Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([CH:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:22](O)=[O:23])[CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN(C1C=CC=CN=1)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:1]1([NH:4][C:22](=[O:23])[CH:21]([N:17]2[CH2:18][CH2:19][CH2:20][CH:15]([NH:14][C:10]3[CH:9]=[C:8]4[C:13](=[CH:12][CH:11]=3)[NH:5][N:6]=[CH:7]4)[CH2:16]2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=C(O)C(c1ccccc1)N1CCCC(Nc2ccc3[nH]ncc3c2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(NC1CC1)C(c1ccccc1)N1CCCC(Nc2ccc3[nH]ncc3c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.4 %

Procedure:
Cyclopropylamine (30 mg) and the compound prepared in Example 222 (88 mg) were dissolved in dimethylformamide (1 ml), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro-chloride (86 mg), 1-hydroxybenzotriazole (77 mg), and dimethylaminopyridine (5 mg) were added to the solution. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol]t to give 64 mg of the title compound as a single diastereomers.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([C:18]([F:21])([F:20])[F:19])=[CH2:17])=[CH:13][CH:14]=2)[C:9]([C:22]2[N:27]=[C:26]([O:28][C@H:29]3[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34][CH2:33][C:30]43[CH2:32][CH2:31]4)[CH:25]=[N:24][CH:23]=2)=[N:8]1>[Pd].C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH:16]([CH3:17])[C:18]([F:21])([F:19])[F:20])=[CH:13][CH:14]=2)[C:9]([C:22]2[N:27]=[C:26]([O:28][C@H:29]3[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:34][CH2:33][C:30]43[CH2:32][CH2:31]4)[CH:25]=[N:24][CH:23]=2)=[N:8]1
Reactant: C=C(c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1)C(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
A suspension of (4R)-tert-butyl 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(3,3,3-trifluoroprop-1-en-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (100 mg, 0.167 mmol) and palladium on carbon (Aldrich, St. Louis, Mo.; 10% w/w; 17.75 mg, 0.017 mmol) in THF (2.0 mL) was cycled under a H2 atmosphere (1 atm; 3× evacuation/refill cycles) and stirred at 25° C. for 16 h. The mixture was filtered through Celite (washing with THF (3×5 mL) to quantitate the transfer) and the filtrate was concentrated in vacuo to provide (4R)-tert-butyl 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(1,1,1-trifluoropropan-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (100 mg, 0.166 mmol, 100% yield; mixture of epimers at C1) as a white foam: 1H NMR (400 MHz, CDCl3) δ ppm 9.03 (1 H, s), 8.39 (1 H, br. s.), 8.20 (1 H, br. s.), 7.64 (1 H, t, J=4.3 Hz), 7.36 (1 H, d, J=8.4 Hz), 5.81 (1 H, d, J=7.2 Hz), 4.66 (1 H, br. s.), 4.41 (1 H, br. s.), 4.28 (1 H, br. s.), 4.03 (1 H, d, J=11.3 Hz), 3.78 (1 H, br. s.), 3.57 (1H, quin, J=8.1 Hz), 3.23 (1 H, d, J=12.5 Hz), 2.95 (1 H, br. s.), 2.57-2.71 (1 H, m), 2.49 (1 H, br. s.), 2.17-2.25 (1 H, m), 2.13 (1 H, br. d, J=12.5 Hz), 1.80 (2 H, d, J=7.4 Hz), 1.71 (1 H, br. s.), 1.58 (3 H, dd, J=7.0, 3.1 Hz), 1.12 (9 H, br. s.), 0.85 (1 H, d, J=12.7 Hz), 0.70 (1 H, br. s.), 0.56-0.62 (1 H, m), 0.54 (2 H, br. s.). 19F NMR (377 MHz, CDCl3) δ ppm −71.44 (3 F, d, J=8.0 Hz). MS (ESI, pos. ion) m/z: 602.3 (M+1).
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=2)[C:15]([NH:26][CH2:27][C:28]([OH:30])=O)=[N:14]1.[C:31]([O:35][C:36]([N:38]1[CH2:41][CH:40]([NH2:42])[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:41][CH:40]([NH:42][C:28](=[O:30])[CH2:27][NH:26][C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=3)[N:13]([CH3:12])[N:14]=2)[CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: Cn1nc(NCC(=O)O)c2cc(C(F)(F)F)ccc21
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: CCN=C=NCCCN(C)C
Product: Cn1nc(NCC(=O)NC2CN(C(=O)OC(C)(C)C)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as white foam from EDCI coupling of (1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetic acid (as prepared in the previous step) and 3-amino-azetidine-1-carboxylic acid tert-butyl ester using the procedure described in Step C of Example 1.
Reaction SMILES: C1C(=O)N([O:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]2[S:19][CH2:18][CH:17]3[NH:20][C:21]([NH:23][CH:16]23)=[O:22])=[O:10])C(=O)C1>CN(C=O)C>[OH:10][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]1[C@@H:16]2[C@@H:17]([NH:20][C:21]([NH:23]2)=[O:22])[CH2:18][S:19]1)=[O:8]
Reactant: O=C1NC2CSC(CCCCC(=O)ON3C(=O)CCC3=O)C2N1
Solvent: CN(C)C=O
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21

