Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([C:11]2[C:12]([CH3:20])=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[CH2:27]([O:1][C:2]1[N:3]=[C:4]([C:11]2[C:12]([CH3:20])=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1OCc1ccccc1
Yield: 59 %

Procedure:
Using methyl 4-hydroxy-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-1,3-thiazole-5-carboxylate (800 mg, 2.5 mmol) produced in Example 13-B(i), potassium carbonate (1.9 g, 5.9 mmol), benzyl bromide (2.8 g, 12 mmol) and N,N-dimethylformamide (50 mL) as starting materials and in the same manner as in Example 27-B(i), the title compound (560 mg, 60%) was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:17]=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[N:7]=1.[Cl:18]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:17]([Cl:18])=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[N:7]=1
Reactant: Cn1cc(Nc2nc(Cl)c3cc[nH]c3n2)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(Nc2nc(Cl)c3c(Cl)c[nH]c3n2)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
To a solution of 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (2 g, 8 mmol) in DMF (35 mL) was added N-chlorosuccinimide (1.28 g, 9.6 mmol). The reaction mixture was stirred at 50° C. overnight. Water (50 mL) was added and the solution was extracted with EtOAc (three×25 mL) and the combined organic layers were dried over Na2SO4, and concentrated to dryness. The residue was purified by preparative HPLC to afford the title compound (0.5 g, 22% yield) as a gray solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.99 (brs, 1H), 9.62 (brs, 1H), 7.88 (s, 1H), 7.52 (s, 1H), 7.38 (s, 1H), 3.35 (s, 3H). m/z for C10H8Cl2N6: 283.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:16][CH3:17])[C:5]([NH:10][C@@H:11]([CH2:14][CH3:15])[CH2:12][OH:13])=[N:6][C:7]=1[CH2:8][CH3:9].[H-].[Na+].I[CH2:21][CH3:22]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]([CH2:16][CH3:17])[C:5]([NH:10][C@H:11]([CH2:12][O:13][CH2:21][CH3:22])[CH2:14][CH3:15])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCI
Reactant: CCc1nc(N[C@@H](CC)CO)c(CC)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC[C@H](CC)Nc1nc(CC)c(Br)nc1CC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.5 %

Procedure:
A dry 50 mL round bottom flask was charged with a solution of (2S)-2-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]butan-1-ol (356 mg, 1.18 mmol) in DMF (12 mL). NaH (70.8 mg, 1.77 mmol) was added to the homogeneous solution. Effervescence was observed and the solution turned cloudy. Iodoethane (0.189 mL, 2.36 mmol) was added at once. The now yellow solution was stirred at ambient temperature for 20 minutes. The same quantities of NaH and iodoethane were added to the reaction mixture two more times in the same manner. The reaction was quenched with water and extracted twice with ethyl acetate. The organics were combined, dried with Na2SO4, filtered and concentrated to give 510 mg of a crude yellow oil. This material was purified by Biotage MPLC (90 g column, using 5% ethyl acetate in heptane) to give 193 mg (50%) of 5-bromo-N-[(1S)-1-(ethoxymethyl)propyl]-3,6-diethylpyrazin-2-amine as a yellow oil. Rf 0.16 (5% ethyl acetate in heptane).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH2:12][CH2:13][CH2:14][CH:15]2[O:19][CH2:18][CH2:17][O:16]2)=[O:10])[CH2:5][CH2:4]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1>[S:26]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH2:12][CH2:13][CH2:14][CH:15]2[O:16][CH2:17][CH2:18][O:19]2)=[O:10])[CH2:5][CH2:4]1)([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(OCCCC1OCCO1)[C@H]1CC[C@H](CO)CC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](C(=O)OCCCC3OCCO3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of trans-3-(1,3-dioxolan-2-yl)propyl 4-(hydroxymethyl)cyclohexanecarboxylate (0.306 g, 1.13 mmol) in pyridine (0.9 mL) was added para-toluenesulfonyl chloride (0.236 g, 1.24 mmol). The reaction mixture was stirred at this temperature for 1 hour and the coolant removed. The reaction mixture was stirred at RT for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water, brine, dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was used directly without purification.
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH:19]2[CH2:22][CH2:21][CH2:20]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2.[NH:23]1[CH:27]=[CH:26][CH:25]=[N:24]1.CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu]I.C(OCC)(=O)C>[CH:19]1([O:18][C:3]2[C:2]([N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)=[CH:11][CH:10]=[C:9]3[C:4]=2[CH2:5][CH2:6][C@H:7]([CH3:17])[N:8]3[C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:22][CH2:21][CH2:20]1
Reactant: C[C@H]1CCc2c(ccc(Br)c2OC2CCC2)N1C(=O)C1CC1
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H]1CCc2c(ccc(-n3cccn3)c2OC2CCC2)N1C(=O)C1CC1
Temperature: 120 °C
Reaction time: 18 h
Yield: 13.1 %

