Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][C:19](=O)[NH2:20])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>ClCCl>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCN1CCC(CCCC(N)=O)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN1CCC(CCCCN)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
A solution of compound 4c (250 mg, 0.80 mmol) in dichloromethane (10 mL) was cooled to 0° C., then DIBAl-H (7.4 mL, 7.4 mmol of 1M in toluene) was added dropwise into the solution over 45 min. The mixture was stirred for 1 hour, then warmed to room temperature and stirred for 14 h. The reaction was quenched with potassium sodium tartrate aqueous solution. The mixture was extracted with dichloromethane (3×10 mL). The combined extracts were washed with water and brine, dried over sodium sulfate and concentrated under vacuum to afford an oil. Purification by column chromatography (silica; 90:10, v/v, dichloromethane/methanol followed by 89:10:1 dichloromethane/methanol/ammonium hydroxide) produced the desired product 5c (54 mg, 23% un-optimized yield) as a clear colorless oil. 1H NMR (500 MHz, CDCl3) δ 1.21-1.26 (m, 8H), 1.42-1.46 (m, 11H), 1.64-1.67 (m, 3H), 1.91-1.99 (m, 2H), 2.41-2.48 (m, 2H), 2.67-2.70 (m, 2H), 2.83-2.86 (m, 2H), 3.20-3.22 (m, 2H), 5.00 (br s, 1H). m/z (ESI): 300 [C16H33N3O2+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][O:10][C:11]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:35])[CH:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[CH:23][CH:22]=4)=[O:19])=[CH:14][C:12]=3[CH:13]=2)=[CH:4][CH:3]=1.[CH3:36][I:37]>CN(C=O)C>[I-:37].[CH3:35][N+:28]([CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)([CH3:36])[CH2:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:18]([C:15]2[CH:16]=[CH:17][C:11]3[O:10][CH2:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=4)=[CH:13][C:12]=3[CH:14]=2)=[O:19])=[CH:22][CH:23]=1
Reactant: CI
Reactant: Cc1ccc(C2=Cc3cc(C(=O)Nc4ccc(CN(C)C5CCOCC5)cc4)ccc3OC2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(C2=Cc3cc(C(=O)Nc4ccc(C[N+](C)(C)C5CCOCC5)cc4)ccc3OC2)cc1
Product: [I-]
Reaction time: 72 h

Procedure:
Into a solution of 3-(4-methylphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-2H-1-benzopyran-6-carboxamide (80 mg) in DMF (30 ml) was added at room temperature methyl iodide (0.04 ml), and the resulting mixture was stirred for 3 days. After evaporation of the solvent under reduced pressure, ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration to obtain N,N-dimethyl-N-[4-[[3-(4-methylphenyl)-2H-1-benzopyran-6-carbonyl]amino]benzyl]-4-tetrahydropyranylammonium iodide (compound 28) (87 mg) as light yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:7])=[CH:4][CH:3]=1.[C:15]1(=O)[CH:20]=[CH:19][C:18](=[O:21])[CH:17]=[CH:16]1>CO.C(OCC)C.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:7][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=3[C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:13][CH:14]=1
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Reactant: O=C1C=CC(=O)C=C1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2ccc(O)cc12
Temperature: 75 °C
Reaction time: 1 h

Procedure:
Using oven dried glassware and under an atmosphere of nitrogen, anhydrous zinc chloride (25 g, 183 mmol) was stirred in anhydrous methanol (60 mL) then heated to a 75° C. internal temperature. Methyl 4-fluorobenzoylacetate (39.6 g, 202 mmol) was added as a single portion followed by dropwise addition of a solution of p-benzoquinone (19.83 g, 183 mmol) in anhydrous diethyl ether (500 mL) over 4 hours. This was performed with a simultaneous distillation of ether from the reaction mixture such that the reaction volume remained approximately constant (a bath temperature of 140° C. maintained an internal temperature initially at 75° C. then gradually increasing to a maximum of 115° C.). 2.5 hours after the start of the benzoquinone addition, more methanol (20 mL) was added to facilitate stirring. After addition of benzoquinone was complete, heating of the reaction mixture at 100° C. (internal) continued for 1 hour. The reaction mixture was cooled to room temperature and partitioned between water (500 mL) and ethyl acetate (800 mL). The insoluble solids were removed from the biphasic solution by filtration and the organic layer was then separated, dried (Na2SO4), filtered and evaporated under vacuum. The brown residue was slurried in warm dichloromethane (˜225 mL) and the mixture was left to stand in a refrigerator for 18 hours. The resulting solids were filtered from the dark brown solution, washed with a small volume of dichloromethane then dried under vacuum to give Methyl 2-(4-fluorophenyl)-5-hydroxy-1-benzofuran-3-carboxylate. LCMS (m/z, ES+)=285 (M−1).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([O:9][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Reactant: BrCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(=O)SCC(CC(C)C)C(=O)OCc1ccccc1
Yield: 83.2 %