Procedure:
Amine functionalized polymer of formula (Vc) is dissolved at 10 mg/mL in anhydrous DMF and divided into two portions. NHS-biotin (0.9 mg in 90 μL, 88 equivalents) (Pierce, 20217) and NHS-LC-LC-biotin (Pierce, 21343) at 10 mg/mL (1.5 mg in 150 μL, 88 equivalents) are dissolved in anhydrous DMF. The NHS-biotin and NHS-LC-LC-biotin solutions are immediately added to the two portions of polymer solution and allowed to mix on a shaker overnight in the dark.
Reaction SMILES: ClS(O)(=O)=O.[CH2:6]([C:10]1([CH2:13][CH3:14])[CH2:12][NH:11]1)[CH2:7][CH2:8][CH3:9]>ClC(Cl)C>[CH2:6]([C@:10]1([CH2:13][CH3:14])[CH2:12][NH:11]1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCC1(CC)CN1
Agent: O=S(=O)(O)Cl
Solvent: CC(Cl)Cl
Product: CCCC[C@]1(CC)CN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
Chlorosulphonic acid (1 molar equivalent) was added to a solution of the product from step (f) (15 g) in dichloroethane (90 ml) at a temperature of <16° C. When addition was complete, the mixture was stirred for 2 hours at room temperature and then evaporated in vacuo. Water (60 ml) and 5% w/v aqu. NaOH (41 ml) were added and the mixture distilled at atmospheric pressure. The organic phase of the distillate was separated and dried over KOH to give a solution of the desired product (77% yield).
Reaction SMILES: C1C2C(COC([C@@H:18]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:19]([NH:21][C:22]3[N:26]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:25]=[C:24]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[CH:23]=3)=[O:20])=O)C3C(=CC=CC=3)C=2C=CC=1.CCCC[N+:50](CCCC)(CCCC)CCCC.[F-].O>C(Cl)Cl>[NH2:50][C@@H:18]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:19]([NH:21][C:22]1[N:26]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:25]=[C:24]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH:23]=1)=[O:20]
Reactant: CCOC(=O)Cn1nc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccccc1)C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Cn1nc(-c2ccncc2)cc1NC(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.9 %