Procedure:
A mixture of (S)-(6-bromo-5-cyclobutoxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.182 g, 0.50 mmol,), 1H-pyrazole (0.340 g, 5.00 mmol), copper (I) iodide (0.038 g, 0.20 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (0.57 g, 0.40 mmol), and potassium carbonate (0.276 g, 2.00 mmol) in 1,4-dioxane (10 mL) stirred for 18 h at 120° C. The reaction mixture was cooled to room temperature and poured into ethyl acetate (50 mL). The mixture was washed with water (3×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 1:2, ethyl acetate/petroleum ether) to afford (S)-(5-cyclobutoxy-2-methyl-6-(1H-pyrazol-1-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.023 g, 13%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.63-0.72 (m, 1H), 0.77-0.91 (m, 2H), 0.99-1.10 (m, 4H), 1.15-1.19 (m, 1H), 1.30-1.53 (m, 2H), 1.72-1.95 (m, 5H), 2.22-2.43 (m, 2H), 2.95-2.96 (m, 1H), 3.88-3.95 (m, 1H), 4.63-4.71 (m, 1H), 6.51 (s, 1H), 7.24 (d, J=8.70 Hz, 1H), 7.41 (d, J=8.70 Hz, 1H), 7.73 (s, 1H), 8.08 (s, 1H). MS (ESI, pos. ion) m/z 352 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[CH:10]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][N:22]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.O.[Cl-].[NH4+]>CO.[Zn]>[CH2:1]([O:8][C:9](=[O:30])[CH:10]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(C(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 89 %

Procedure:
A solution of 2-(5-nitro-pyridin-2-yl)-malonic acid dibenzyl ester in a mixture of methanol, tetrahydrofuran, and water was treated with ammonium chloride (25 eq.) and zinc dust (>10 micron,10 eq.). The mixture was stirred at 25° C. for 40 min. At this time, the reaction was filtered through celite. The filtrate was concentrated in vacuo. The aqueous residue was extracted with ethyl acetate. The organics were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(5-amino-pyridin-2-yl)-malonic acid dibenzyl ester as a yellow viscous oil (89%); LRMS for C22H20N2O4 (M+H)+ at m/z=377.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25](O)=[O:26])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.[NH2:41][CH2:42][CH2:43][OH:44].CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH2:1]([O:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25]([NH:41][CH2:42][CH2:43][OH:44])=[O:26])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=C(O)c1cc(CNc2ccccc2C(=O)NOCc2ccccc2)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCCO)c1cc(CNc2ccccc2C(=O)NOCc2ccccc2)ccc1F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
5-[(2-Benzyloxycarbamoyl-phenylamino)-methyl]-2-fluoro-benzoic acid (Example 498, 96.5 mg) and 1-hydroxybenzotriazole hydrate (36 mg) was dissolved in DMF (1.0 ml). 2-Amino-ethanol (15 μl), N-methylmorpholine (28 μl), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (50.1 mg) was added in that order. The reaction mixture was shaken at room temperature for 15 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane and evaporated onto silica gel. Purification by column chromatography on silica gel (elution with 50-100% EtOAc in petroleum ether) gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[S:25][C:24]([C:26](O)=[O:27])=[CH:23][CH:22]=3)[O:18][N:17]=2)[N:3]=1.Cl.CN(C)CCCN=C=NCC.C1C=NC2N(O)N=NC=2C=1.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[S:25][C:24]([C:26]([N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[O:27])=[CH:23][CH:22]=3)[O:18][N:17]=2)[N:3]=1
Reactant: C1COCCN1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(C(=O)O)s3)n2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(C(=O)N4CCOCC4)s3)n2)n1
Reaction time: 2 h
Yield: 71 %