Procedure:
A solution of 3-acetylthio-2-isobutylpropionic acid [obtained by Michael addition of thiolacetic acid onto 2-isobutylacrylic acid] (7 g, 34.3 mmol), benzyl bromide (4.29 ml, 36 mmol) and DBU (5.2 ml, 35 mmol) in toluene (55 ml) was stirred for 18 hours at room temperature. The solvents were evaporated in vacuo. The residue was partitioned between ethyl acetate and 5% sodium bicarbonate. The organic layer was washed with brine and dried over MgSO4. Purification of the residue by chromatography on silica gel (eluant: dichloromethane-ether (9:1)) gave benzyl 3-acetylthio-2-isobutylpropionate (8.4 g)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C@H:6]1[CH2:28][C@@:27]2([CH3:29])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:26]2[C:25](=[O:30])[CH2:24][C@@:23]2([CH3:31])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17]2(OCC[O:19]2)[CH3:18])[CH2:8][C@@H:7]1[OH:32].O.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[OH:32][C@@H:7]1[C@@H:6]([O:5][CH2:4][CH2:3][CH2:2][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:28][C@@:27]2([CH3:29])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:26]2[C:25](=[O:30])[CH2:24][C@@:23]2([CH3:31])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17](=[O:19])[CH3:18])[CH2:8]1
Reactant: C1COCCN1
Reactant: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](OCCCCl)C[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1
Solvent: O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCN5CCOCC5)C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
2β-(3'-Chloropropoxy)-20,20-ethylenedioxy-3α-hydroxy-5α-pregnan-11-one (500 mg.) was dissolved in morpholine (5 ml.) and the solution heated on a steambath for 8 hours. The solution was poured into water and the precipitate extracted into ether (70 ml.). The ethereal solution was washed with water, dried over anhydrous sodium sulphate and evaporated to a white foam (480 mg.) which was dissolved in 35% aqueous acetic acid and the solution heated on a steam-bath for 3 hours. The solution was cooled in ice and an ice-cooled solution of 10N-potassium hydroxide added to the stirred solution in the presence of ether (100 ml.) until the aqueous layer was basic. The aqueous layer was extracted with ether (50 ml.) and the combined ether extracts washed with water, dried over anhydrous sodium sulphate and evaporated to a white foam (390 mg.) which was purified by preparative TLC in acetone to give the title compound (250 mg.) as a white foam, [α](c D + 65.0° (C 1.02).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12](=[N:14]O)[CH3:13])[CH:3]=1.[NH4+].[Cl-]>CO.[Zn]>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([CH:12]([NH2:14])[CH3:13])[CH:3]=1
Reactant: CC(=NO)c1cc(F)cc2c1cnn2C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(N)c1cc(F)cc2c1cnn2C
Yield: 99.1 %

