric acid and concentrated sulfuric acid (1 mL:1 mL), and the resultant mixture was heated at 90° C. for 30 minutes. The reaction mixture was then cooled to rt, and poured into a mixture of sodium bicarbonate and ice. The resultant solution was warmed up to rt and extracted with 300 mL of EtOAc. The organic extract was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography to provide 70.2 mg of 3-methyl-5-nitro-pyrazolo[3,4-b]pyridine.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([CH3:11])[CH:5]=1)[CH3:2].[C:12]([N:15]1[CH2:17][CH2:16]1)(=[O:14])[CH3:13]>CO>[C:12]([NH:15][CH2:17][CH2:16][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([CH3:11])[CH:5]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CC1
Reactant: CCNc1ccc(F)c(C)c1
Solvent: CO
Product: CCN(CCNC(C)=O)c1ccc(F)c(C)c1

Procedure:
7.66 g (50 mMol) N-ethyl-4-fluoro-3-methyl-aniline and 4.68 g (55 mMol) N-acetylaziridine are refluxed in 100 ml methanol (abs.) for 15 hours. Then the reaction mixture is evaporated on a rotary evaporator and the residue is digested with diisopropylether. The solid thus obtained is filtered with suction, washed with diisopropylether and dried.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:8]=2[C:9]#[N:10])[CH:6]=1.[CH3:19][N+:20]([CH3:22])=[CH2:21].[I-]>CN(C=O)C>[CH3:19][N:20]([CH2:22][C:6]1[N:5]([C:7]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][C:8]=2[C:9]#[N:10])[CH:4]=[N:3][C:2]=1[CH3:1])[CH3:21]
Reactant: C=[N+](C)C
Reactant: Cc1cn(-c2ccc(C(F)(F)F)cc2C#N)cn1
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc(C(F)(F)F)cc2C#N)c1CN(C)C
Yield: 53 %

Procedure:
As described for example 84b, 2-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzonitrile (+regioisomer) was reacted with Eschenmoser's salt in DMF for 16 h at 90° C. Evaporation of the solvent, aqueous workup and chromatography afforded the title compound as a yellow oil that was sufficiently pure to be used in the next step (yield: 53%). MS: m/e=309.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2)[N:3]=1.[H][H]>C(O)C.[C].[Pd]>[CH3:19][O:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[CH:2][CH:11]=[C:10]2[CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16]
Reactant: [H][H]
Reactant: COc1ccc2nc(Cl)cc(CCNC(C)=O)c2c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2nccc(CCNC(C)=O)c2c1
Yield: 68.7 %

Procedure:
To a solution of N-[2-(2-chloro-6-methoxyquinolin-4-yl)ethyl]acetamide (3.65 g, 13.1 mmol) in ethanol (100 ml) was added 5% palladium carbon (containing water (50%), 9.0 g). The reaction mixture was subjected to catalytic reduction under an atmosphere of hydrogen at atmospheric pressure. After a theoretical amount of hydrogen was added, the palladium carbon was filtered off. The solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (ethyl acetate:methanol=95:5) to obtain the title compound (2.2 g, 69%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[N:17]=[C:16]([N:28]3[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH3:36])[CH2:30][CH2:29]3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[Cl:27][C:22]1[CH:21]=[C:20]([C:18]2[CH:19]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:15]=[C:16]([N:28]3[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][CH3:36])[CH2:32][CH2:33]3)[N:17]=2)[CH:25]=[CH:24][C:23]=1[F:26]
Reactant: CCCN1CCN(c2nc(-c3ccc(F)c(Cl)c3)cc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCCN1CCN(c2nc(-c3ccc(F)c(Cl)c3)cc(N3CCNCC3)n2)CC1
Reaction time: 2 h

Procedure:
Dissolve 4-[6-(3-chloro-4-fluoro-phenyl)-2-(4-propyl-piperazin-1-yl)-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (2.0 g) in dioxane and then add a 4M solution of HCl in dioxane (15 mL). After the formation of precipitate stir the suspension vigorously for 2 h. Collect the solid and wash with ether and then freebase the material by partitioning between 10% NaOH solution and DCM. Separate the organic layer, dry (Na2SO4) and concentrate to give the title compound as an off-white solid.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[Cl-].COCP(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:35][C:36]([F:47])([F:46])[O:37][C:38]1[CH:45]=[CH:44]C(C=O)=[CH:40][CH:39]=1>O>[F:35][C:36]([F:47])([F:46])[O:37][C:38]1[CH:45]=[CH:44][C:2]([CH:1]=[CH:5][O:4][CH3:3])=[CH:40][CH:39]=1
Reactant: C1CCOC1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: COC[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: O
Product: COC=Cc1ccc(OC(F)(F)F)cc1
Reaction time: 3 h
Yield: 79.7 %

