Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1(=O)[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1.[CH2:16](O)C>>[OH:14][C:11]1[CH:12]=[CH:13][C:1]([N:2]2[CH2:7][CH2:6][CH:5]([CH3:16])[CH2:4][CH2:3]2)=[CH:9][CH:10]=1
Reactant: CN1CCCCC1
Reactant: O=C1CCC(=O)CC1
Reactant: CCO
Product: CC1CCN(c2ccc(O)cc2)CC1
Yield: 33.9 %

Procedure:
1.00 g of 1-methylpiperadine and 2.24 g of 1,4-cyclohexanedione were heated with stirring in 15 ml of ethanol at 50° C. to 60° C. and reacted in air for 8 hours. During the reaction, ethanol was added as needed. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure and the resultant was purified by silica gel column chromatography (ethyl acetate:methanol=3:1) and 0.65 g of 1-(4-hydroxyphenyl)-4-methylpiperadine was obtained (yield 33.9%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[O:6][C:17]1[CH:18]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=1[Cl:19]
Reactant: OC(CCCCl)c1cccs1
Reactant: Oc1cc(Cl)ccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClCCCC(Oc1cc(Cl)ccc1Cl)c1cccs1
Temperature: 0 °C
Reaction time: 5 h
Yield: 57.3 %

Procedure:
4-Chloro-1-thiophen-2-yl-butan-1-ol (2.98 g, 15.6 mmol), 2,5-dichlorophenol (2.55 g, 15.6 mmol) and triphenylphosphine (4.91 g,18.7 mmol) were dissolved in anhydrous tetrahydrofuran (80 ml) and the solution cooled to 0° C. Diethyl azodicarboxylate (3.26 g, 18.7 mmol) was added dropwise and the reaction allowed to warm to room temperature, then stirred for 5 hours. The solvent was removed in vacuo and the residue passed down a flash silica chromatography column, eluting with hexane:ethyl acetate (9:1) to give the title compound as a colourless oil (3.0 g, 57%).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[CH2:26](Br)[CH:27]=[CH2:28].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([O:20][CH2:28][CH:27]=[CH2:26])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reaction time: 6.5 h
Yield: 14 %