Procedure:
To the solution of 1-(6-fluoro-1-methyl-1H-indazol-4-yl)ethanone oxime (848 mg, 4.10 mmol) in MeOH (60 mL) was added powdered Zn (13.6 g, 212.5 mmol, 50.0 eq.) and NH4Cl (13.6 g, 251 mmol, 60.0 eq.). The mixture was heated at reflux overnight, filtered, and concentrated in vacuo. To the residue was added DCM, and the mixture was washed with water, dried (MgSO4) and concentrated in vacuo to afford 1-(6-fluoro-1-methyl-1H-indazol-4-yl)ethanamine (131) as syrup (785 mg, 87%). MS (ESI): m/z=177.2 [M−NH2]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=3[F:25])[CH:9]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[O:39])[CH2:35][C:36](O)=[O:37].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([N:3]1[C:7]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:24]=[CH:23][C:21]([NH:22][C:36](=[O:37])[CH2:35][C:34]([NH:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[F:26])=[O:39])=[CH:20][C:19]=3[F:25])[CH:9]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2]
Reactant: O=C(O)CC(=O)Nc1ccccc1F
Reactant: CCn1cncc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCn1cncc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccccc4F)cc3F)c2s1
Reaction time: 1 h
Yield: 60.4 %

Procedure:
To a solution of the amino compound 120 (400 mg, 1.08 mmol) in DMF (10 mL), 3-(2-fluorophenylamino)-3-oxopropanoic acid (444 mg, 2.25 mmol), EDC (519 mg, 2.70 mmol) was added HOBT (364 mg, 2.70 mmol). The reaction mixture was allowed to stir for 1 hr. The solution was extracted with EtOAc and the extract was washed with water, aqueous ammonium chloride and brine then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (eluents DCM-MeOH, 98:2, 95:5) to afford title compound 117 (348 mg, 58% yield) as a white solid. 1H NMR (DMSO-d6). δ ppm: 10.58 (s, 1H), 10.06 (s, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.10-7.76 (m, 1H), 7.94 (d, J=1.2 Hz, 1H), 7.88 (dd, J=2.4 and 13.2 Hz, 1H), 7.74 (s, 1H)), 7.51 (t, J=8.8 Hz, 1H), 7.43 (dd, J=1.6 and 8.8 Hz, 1H), 7.39 (d, J=1.2 Hz, 1H), 7.32-7.25 (m, 1H), 7.21-7.14 (m, 2H), 6.66 (d, J=5.6 Hz, 1H), 4.29 (q, J=7.2 Hz, 2H), 3.62 (s, 2H), 1.34 (t, J=7.2 Hz, 3H). MS (m/z): 534.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=2[OH:25])([CH2:15]O)[C:7]1=[O:26])[CH3:2].ClC1C=CC(Cl)=C2C=1C(C1C(O)=CC3OCOC=3C=1)(CO)C(=O)N2CCCCC>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=3[O:25][CH2:15]2)[C:7]1=[O:26])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)C(CO)(c2cc(F)c(F)cc2O)c2ccccc21
Agent: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2c(Cl)ccc(Cl)c21
Product: CCOC(=O)CN1C(=O)C2(COc3cc(F)c(F)cc32)c2ccccc21
Yield: 46 %

Procedure:
Following the procedure as described in EXAMPLE 1.22, and making non-critical variations using ethyl[3-(4,5-difluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate to replace 4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 46% yield as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.31 (dt, 1H), 7.16 (dd, 1H), 7.08 (dt, 1H), 6.81-6.71 (m, 2H), 6.67 (dd, 1H), 4.98 (d, 1H), 4.74 (d, 1H), 4.64 (d, 1H), 4.37 (d, 4.24 (q, 7.1 Hz), 1.28 (t, 3H); MS (ES+) m/z 360.5 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[CH:18][CH:17]=1)[C:11]([O:13]CC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:16]1[CH:17]=[CH:18][C:19]([CH2:22][O:23][Si:24]([CH:25]([CH3:27])[CH3:26])([CH:28]([CH3:30])[CH3:29])[CH:31]([CH3:32])[CH3:33])=[CH:20][CH:21]=1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(CNC(=O)OC(C)(C)C)c1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[Si](OCc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)O)cc1)(C(C)C)C(C)C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3-(tert-butoxycarbonylamino)-2-(4-((triisopropylsilyloxy)methyl)phenyl)propanoate (E202) in methanol was added dropwise 4 N NaOH. The mixture was stirred for 2 h, adjusted the pH to 7 with 2 N HCl, and extracted with ethyl acetate. The combined organic layers were washed with 0.5 N HCl and brine, dried (MgSO4), and concentrated in vacuo to afford 3-(tert-butoxycarbonylamino)-2-(4-((triisopropylsilyloxy)methyl)phenyl)propanoic acid (E203) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@H:4]([CH2:13][C:14]1(CC2C=CC=CC=2)[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:27])[NH:22][CH:23]=[C:24]([Cl:26])[CH:25]=2)=[CH:16][CH2:15]1)[NH:5]C(OC(C)(C)C)=O>Cl.O1CCOCC1>[CH3:1][O:2][C:3](=[O:35])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:27])[N:22]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:23]=[C:24]([Cl:26])[CH:25]=2)=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](CC1(Cc2ccccc2)C=CC(c2cc(Cl)c[nH]c2=O)=CC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)Cc1ccc(-c2cc(Cl)cn(Cc3ccccc3)c2=O)cc1
Yield: 203.6 %