Procedure:
To a rt solution of 26.B (341 mg, 0.63 mmol) in CH2Cl2 (5 mL) was added TBAF (available from Aldrich) (1.0 M, 3.2 mL, 3.2 mmol). The resulting mixture was stirred at rt for 12 hr, treated with water (15), and extracted with 30% iPrOH/CHCl3 (3×15 mL). The combined organic layers were washed with water, brine and dried over MgSO4. After removal of organic solvent under reduced pressure, purification of the residue by flash chromatography on silica gel using 0-10% MeOH/CH2Cl2 for elution gave the title product 26.C as colorless solid (141 mg, 71%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:11][C:10]1[CH:9]=[CH:8][C:7]([C:14](=[O:16])[CH3:15])=[CH:6][C:5]=1[O:4][C:3]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:2]=1[F:1]
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)c1ccc(N)c(Oc2ccc(F)cc2F)c1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A mixture of 3'-(2,4-difluorophenoxy)-4'-nitroacetophenone (2.5 g), iron powder (2.5 g) and ammonium chloride (0.25 g) in ethanol (40 ml) and water (20 ml) was refluxed with stirring for 30 minutes. The insoluble materials were filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated to give a powder of 4'-amino-3'-(2,4-difluorophenoxy)acetophenone (2.2 g).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:29]=[CH:28][C:14]([C:15](OC3C=C(F)C(C#N)=C(F)C=3)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH3:2].C(OC[C@H]1CC[C@H](C2C=CC(C(O)=O)=CC=2)CC1)C.S(Cl)([Cl:51])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:29]=[CH:28][C:14]([C:15]([Cl:51])=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH3:2]
Reactant: CCOC[C@H]1CC[C@H](c2ccc(C(=O)Oc3cc(F)c(C#N)c(F)c3)cc2)CC1
Reactant: O=S(Cl)Cl
Agent: CCOC[C@H]1CC[C@H](c2ccc(C(=O)O)cc2)CC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC[C@H]1CC[C@H](c2ccc(C(=O)Cl)cc2)CC1

Procedure:
Preparation of 3,5-difluoro-4-cyanophenyl 4-(trans-4-(ethoxymethyl)cyclohexyl)benzoate (in the formula (1), R=C2H5, l=1, m and n=both, 1, o=0, A1 =trans-1,4-cyclohexylene group, A2 =1,4-phenylene group, Z1 =covalent bond, Z2 =--COO--, X=CN, and Y1 and Y2 =both, F) (Compound No. 187) 4-(Trans-4-(ethoxymethyl)cyclohexyl)benzoic acid (1.9 g, 7.1 mmol) was mixed with thionyl chloride (1.3 g, 10.6 mmol), pyridine (0.1 ml) and toluene (4 ml), followed by reacting them at 80° C. for 2 hours, and distilling off superfluous thionyl chloride and toluene under reduced pressure, to obtain raw 4-(trans-4-(ethoxymethyl)cyclohexyl)benzoyl chloride.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[F:15][C:16]1[CH:17]=[C:18]([N:28]2[CH2:32][CH:31]([CH2:33][NH2:34])[O:30][C:29]2=[O:35])[CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.FC1C=C(N2C[C@H](CN)OC2=O)C=CC=1N1CC[O:46][CH2:45][CH2:44]1>>[F:15][C:16]1[CH:17]=[C:18]([N:28]2[CH2:32][C@H:31]([CH2:33][NH:34][C:45](=[O:46])[CH3:44])[O:30][C:29]2=[O:35])[CH:19]=[CH:20][C:21]=1[N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: NCC1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Yield: 90 %