Procedure:
To 5-{3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazol-5-yl}-thiophene-2-carboxylic acid (prepared in an analogous manner to Intermediate 62, 24 mg, 61 μmol) in anhydrous DMF (0.5 mL) was added (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (17 mg, 73 μmol), HOAt (4.1 mg, 31 μmol) and morpholine (10 μL, 92 μmol). The reaction mixture was stirred for 2 h, further morpholine (10 μL, 92 μmol) and (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (9 mg, 39 μmol) were added. The mixture was stirred for a further 2 h then diluted with ethyl acetate (5 mL) and extracted with aqueous citric acid (1M, 5 mL), 1 M NaOH (5 mL), saturated brine (5 mL) and dried over sodium sulphate. Removal of the solvent gave a gum with was purified on silica eluting with ethyl acetate-10% heptanes to give the title compound (20 mg, 71%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:3]=1.[Br:18]N1C(=O)CCC1=O>>[Br:18][CH2:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:3]=1
Reactant: COC(=O)c1sc(C)cc1-c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Product: COC(=O)c1sc(CBr)cc1-c1ccc(F)cc1

Procedure:
A solution of methyl 1-[5-methyl-3-(4-fluorophenyl)-thien-2-yl]methanoate (12.9 g; 0.05 mol), N-bromosuccinimide (11.02 g; 0.0619 mol) and 2-2′-azobisisobutyronitrile (0.339 g; 2.06 mmol) in Cl4 (300 ml) was reflux under argon atmosphere for 90 minutes under UV irradiation. After filtration of the precipitate, the filtrate was evaporated to dryness to give methyl 1-[5-bromomethyl-3-(4-fluorophenyl)-thien-2-yl]methanoate as a solid which was used in the next step without purification.
Reaction SMILES: C(OC(N1[C@H](C=CCCCO)COC1(C)C)=O)(C)(C)C.C[Si](C)(C)Br.C([O:28][C:29](=[O:49])[CH:30]([NH:45][C:46](C)=O)/[CH:31]=[C:32](\[CH3:44])/[CH2:33][P:34]([O:40]C(C)C)([O:36]C(C)C)=[O:35])C.C1OC1C>ClCCl.C(O)C>[CH3:46][NH:45][CH:30](/[CH:31]=[C:32](\[CH3:44])/[CH2:33][P:34]([OH:36])([OH:40])=[O:35])[C:29]([OH:49])=[O:28]
Reactant: CCOC(=O)C(/C=C(\C)CP(=O)(OC(C)C)OC(C)C)NC(C)=O
Agent: CC(C)(C)OC(=O)N1[C@H](C=CCCCO)COC1(C)C
Agent: CC1CO1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCO
Product: CNC(/C=C(\C)CP(=O)(O)O)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
E-2-methylamino-4-methyl-5-phosphono-3-pentenoic acid (3) 20 ml of trimethylbromosilane are added dropwise at 20° within a period of 10 minutes under argon to a solution of 9.50 g of E-2-(N-methylformylamino)-4-methyl-5-diisopropylphosphono-3-pentenoic acidethyl ester in 40 ml of dry dichloromethane. After stirring at room temperature for 20 hours, 37 ml of ethanol are added dropwise within a period of 15 minutes, and the whole is stirred for a further 20 hours. Theclear reaction solution is then concentrated to dryness by evaporation in vacuo. The residue is concentrated by evaporation twice more in each case after the addition of 30 ml of toluene. 128 ml of 2N hydrochloric acid areadded to the resulting oil, and the mixture is stirred at a bath temperature of 85° for 16 hours. The reaction mixture is concentrated by evaporation in vacuo. Concentration by evaporation twice after the addition of ethanol/toluene 1:1 yields an oily residue, which isdissolved in 51 ml of ethanol and to which there is added dropwise a solution of 51 ml of propylene oxide in 51 ml of ethanol. The product obtained in crystalline form is filtered off after 2 hours and recrystallised from water/ethanol. In this manner there is obtained E-2-methylamino-4-methyl-5-phosphono-3-pentenoic acid, m.p. 239° (decomp.).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N+:12]([C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:35])=[CH:20][C:16]=1[C:17](Cl)=[O:18])([O-:14])=[O:13].O>CN(C)C=O>[N+:12]([C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:26]=2[Cl:35])=[CH:20][C:16]=1[C:17]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])=[O:18])([O-:14])=[O:13]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=C1NC(=O)c2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of phthalimide (4.63 grams; 0.025 mole) dissolved in dimethylformamide (50 ml) was charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. 2-Nitro-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl chloride (9.5 grams; 0.025 mole) was added and the reaction mixture was stirred at room temperature overnight. After this time the mixture was poured into water and was thereafter extracted with toluene. The toluene extract was evaporated to dryness leaving a dark reddish solid. This solid was recrystallized from toluene to yield the desired product N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl]phthalimide as a white powder melting at 160° C.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[CH:17]=[O:18])[CH2:3]1.C(=O)([O-])[O-:20].[K+].[K+].OO.CS(C)=O>CC(C)=O.[Cl-].[Na+].O>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:12]([C:13]([NH2:14])=[O:20])=[CH:11][C:10]=2[CH:17]=[O:18])[CH2:3]1
Reactant: C[C@@H]1CN(c2ccc(C#N)cc2C=O)C[C@H](C)O1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(C)=O
Product: C[C@@H]1CN(c2ccc(C(N)=O)cc2C=O)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.4 %