Procedure:
A solution of 1-benzyl-4-(5-chloro-2-oxo-3-pyridinyl)-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (248 mg, 0.50 mmol) in 4 N HCl in dioxane (10 mL) was stirred for 1 hr and was concentrated. The residue was triturated with ether (15 mL) and was filtered to give 4-(1-benzyl-5-chloro-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (202 mg, 94%) as a white powder. LR-Electrospray: m/z 1015 (2M+Na, 4 Cl), 519 (M+Na) 514 (M+NH4), 497 (M+H). HRMS: Obs. Mass 496.1774. Calcd. Mass 496.1765 (M+H).
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](NCC3C=CC=CN=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:25]([C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1)([CH3:27])[CH3:26]>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:33][CH2:32][C:31]3[CH:30]=[CH:29][C:28]([CH:25]([CH3:27])[CH3:26])=[CH:35][CH:34]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: CC(C)c1ccc(CN)cc1
Agent: Cl
Product: Cc1nc(NCc2ccc(C(C)C)cc2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using (4-isopropylbenzyl)amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.08 (d, J=15.04 Hz, 1H), 1.17 (d, J=6.72 Hz, 6H), 1.24-1.31 (m, 4H), 1.60 (s, 1H), 1.68 (t, J=11.95 Hz, 4H), 1.87 (s, 3H), 2.22 (s, 3H), 2.84 (t, J=13.90, 6.88 Hz, 1H), 3.89 (d, J=7.52 Hz, 1H), 4.48 (d, J=5.37 Hz, 2H), 7.14-7.28 (m, 4H), 7.55 (d, J=7.52 Hz, 1H), 8.06 (s, 1H), 12.69 (bs, 1H); MS (ESI) m/z 353.0 (M+1)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].[Cl:9][C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:12]([NH:22][CH2:23][CH:24](O)[CH2:25][CH3:26])[N:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:9][C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=[C:12]([N:22]2[CH2:23][CH:24]([CH2:25][CH3:26])[O:8][CH:7]2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:11]=1
Reactant: O=Cc1ccccn1
Reactant: CCC(O)CNc1cc(C(F)(F)F)c(C#N)c(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCC1CN(c2cc(C(F)(F)F)c(C#N)c(Cl)n2)C(c2ccccn2)O1