Procedure:
THF (1.8 l) was added to methoxymethyltriphenylphosphine chloride (350 g, 1.02 mol), followed by adding to the mixture, potassium-t-butoxide (114 g, 1.02 mol), stirring the mixture at the same temperature, for 3 hours, dropwise adding to the reaction solution, a 750 ml THF solution of commercially available 4-trifluoromethoxybenzaldehyde (150.0 g, 0.79 mol), stirring the mixture at the same temperature for one hour, further stirring it at room temperature for 3 hours, adding water (1.5 l) to the reaction solution, extracting the resulting product with ethyl acetate, washing the organic layer successively with a saturated, aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, distilling off the solvent, purifying the resulting yellow solution according to column chromatography treatment using heptane/ethyl acetate (3/2) as a developing solvent, on silica gel, and distilling the purified product under reduced pressure, by means of Vigoureux tube, to obtain 1-trifluoromethoxy-4-(2-methoxyvinyl)benzene (138 g, 0.63 mol). (b.p. 91° C. under 9 Torr). Yield: 79.7%.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH2:14][CH2:15][CH2:16][C:10]3=[N:9][C:8]=2[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1.O>[C:1]1([C:7]2[N:12]=[C:11]3[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:14][CH2:15][CH2:16][C:10]3=[N:9][C:8]=2[C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccccc3)nc21
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3c(nc2-c2ccccc2)N(CCCCCCC(=O)O)CCC3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 7-(3-phenyl-2-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (158 mg, 0.345 mmol) in THF (4 ml) and water (1 ml) at RT was treated with LiOH monohydrate (43.5 mg, 1.036 mmol) and stirred at RT for 16 hours. The organic solvent was removed in vacuo and the residue was diluted with water (20 ml). The pH was adjusted to pH4 with aqueous 10% citric acid solution. The mixture was extracted with DCM (×3) and the organic extracts were passed through a phase separating column and concentrated in vacuo. The resulting crude product was purified by chromatography on silica eluting with 0-40% EtOAc/iso-hexane followed by chiral separation using Supercritical Fluid Chromatography to afford the title compound;
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(=O)([O-])[O-].[Cs+].[Cs+].[C:13]([C:15]1([NH:18][C:19]([C@@H:21]2[CH2:25][C@@H:24]([S:26]([C:29]3[CH:34]=[CH:33][C:32](F)=[CH:31][C:30]=3[C:36]([F:39])([F:38])[F:37])(=[O:28])=[O:27])[CH2:23][N:22]2[C:40]2[N:41]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=3)[N:42]=[C:43]([CH3:45])[CH:44]=2)=[O:20])[CH2:17][CH2:16]1)#[N:14].C(OC(C)=O)(C)C>CN(C)C(=O)C>[C:13]([C:15]1([NH:18][C:19]([C@@H:21]2[CH2:25][C@@H:24]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:31][C:30]=3[C:36]([F:37])([F:38])[F:39])(=[O:27])=[O:28])[CH2:23][N:22]2[C:40]2[N:41]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=3)[N:42]=[C:43]([CH3:45])[CH:44]=2)=[O:20])[CH2:16][CH2:17]1)#[N:14]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(-c2ccc(C(F)(F)F)cc2)n1
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CC(=O)OC(C)C
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(OCC(F)(F)F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 40 °C
Reaction time: 5 h
Yield: 41.3 %

Procedure:
2,2,2-Trifluoroethanol (2.2 ul, 29 umol) and cesium carbonate (9 mg, 29 umol) were added to a solution of (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (15 mg, 24 umol; example 267c) in N,N-dimethylacetamide (0.2 ml) under an argon atmosphere. The mixture was stirred for 12 h at ambient temperature and for 5 h at 40° C. Ice water/0.1 N aqueous HCl solution 1/1 and iPrOAc were added and the layers were separated. The aqueous layer was extracted one more time with iPrOAc, the combined organic layers were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a yellow oil which was purified by preparative thin layer chromatography (silica gel, iPrOAc/heptane) to obtain the title compound (7 mg, 9.9 umol; 44%) as colorless oil. MS (ESI): m/z=710.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:19]([O-])([O-])[O:20][CH2:21][CH3:22].C(OC(=O)C)(=O)C>>[F:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([C:6](=[CH:19][O:20][CH2:21][CH3:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC([O-])[O-]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 150 °C
Yield: 94.3 %

Procedure:
A mixture of ethyl α-(2,3,4,5-tetrafluorobenzoyl)acetate (0.7 g), ethyl orthoformate (0.67 g) and acetic anhydride (0.74 g) is heated at 150° C. for 1.5 hour. After the reaction, the volatile material is distilled off at 120° C. under reduced pressure with a water pump to give ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-ethoxyacrylate (0.8 g) as a mixture of cis and trans isomers.
Reaction SMILES: I[C:2]1[CH:20]=[CH:19][C:5]([N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCN(CC)CC>[CH3:21][Si:22]([C:25]#[C:26][C:2]1[CH:20]=[CH:19][C:5]([N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1)([CH3:24])[CH3:23]
Reactant: CCCCCCN(CCCCCC)c1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCCCCN(CCCCCC)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 45 °C
Reaction time: 18 h

Procedure:
4-Iodo-N,N-dihexylaniline (3.150 g, 8.13×10−3 mol), Pd(PPh3)2Cl2 (0.332 g, 4.73×10−4 mol), CuI (0.130 g, 6.83×10−4 mol) and Et3N (20 ml) were added to a 100-ml round-bottom flask. Ar was bubbled into the reaction mixture for 5 min before (trimethylsilyl)acetylene (2.40 ml, 1.70×10−2 mol) was added. The reaction mixture was stirred at 45° C. for 18 h under Ar. After the solvent was removed in vacuo, the residue was chromatographed on silica gel 4:1 hexane:CHCl3 as the eluent. Yield=2.861 g (98% based on 3.150 g of 4-iodo-N,N-dihexylaniline). 1H NMR (250 MHz, CDCl3): δ 7.29 (d, 2H, J=9.0 Hz, Ph), 6.50 (d, 2H, J=9.0 Hz, Ph), 3.24 (t, 4H, J=7.7 Hz, —NCH2—), 1.43-1.65 (m, 4H, —NCH2CH2—), 1.19-1.41 (m, 12H, —CH3—), 0.89 (t, 6H, J=6.5 Hz, —CH3), 0.22 (s, 9H, Si—CH3). CI MS m/z: 358.292 ((M+H)+) (calcd 358.293).