Procedure:
A solution of 4-(cis-2,6-dimethylmorpholin-4-yl)-3-formylbenzonitrile (Example 6, Step 1) (0.244 g, 1.00 mmol) in acetone (4 mL) is treated with anhydrous powdered potassium carbonate (0.028 g, 0.20 mmol) followed by 30% hydrogen peroxide (0.204 g, 6.00 mmol).The reaction mixture is stirred at room temperature. After 24 h, additional 30% hydrogen peroxide (6.0 mmol) and acetone (2 mL) is added. After stirring at RT for 5 days, an additional potassium carbonate (0.96 g) and DMSO (4 mL) is added and stirred at RT for 24 h. The reaction mixture is poured into 50% saturated brine (40 mL), extracted with ether (3×), dried (NaSO4) and concentrated. The resulting residue is purified by silica gel chromatography using acetone-methylene chloride (1:4) as the eluent, to afford 28 mg (11%) of the desired amide as a yellow foam. 1H NMR (400 MHz, CDCl3) δ 10.20, 8.20, 8.09, 7.12, 6.47-5.88, 4.00-3.86, 3.20, 2.74, 1.25.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].S(=O)(=O)(O)O.CO[C:13]1[CH:19]=CC(O)=[CH:15][CH:14]=1>C(O)CCC>[C:1]([O:5][CH2:19][CH2:13][CH2:14][CH3:15])(=[O:4])[CH:2]=[CH2:3]
Reactant: COc1ccc(O)cc1
Reactant: C=CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: C=CC(=O)OCCCC
Reaction time: 2.5 h