Procedure:
The procedure is the same as in Example 45 except that the dihydrochloride of 3-(3-fluoro-4-morpholinylphenyl-5-aminomethyl-1,3-oxazolidin-2-one (5a) was replaced by dihydrochloride of 3-(3-fluoro-4-morpholinylphenyl)-5(S)-aminomethyl-1,3-oxazolidin-2-one ((S)-5b) to obtain (S)—N-((3-(3-fluoro-4-(4-morpholinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)acetamide (Linezolid) having a melting point of 78-179° C. and at a yield of 90%; [∝]D20=−9.1° (c 1.0, CHCl3); 1H NMR(CDCl3, 400 MHz) δ 7.43 (dd, J1=2.8 Hz, J2=14.4 Hz, 1H, Ar—H), 7.06 (dd, J1=1.6 Hz, J2=8.8 Hz, 1H, Ar—H), 6.94 (t, J=9.2 Hz, 1H, Ar—H), 6.17 (t, J1=6.0 Hz, 1H, NH), 4.80-4.74 (m, IH, CHO), 4.02 (t, J=8.8 Hz, 1H, CH2CHO), 3.86 (t, J=4.8 Hz, 4H, 2×OCH2), 3.75 (dd, J1=6.8 Hz, J2=8.8 Hz, 1H, CH2CHO), 3.71-3.58 (m, 2H, CH2NH), 3.06 (t, J=4.8 Hz, 4H, 2×NCH2), 2.02 (s, 3H, CH3CO); 13C NMR (CDCl3, 100 MHz) 171.4, 155.7 (d, J=245 Hz), 154.5, 136.4 (d, J=8.8 Hz), 132.8 (d, J=10.4 Hz), 118.6 (d, J=3.9 Hz), 113.8 (d, J=3.0 Hz), 107.4 (d, J=26.1 Hz), 72.0, 66.8, 50.8, 47.5, 41.7, 22.8; HR-TOF-MS (+Q) m/z: 338.1518 (Calculated [C16H20FN3O4+H]+: 338.1516).
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][C:16]2=[CH:19][NH:20][CH:21]=[C:15]2[C:14]1=[O:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].CN([CH:26]=[O:27])C>>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][C:16]2=[C:19]([CH:26]=[O:27])[NH:20][CH:21]=[C:15]2[C:14]1=[O:22])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCc2c[nH]cc2C1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCc2c(c[nH]c2C=O)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
POCl3 (0.646 mL, 6.93 mmol) was added dropwise to the ice-cooled DMF (1.5 mL, 18.9 mmol). After stirring at room temperature for 30 minutes, the mixture was re-cooled to −5° C. and to it was added a solution of the above 4-oxo-2,4,6,7-tetrahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid tert-butyl ester (1.5 g, 6.3 mmol) in DMF (3 mL). The mixture was stirred at room temperature for 6 hours. The reaction mixture was quenched with ice cubes followed by the addition of 10 N potassium hydroxide, adjusting pH to 11-12. After stirring for 30 minutes, the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried, and concentrated to give 1.2 g of 1-formyl-4-oxo-2,4,6,7-tetrahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid tert-butyl ester.
Reaction SMILES: C([O:8][C:9](=[O:25])[C:10]([C:13]1[N:14](CC2C=CC=CC=2)[CH:15]=[CH:16][N:17]=1)([CH3:12])[CH3:11])C1C=CC=CC=1>C(O)C>[NH:14]1[CH:15]=[CH:16][N:17]=[C:13]1[C:10]([CH3:12])([CH3:11])[C:9]([OH:25])=[O:8]
Reactant: CC(C)(C(=O)OCc1ccccc1)c1nccn1Cc1ccccc1
Solvent: CCO
Product: CC(C)(C(=O)O)c1ncc[nH]1

Procedure:
3.334 g of 2-(1-benzyl-1H-imidazol-2-yl-2-methyl-propionic acid benzyl ester are hydrogenated at 440 psi in ethanol (50 ml) at 50° C. for 24 hours. The catalyst is removed by filtration over Hyflo and the filtrate is concentrated under reduced pressure to provide the title compound which can be used without further purification.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1B(O)O.[N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][CH:14]=1>ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1
Reactant: OB(O)C1=Cc2ccccc2C1
Reactant: c1ccc2[nH]cnc2c1
Solvent: ClCCl
Product: C1=C(n2cnc3ccccc32)Cc2ccccc21
Reaction time: 20 h