Procedure:
46 mg of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid was dissolved in N,N-dimethylformamide (0.5 mL), and 21 mg of sodium hydrogen carbonate and 30 μL of allyl bromide were added, followed by stirring for 6.5 hours. Ethyl acetate was added to the reaction solution, followed by sequential washing with water and saturated brine and drying over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate=3/1) to afford 7.5 mg of the title compound as a colorless solid (yield 14%). The resulting solid was recrystallized from ethyl acetate-hexane, the generated precipitate was filtered off, the wet crystal was washed with hexane, and subsequently dried under reduced pressure at room temperature to afford the title compound as a colorless crystalline powder. Enantiomeric excess: 99.9% ee or more (CHIRALPAK AD-H, 4.6×150 mm, hexane/ethanol=2/1, UV 210 nm, flow rate 1 mL/min., retention time 8.0 minutes).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:33][CH3:34])=[C:16]([CH:22]4[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10](Br)[C:3]=12.[CH3:35][C:36]1(C)C(C)(C)OB(C=C)O1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:33][CH3:34])=[C:16]([CH:22]4[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH:35]=[CH2:36])[C:3]=12
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: COc1c(C(C)n2nc(Br)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
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: CN(C)C=O
Solvent: O
Product: C=Cc1nn(C(C)c2cc(Cl)c(C)c(C3CN(C(=O)OC(C)(C)C)C3)c2OC)c2ncnc(N)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a solution of tert-butyl 3-{3-[1-(4-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate (1.1 g, 2.0 mmol, racemic intermediate from Example 125, Step 1) in N,N-dimethylformamide (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (230 mg, 0.20 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.68 mL, 4.0 mmol). 2.0 M sodium carbonate in water (5.0 mL, 1.0 mmol) was added under N2 and the mixture heated at 100° C. for 3 h then stirred at room temperature overnight. The reaction mixture was filtered through Celite, and washed with EtOAc. The filtrates were washed with water and brine, dried (MgSO4), filtered, and concentrated. The crude material was purified on silica gel (eluted with 40-100% ethyl acetate in hexanes) to give 0.75 g (75%) of the desired product. LCMS calculated for C25H32ClN6O3 (M+H)+: m/z=499.2; Found: 499.0 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.30 (s, 1H), 7.50-7.40 (m, 1H), 6.99 (dd, J=17.7, 11.3 Hz, 1H), 6.44 (q, J=7.0 Hz, 1H), 5.95 (dd, J=17.7, 1.3 Hz, 1H), 5.83 (br s, 1H), 5.65 (dd, J=11.3, 1.3 Hz, 1H), 4.39-3.96 (m, 4H), 3.63 (d, J=6.7 Hz, 3H), 2.99-2.78 (m, 1H), 2.22 (s, 4H), 1.84 (d, J=7.1 Hz, 3H), 1.43 (s, 9H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][CH:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[CH:6]2[CH2:5]1.[CH2:18]([C:20]1([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:22][O:21]1)[CH3:19]>CN(C=O)C>[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[N:8]([CH2:22][C:20]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)([OH:21])[CH2:18][CH3:19])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1
Reactant: Cc1ccc2c(c1)C1CN(C)CCC1N2
Reactant: CCC1(c2ccncc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(O)(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A flask was charged with sodium hydride (0.640 g, 50-60%) in dry DMF (10 mL) at 0° C. and to this was added 2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (0.8 g). The mixture was stirred at RT for 30 min. and then 4-(2-ethyloxiran-2-yl)pyridine (0.834 g) dissolved in DMF (2 mL) was added, stirred at RT for 12 h. The reaction mixture was diluted with ice-water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated. The crude product was triturated with diethyl ether to obtain the desired compound. 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 8.45 (d, 2H), 7.42 (d, 2H), 7.30 (d, 1H), 7.10 (s, 1H), 6.82 (d, 1H), 4.30 (d, 1H), 4.18 (d, 1H), 3.60 (s, 2H), 3.50 (m, 2H), 3.38 (m, 1H), 3.0 (m, 2H), 2.90 (s, 3H), 3.32 (s, 3H), 2.10 (m, 1H), 0.6 (t, 3H).
Reaction SMILES: [C:1]([C:3]([C:19]#[N:20])=[C:4]([OH:18])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)#[N:2].[CH:21](N(C(C)C)CC)(C)C.C[Si](C=[N+]=[N-])(C)C>C(#N)C.CO.C1COCC1>[C:1]([C:3]([C:19]#[N:20])=[C:4]([O:18][CH3:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)#[N:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: N#CC(C#N)=C(O)c1ccc(Oc2ccccc2)cc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CO
Product: COC(=C(C#N)C#N)c1ccc(Oc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
1,1-Dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene (56.5 g) in acetonitrile (780 mL) and methanol (85 mL) is stirred under nitrogen at 0° C. while adding diisopropylethylamine (52.5 mL) followed by 2M trimethylsilyldiazomethane (150 mL) in THF. The reaction is stirred for 2 days at 20° C., and then 2 g of silica is added (for chromatography). The brown-red solution is evaporated in vacuo, the residue dissolved in ethyl acetate and washed well with water then brine, dried and evaporated. The residue is extracted with diethyl ether (3×250 mL), decanting from insoluble oil. Evaporation of the ether extracts gives 22.5 g of 1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene as a pale orange solid. The insoluble oil is purified by flash chromatography to give 15.0 g of a red-orange oil.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[N:19]1([C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26](O)=[O:27])[CH:23]=[CH:22][CH:21]=[CH:20]1>>[N:19]1([C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:27])[CH:23]=[CH:22][CH:21]=[CH:20]1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: O=C(O)c1ccccc1-n1cccc1
Product: O=C(c1ccccc1-n1cccc1)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 2-pyrrol-1-yl-benzoic acid. MS (ESI) mass calcd. for C25H23N5O, 409.49; m/z found, 410.2 [M+H]+.
Reaction SMILES: [C:1]1([C@@:7]23[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C@@H:8]2[CH2:9][NH:10][CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>C(Cl)(Cl)Cl>[CH:27]1([C:30]([N:10]2[CH2:11][CH2:12][C@:7]3([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C@@H:8]3[CH2:9]2)=[O:31])[CH2:29][CH2:28]1
Reactant: O=C(Cl)C1CC1
Reactant: c1ccc([C@]23CCNC[C@H]2c2ccccc2O3)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(C1CC1)N1CC[C@]2(c3ccccc3)Oc3ccccc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.1 %