Procedure:
For comparison, a known esterification process was carried out using only one reaction region. In this Comparative Example, 4 mol/h of acrylic acid, 4 mol/h of fresh butanol and 1.6 mol/h of recycled butanol (distillate from the butanol recovery) were fed to a circulation evaporator (2.5 l, level of fill 2 l). The residence time was 2.5 h. The esterification was carried out in the presence of 9.7% by weight (based on the reaction mixture) of sulfuric acid at 126° C. The reactor was connected to a bubble-cap column (30 trays), which was stabilized with 15 ml/h of hydroquinone monomethyl ether (MeHQ) in butanol. Butyl acrylate formed was removed via the top by adding 340 ml/h of water as a reflux (azeotropic entraining agent) to the column. In addition, 175 ml/h of organic reflux were added to the column in order to suppress the acrylic acid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1.C([Li])CCC.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>O1CCCC1>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][C:8]2[O:7][C:6]([CH:2]3[O:3][CH2:4][CH2:5][O:1]3)=[CH:10][CH:9]=2)=[CH:19][CH:18]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: c1coc(C2OCCO2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1ccc(Cc2ccc(C3OCCO3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a tetrahydrofuran (50 mL) solution of 2-(1,3-dioxolan-2-yl-furan (5 g, 35.7 mmol) was added n-butyl lithium (15.6 mL, 2.64 M hexane solution, 41.1 mmol) at −78° C., which was stirred for 1 hour at that temperature. A tetrahydrofuran solution of 4-fluorobenzyl bromide (6.9 g, 36.5 mmol) was added dropwise to this mixture, which was stirred for another hour at −78° C. The mixture was raised to room temperature and partitioned into ethyl acetate and a saturated ammonium chloride aqueous solution. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:10 to 1:3) to obtain the title compound (4.51 g, 51%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.[C:13]([Cu])#[N:14].CN(C=O)C.[OH-].[NH4+]>C(Cl)Cl.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:13]#[N:14]
Reactant: Nc1ccc(C(F)(F)F)cc1I
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(C(F)(F)F)ccc1N

Procedure:
A 2-liter flask was charged with 100 g (0.348 mol) of 4-amino-3-iodobenzotrifluoride, 40 g of CuCN and 750 mL of DMF. The mixture was heated to and then maintained at reflux for 1 hour. The reaction was cooled and poured into 3 L of water containing 300 mL of concentrated ammonium hydroxide. To the mixture was added 1 L CH2Cl2. The mixture was then filtered through celite. The layers were separated and the aqueous layer was back extracted with CH2Cl2. The organic extracts were combined and the solvent removed under reduced pressure. The residue was dissolved in 1.5 L of ether and the resulting solution was washed with 1N ammonium hydroxide, aqueous sodium bisulfate, 1N aqueous HCl and brine. The solution was dried over anhydrous MgSO4 and filtered through a silica gel plug containing a layer of MgSO4 on top. The plug was washed with 0.5 L ether. The ether solutions were combined and concentrated to 750 mL and let stand at room temperature. After 2 days the resulting solids were collected, washed with hexanes and dried under reduced pressure to afford 2-amino-5-(trifluoromethyl)benzonitrile 1H NMR (CDCl3, 500 MHz) δ 7.68 (s, 1H), 7.58 (d, J=8.5 Hz, 1H), 6.81 (d, J=8.5 Hz, 1H), 4.80 (br s, 2H).
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].CS(O[CH2:20][CH2:21][C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2)(=O)=O.[ClH:32]>C(O)C.C(OCC)(=O)C>[ClH:32].[C:22]12([CH2:21][CH2:20][NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2
Reactant: CCCCCN
Reactant: CS(=O)(=O)OCCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCNCCC12CC3CC(CC(C3)C1)C2

Procedure:
Pentylamine (2.69 ml, 23.2 mmol), potassium carbonate (2.14 g, 15.5 mmol) and sodium iodide (2.30 g, 15.3 mmol) were added to a solution of 2-(1-adamantyl)ethyl methanesulfonate (2.07 g, 8.01 mmol) in ethanol (45.8 ml), and the mixture was refluxed for 17 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was diluted with chloroform (100 ml). This was washed with a 1 N aqueous sodium hydroxide solution (100 ml) and a saturated aqueous sodium chloride solution (100 ml) successively, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography. A 4 N solution of hydrogen chloride in ethyl acetate (3.1 ml) was added to a solution of the resulting free form (1.52 g, 6.10 mmol) of the titled compound in ethyl acetate (0.50 ml). The precipitated solid was washed with ethyl acetate and filtered off to give 1.33 g (60%) of the titled compound.