Procedure:
In 100 ml Erlenmeyer flask a mixture of 3.20 g (20.0 mmol) of 1H-inden-2-ylboronic acid, 1.18 g (10.0 mmol) of benzimidazole, 0.93 g (2.00 mmol) of [(TMEDA)CuOH]2Cl2, and 40 ml of dichloromethane was stirred for 20 hours (in air). The resulted mixture was passed through short column with Silica Gel 60 (40-63 μm, d 40 mm, l 20 mm). This column was additionally washed by 500 ml of dichloromethane. The combined elute was evaporated to dryness. The crude product was purified using medium-pressure chromatography on Silica Gel 60 (40-63 μm, d 40 mm, l 350 mm; eluent: hexanes/dichloromethane=1/1). Yield 530 mg (23%) of white solid.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH:4]([NH2:12])[CH2:3][CH2:2]1.[CH3:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:17]=1[N:25]=[C:26]=[O:27])[CH3:15]>C(OCC)(=O)C>[CH3:15][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:23])[CH3:24])[C:17]=1[NH:25][C:26]([NH:12][CH:4]1[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH2:2][CH2:3]1)=[O:27])[CH3:13]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: NC1CCOc2ccccc2C1
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NC1CCOc2ccccc2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.7 %

Procedure:
To a solution of 2,3,4,5-tetrahydro-benzoxepin-4-amine (0.95 g, 5.8 mmol) in 50 ml of ethyl acetate was added 1.18 g (5.8 mmol) of 2,6-bis(1-methylethyl)phenyl isocyanate. The resulting mixture was stirred at room temperature for 20 hours. The precipitated solid was collected by filtration, washed with ethyl acetate, and dried to yield 1.1 g of N-[2,6-bis(1-methylethyl)-phenyl]-N'-(2,3,4,5-tetrahydrobenzoxepin-4-yl)urea, mp 184-186° C.
Reaction SMILES: [CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][C@H:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1.[CH:41](=O)[CH2:42][CH3:43].CC#N.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.O>[CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][CH:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:30][CH2:31][N:32]([CH2:41][CH2:42][CH3:43])[CH2:33][CH2:34]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCNCC2)C4)c(C)c1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: CCCN1CCC(N2Cc3cc4nc(-c5c(NCC(O)COc6ccc(C)cc6C)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 57 %

Procedure:
To a solution of 2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (27.1 mg, 0.05 mmol) and propionaldehyde (150 μL) in a mixed solvent of CH3CN (6 mL) and H2O (2 mL) was added HOAc (500 μL) at 0° C. and the resulting reaction mixture was stirred at 0° C. for 20 min and followed by addition of Na(OAc)3BH (254 mg, 1.2 mmol). The reaction mixture was stirred at 0° C. for 1 h and at the room temperature for 1 h and then evaporated. Chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (490:10:1) afforded the title compound (16.5 mg, 57%). 1H NMR (DMSO-d6) δ 0.87 (t, J=6 Hz, 3H, CH3), 1.45 (m, 2H), 1.70 (m, 2H), 1.80 (m, 2H), 2.04 (m, 2H), 2.19 (s, 3H, CH3), 2.22 (s, 3H, CH3), 2.97 (m, 2H), 3.55 (m, 1H), 3.70 (m, 1H), 3.95-4.06 (3H), 4.11 (m, 1H), 4.42 (s, 1H), 4.47 (s, 1H), 5.47 (d, J=3 Hz, 0.5H, NH), 5.52 (d, J=3 Hz, 0.5H, NH), 6.22 (m, 1H), 6.81 (m, 1H), 6.89-6.99 (2H), 7.32-7.38 (1.5H), 7.68 (s, 0.5H), 7.80 (s, 0.5H), 7.94 (s, 0.5H), 11.15 (d, J=6 Hz, 1H, NH), 11.21 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 585.5 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:17](O)[CH2:18][OH:19].C(OC)(OC)OC>>[OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]2([C:8]3[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=3)[O:19][CH2:18][CH2:17][O:7]2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: COC(OC)OC
Product: Oc1ccc(C2(c3ccc(O)cc3)OCCO2)cc1
Reaction time: 18 h