Procedure:
To a solution of 3.77 g of cis-1,2,3,4,4a,9b-hexahydro-4a-phenylbenzofuro[3,2-c]pyridine in 100 ml of chloroform containing 1.67 g of triethylamine was added dropwise with stirring under nitrogen a solution of 1.65 g of cyclopropane carbonyl chloride in 25 ml of chloroform. The reaction mixture was stirred at room temperature for 4 hours, diluted with 100 ml of chloroform and washed with 100 ml of 2N HCl and 100 ml of 10% aqueous NaOH. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to afford 4.70 g (98.1%) of a glass.
Reaction SMILES: [S-2].[Na+].[Na+].[NH2:4][C:5]1[C:10]([C:11]#[N:12])=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=2)[C:8]([C:25]#[N:26])=[C:7]([S:27]CC2C=CC=CC=2)[N:6]=1.Cl.O>CN(C=O)C>[NH2:4][C:5]1[C:10]([C:11]#[N:12])=[C:9]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:17][CH:18]=2)[C:8]([C:25]#[N:26])=[C:7]([SH:27])[N:6]=1
Reactant: CN(C)CCOc1ccc(-c2c(C#N)c(N)nc(SCc3ccccc3)c2C#N)cc1
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.97 g (12.41 mmol) of sodium sulphide is added to a solution of 3.56 g (8.28 mmol) of the compound from Example 33A in 13 ml of dry DMF. The reaction mixture is stirred at +80° C. for 2 h. After cooling to RT, 2 ml of 37% strength hydrochloric acid are added to the reaction mixture, whose temperature rises to 65° C. After addition of 2.6 ml of water, the reaction mixture is cooled back to RT. After addition of a further 5 ml of water, the mixture is washed with 5 ml of ethyl acetate and made alkaline by addition of 40% strength sodium hydroxide solution. Yellow crystals precipitate, and these are filtered off with suction, washed with 10 ml of water and 10 ml of diethyl ether and then dried under reduced pressure. The filtrate is concentrated using a rotary evaporator and stirred with a little water. The resulting crystals are filtered off with suction, washed with in each case 10 ml of water and diethyl ether and dried under reduced pressure.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:17])=[N:7][CH:8]=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[Br:18]Br>CC(O)=O>[Br:18][CH2:17][C:6]1[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[CH:8][N:7]=1
Reactant: BrBr
Reactant: CCCCc1c(C)ncnc1-c1ccccc1
Solvent: CC(=O)O
Product: CCCCc1c(CBr)ncnc1-c1ccccc1

Procedure:
A solution of 5-butyl-4-methyl-6-phenyl-pyrimidine (320 mg, 1.14 mmol) and Br2 (0.08 ml, 1.48 mmol) in AcOH (2 mL) is stirred at 80° C. for 2 hours. After cooling, the solution is concentrated. The residue is then partitioned between Et2O and half saturated aqueous NaHCO3. The layers are separated, and the aqueous layer is reextracted once with Et2O. The combined extracts are dried over Na2SO4 and concentrated. The residue is purified by flash chromatography on silica gel. Elution with 3:1 hexanes-EtOAc affords 4-bromomethyl-5-butyl-6-phenyl-pyrimidine and a small amount of an unidentified impurity. 1H NMR (CDCl3, 300 MHz) δ 9.08 (s, 1H), 7.47 (s, 5H), 4.57 (s, 2H), 2.79–2.74 (m, 2H), 1.52–1.42 (m, 2H), 1.38–1.20 (m, 2H), 0.80 (t, J=7.4 Hz, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]([O:19]C)=[O:18])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1>[OH-].[Na+].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]([OH:19])=[O:18])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c(-c2ccc(F)cc2)nn2ccccc12

Procedure:
A solution of methyl 2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylate (5.0 g, 18.5 mmol) in 2N aqueous sodium hydroxide (50 ml) and methanol (30 mL) was-heated at reflux for about 3 hours. The mixture was filtered and the filtrate was washed with diethyl ether (20 mL) and then concentrated under reduced pressure to about half the original volume. Concentrated hydrochloric acid was added to adjust the pH to about 2 and the resulting solid was collected by filtration and washed with water and dried under vacuum to give the title compound as a white solid, 4.8 g (ca. 100%). 1H NMR (d6 DMSO) δ 12.43 (br s, 1h), 8.84 (d, 1H, J=6.9 Hz), 8.14 (d, 1H, J=9 Hz), 7.82 (m, 2H), 7.57 (t, 1H, J=8.1 Hz), 7.28 (t, 2H, J=9 Hz), 7.15 (td, 1H, J=6.9, 1.2 Hz). MS (+ve ion electrospray) 257 (100), (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1)[CH3:2].[Cl:13]N1C(=O)CCC1=O.C(Cl)(Cl)Cl.CCCCCC>CN(C=O)C>[Cl:13][C:8]1[C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=[C:3]([CH2:1][CH3:2])[CH:9]=1
Reactant: CCc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1cc(Cl)c(N)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 14.5 %

Procedure:
To a stirred solution of 4-ethyl-2-nitroaniline (26.3 g, Example 13a) in DMF (100 ml) at -25° C. was added N-chlorosuccinimide (25.4 g) in portions. The mixture was stirred for 1 h at 0° C. and 30 minutes at ambient temperature before evaporation of the solvent under vacuum. Addition of CHCl3 /hexane (1:1) to the residue followed by filtration removed crystalline succinimide. 6-Chloro-4-ethyl-2-nitroaniline (4.6 g) was isolated from the filtrate after chromatography on silica. δ (360 MHz, CDCl3) 1.22 (3H, t, CH3), 2.56 (2H, q, CH2), 6.38 (2H. s, NH2), 7.4 (1H, d, 5-H) and 7.90 (1H, s, 3-H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][S:8][CH2:9][CH:10]1[CH2:12][O:11]1)[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+]>>[CH2:1]([O:5][CH2:6][CH2:7][S:8][CH:9]=[CH:10][CH2:12][OH:11])[CH2:2][CH2:3][CH3:4].[CH:1]([OH:5])=[CH:2][CH3:3]
Reactant: CCCCOCCSCC1CO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CC=CO
Product: CCCCOCCSC=CCO
Yield: 950.6 %

Procedure:
Following the procedure of Example 10, 2-butoxyethyltosylate (26.85 g, 98.7 mmol) and 3-mercapto-1,2-propanediol (10.68 g, 98.7 mmol) are reacted together to give 3-(2-butoxyethylthio)-1,2-propanediol, which diol (10.0 g, 52.5 mmol) is reacted with tosyl chloride (10.0 g) in pyridine. The tosylate (9.27 g, 25.6 mmol) is reacted with NaOH (1.02 g, 25.6 mmol) to give 2-(2-butoxyethylthiomethyl)oxirane. The oxirane (1.0 g, 5.26 mmol) and potassium t-butoxide (0.18 g, 1.58 mmol) are reacted together to give 3-(2-butoxyethylthio)-2-propenol, which propenol (4.72 g, 25.0 mmol) is reacted with acetic anhydride to give 3-(2-butoxyethylthio)-2-propenyl acetate.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[CH:5]#[C:6][CH2:7][C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].Cl>CCOCC>[CH:1]([C:8]([OH:14])([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][C:6]#[CH:5])=[CH2:2]
Reactant: C#CCC(=O)CCCCC
Reactant: C=C[Mg]Cl
Agent: Cl
Solvent: CCOCC
Product: C#CCC(O)(C=C)CCCCC

Procedure:
A solution of 130 ml of 2.3 molar vinyl magnesium chloride in 100 ml of ether is cooled to 0° and treated dropwise with 14 g of 1-nonyn-4-one in 50 ml of ether. The reaction mixture is allowed to come to room temperature and poured into ether and dilute hydrochloric acid. The organic layer is separated, washed with water, dried over sodium sulfate, stripped of solvent and the residue is chromatographed on silica gel with 20% ethyl acetate in hexane as eluent to give the title product.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][N:7]([C:15]1[CH:37]=[CH:36][C:18]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH2:23][CH2:22]2)=[O:20])=[CH:17][CH:16]=1)[C:8](=[O:14])[CH2:9][O:10]C(=O)C)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O>[ClH:35].[CH:1]([O:4][CH2:5][CH2:6][N:7]([C:15]1[CH:37]=[CH:36][C:18]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH2:25][CH2:26]2)=[O:20])=[CH:17][CH:16]=1)[C:8](=[O:14])[CH2:9][OH:10])([CH3:3])[CH3:2]
Reactant: CC(=O)OCC(=O)N(CCOC(C)C)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)OCCN(C(=O)CO)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.2 g of 1-{4-[N-(2-isopropyloxyethyl)-N-acetoxyacetylamino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine (Example 41) are dissolved in 20 ml of ethanol. 1.5 ml of 2N sodium hydroxide solution in 5 ml of water are added thereto, and the mixture is stirred at RT for one hour. After concentration by evaporation, the residue is dissolved in ethyl acetate and washed with water. Concentration by evaporation and treatment with ethereal hydrochloric acid yield 1-{4-[N-(2-isopropyloxyethyl)-N-hydroxyacetylamino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine hydrochloride having a melting point of 99°-101°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:17])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Cl:20][C:21]1[CH:27]=[C:26]([Cl:28])[C:25]([O:29][CH3:30])=[CH:24][C:22]=1[NH2:23].Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:20][C:21]1[CH:27]=[C:26]([Cl:28])[C:25]([O:29][CH3:30])=[CH:24][C:22]=1[NH:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:17])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: COCCOc1cc2c(Cl)c(C#N)cnc2cc1F
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COCCOc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Temperature: 102.5 °C
Yield: 73.4 %