Procedure:
2,2-bis(4-hydroxyphenyl)-1,3-dioxolane was prepared by the procedure of Example 5 by mixing together, in a reaction flask fitted with a mechanical stirrer, thermometer, and variable take-off distillation head, 99 gm of 4,4'-dihydroxybenzophenone (97% pure, 0.448 mole), 269 gm of ethylene glycol (4.3 moles), 96 gm of trimethyl orthoformate (0.91 mole), and 150 gm of montmorillonite clay (K-10, United Catalysts) and heating the reaction mixture at 70° to 90° to give slow distillation of the reaction by-products. After about 18 hours, 66 gm of distillate had been collected, an additional 64 gm of trimethylorthoformate (0.60 mole) was added to the reaction mixture, and the reaction continued. After a total of 24 hours reaction time, NMR analysis of a reaction sample showed about 2.23 mole ratio of ketal product to ketone starting material; after a total of 48 hours reaction time, NMR analysis of a second reaction sample showed the mole ratio was about 19 (about 95% conversion to ketal product). The reaction mixture was heated for an additional 8 hours and then cooled; NMR analysis again showed about 95% conversion.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH3:12][C:13]1[O:17][N:16]=[CH:15][C:14]=1[C:18](Cl)=[O:19]>C([O-])(O)=O.[Na+].CN(C)C(=O)C.C1(C)C=CC=CC=1>[CH3:12][C:13]1[O:17][N:16]=[CH:15][C:14]=1[C:18]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:9][CH:8]=1)=[O:19]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1oncc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: Cc1oncc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
4-Trifluoromethylaniline (5.75 g, 35.7 mm) was dissolved in a mixture of NaHCO3 (3.16 g, 37.6 mm), N,N-dimethylacetamide (0.7 ml, 7.5 mm) and toluene (70 ml). The mixture was warmed to 40° C. and 5-methylisoxazole-4-carboxylic acid chloride (5 g, 34.4 mm) was added dropwise over 20 min. The mixture was stirred at this temperature for another 3 h. and then it was heated to reflux temperature. The hot mixture was washed with water (3×10 ml). The organic phase was allowed to cool to ambient temperature, which induced leflunomide to precipitate as a white powder. The powder was isolated by filtration and then dried at 60° C. to give leflunomide (8.0 g, 86%) in 99.5% purity.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].[H][H]>>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9]
Reactant: OCCc1ccccn1
Reactant: [H][H]
Product: OCCC1CCCCN1

Procedure:
Low pressure hydrogenations were carried out by charging 250 mL of solvent, 246 g of 2-pyridineethanol, and catalyst into a pressure vessel capable of agitation, agitating the resulting mixture and pressurizing the vessel and its contents to 500 psi with hydrogen. Under constant hydrogen pressure and continued agitation, the reaction mixture was heated to 150° C. until hydrogen uptake ceased. The pressure vessel and its contents were cooled, vented and the catalyst removed with vacuum filtration. Upon distillation of the filtrate, 2-piperidineethanol was obtained and analyzed on two separate gc columns (6′ CW 20M 160° C. and 15M DB-1 80° C.→220° C.@ 16° C./m capillary column) to provide product yield and composition of the distillate. The results are provided in Table I.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O:34]CC)=[O:33].[OH-].[Na+].C1COCC1.Cl>C(OCC)(=O)C.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH2:22][C:23]3[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4cc(Cl)cc(Cl)c4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(NCCc1cc(Cl)cc(Cl)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Yield: 82.7 %

Procedure:
ethyl 6-chloro-7-(4-(3,5-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate (76.4 mg, 0.139 mmol) was reacted with 1.0 molar sodium hydroxide (557 μl, 0.557 mmol) in a 3:1 THF:Ethanol solution (0.05 M). After 2 hours the reaction was diluted with ethyl acetate, neutralized with 1.0 molar hydrochloric acid (585 μl, 0.585 mmol) and partitioned between saturated aqueous sodium chloride. The organic layer was dried with sodium sulfate, filtered, concentrated, and dried under high vacuum to provide the title compound (72.5 mg, 0.115 mmol, 82.8% yield) as a solid.