Procedure:
A mixture of 4-chloro-7-fluoro-6-(2-methoxyethoxy)-3-quinolinecarbonitrile (1.00 g, 3.59 mmol), 2,4-dichloro-5-methoxyaniline (727 mg, 3.77 mmol) and pyridine hydrochloride (620 mg, 5.34 mmol) in 18 mL of 2-ethoxyethanol is heated at 100-105° C. for 2 hours. The reaction mixture is cooled to room temperature and then poured into ice cold saturated sodium bicarbonate. The solids are collected, washed with water and then treated with methanol and dichloromethane. The mixture is filtered and the filtrate is concentrated. The solid residue is slurried with hexane, and the solids are collected by filtration to provide 1.15 g of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-(2-methoxyethoxy)-3-quinolinecarbonitrile, mp 170-172° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[CH:15]3)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1[CH2:34][CH2:33]OCC1>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>[NH2:11][C:12]1[CH:20]=[C:19]([C:2]2[N:3]=[C:4]([NH:11][C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][N:16]=[CH:15]4)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=2)[CH:18]=[CH:33][CH:34]=1
Reactant: Brc1cn2ccnc2c(Nc2ccc3[nH]ncc3c2)n1
Reactant: C1COCCO1
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: O
Product: Nc1cccc(-c2cn3ccnc3c(Nc3ccc4[nH]ncc4c3)n2)c1
Temperature: 25 °C

Procedure:
A mixture of 1.00 eq. of (6-Bromo-imidazo[1,2-a]pyrazin-8-yl)-(1H-indazol-5-yl)-amine, 1.1 eq. of R4-substituted boronic acid, and 0.10 eq. of Pd(PPh3)4, 2.2 eq. of K3PO4 in 4:1 1,4-dioxane:water is heated to 90° C. for 24 hr. The mixture is cooled to RT and partitioned between EtOAc and sat. NaHCO3. The aqueous phase is extracted with EtOAc and combined extracts are dried over Na2SO4. The solvent is removed under reduced pressure and the resulting residue is purified by flash chromatography (EtOAc) to yield (5).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][CH2:19][C@@H:20]([CH3:23])[CH2:21][OH:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:11]([O:18][CH2:19][C@H:20]([CH3:23])[CH:21]=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@@H](CO)COCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](C=O)COCc1ccccc1
Temperature: -78 °C

Procedure:
An oven dried three-necked 2 L round bottom flask was equipped with a mechanical stirrer, a thermometer, an N2 inlet, and a septum. The flask was charged with 24.050 g (0.189 mol) of oxalyl chloride and 425 mL CH2Cl2. The reaction mixture was stirred under an N2 atmosphere and cooled to −78° C. with an external dry ice-acetone bath. A solution of methyl sulfoxide (29.607 g; 0.379 mol) in 85 mL CH2Cl2 was then added over 5 min to the reaction mixture via cannula. After the adition, the reaction was stirred an additional 5 min and then a solution of 31.048 g (0.172 mol) of (S)-3-benzyloxy-2-methylpropan-1-ol in 170 mL CH2Cl2 was added via cannula. When the second addition was completed the reaction mixture was stirred for 15 min at −78° C. then 111.32 g (0.861 mol) of N,N-diisopropylethylamine was added via syringe. The reaction mixture was stirred an addition 15 min at −78° C., the cooling bath was removed and the reaction was allowed to warm. When the internal temperature had reached −15° C., 350 mL of a 10% aqueous NaHSO4 solution was slowly added and the mixture was transferred to a separatory funnel. The organic layer was separated, washed with aqueous NaHSO4 (2×250 mL), saturated NaCl, dried (MgSO4), filtered and evaporated. The residue was used immediately in the next step without further purification.