Procedure:
Pyridine-2-carboxaldehyde (207 mg, 1.9 mmol) was added to a toluene solution (15 mL) of 2-chloro-6-(2-hydroxybutylamino)-4-(trifluoromethyl) pyridine-3-carbonitrile (400 mg, 1.3 mmol) followed by a catalytic amount of para-toluene sulfonic acid (50 mg). The reactants were refluxed for 6 hours in a Dean-Stark apparatus, concentrated under reduced pressure, adsorbed onto silica and purified using a neutral alumina column, eluting with a mobile phase of 10% ethyl acetate in hexane. 2-Chloro-6-[5-ethyl-2-(2-pyridyl)oxazolidin-3-yl]-4-(trifluoromethyl) pyridine-3-carbonitrile (Compound 19) was isolated as a solid in 46% yield. mp 99-102° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:16][CH3:17])[C:5]([O:14][CH3:15])=[C:6]([CH:8]2[O:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH:7]=1.[Li]C(C)(C)C.[C:23]1([CH3:31])[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=1.O>C1COCC1>[O:9]1[CH2:10][CH2:11][CH2:12][O:13][CH:8]1[C:6]1[CH:7]=[C:2]([CH:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:31])=[CH:24][CH:25]=2)[OH:30])[CH:3]=[C:4]([O:16][CH3:17])[C:5]=1[O:14][CH3:15]
Reactant: COc1cc(Br)cc(C2OCCCO2)c1OC
Reactant: Cc1ccc(C=O)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(O)c2ccc(C)cc2)cc(C2OCCCO2)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(5-Bromo-2,3-dimethoxy-phenyl)-[1,3]dioxane (2 g, 6.6 mmol) in 13 mL dry THF cooled to −78° C., t-BuLi (1.5M solution in pentane, 2.5 eq.) was added dropwise via a syringe and the resulting dark red suspension was stirred 30 min. at −78° C. p-Tolualdehyde (1.2 g, 10 mmol, 1.5 eq.) was added dropwise to the mixture and the resulting clear solution was stirred 30 min at −78° C., then 30 min at 0° C. H2O (25 mL) was slowly added and the resulting solution was extracted with EtOAc (3×25 mL). The pooled organic fractions were dried over MgSO4 and evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc 3:2) to yield the desired compound as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[C:5]([CH:20]=O)[CH:4]=1)#[N:2].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(O)(=O)C.C([BH3-])#N>CO.O>[OH:16][B:15]1[C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]3[CH:18]=[CH:19][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[CH2:20][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:17][C:12]=2[CH2:13][O:14]1
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(C=O)c1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.7 %

Procedure:
A mixture of 5-(4-Cyano-2-formylphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (D23) (0.400 g, 1.43 mmol), morpholine (0.375 mL, 4.29 mmol), and acetic acid (0.246 mL, 4.29 mmol) in methanol (10 mL) was stirred for five minutes under nitrogen at room temperature. Cyanoborohydride (0.270 g, 4.29 mmol) was added, and the mixture was stirred at room temperature under nitrogen for two hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (5:5 ethyl acetate: hexanes to 4:1 dichloromethane/methanol). The desired fractions were combined and the solvent was removed under reduced pressure. Water and toluene were added and removed under reduced pressure to give pure 4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-3-(morpholinomethyl)benzonitrile (0.399 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:31].[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(C(C)C)CC)(C)C.O>O1CCCC1>[CH3:32][S:33]([O:31][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:9][S:10](=[O:12])(=[O:13])[C:11]=2[C:2]=1[NH2:1])(=[O:35])=[O:34]
Reactant: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3c(ccc(O)c3N)N2)c(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3c(ccc(OS(C)(=O)=O)c3N)N2)c(O)c2ccccc21
Yield: 247.5 %

Procedure:
A solution of the product of Example 354 (44 mg, 0.099 mmol) and methane sulfonyl chloride (0.010 mL, 0.011 mmol) in tetrahydrofuran (4 mL) was treated with diisopropylethylamine (0.075 mL, 0.040 mmol) at roo, temperature for 2 hours. The solution was poured into water. The resulting the precipitate was filtered, dried, and purified by flash column, eluting with 1% methanol in dichloromethane to yield the title compound (14.2 mg, 28%). The sodium salt was made by the procedure of Example 1D. MS (ESI−) m/z 520 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 1.03 (d, J=6.62 Hz, 6 H) 1.88 (m, 1 H) 2.71 (m, 2 H) 3.46 (s, 3 H) 5.94 (m, 1 H) 6.53 (m, 1 H) 7.16 (m, 1 H) 7.35 (m, 1 H) 7.64 (m, 2 H) 8.09 (d, J=7.35 Hz, 1 H) 16.23 (s, 1 H).
Reaction SMILES: [Li]CCCC.[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][CH:22]=[CH:23][CH:24]=3)=[C:16]([F:25])[CH:15]=2)=[CH:10][CH:9]=1)[CH3:7].[CH:26](N1CCOCC1)=[O:27]>C1COCC1.ClCCl.Cl>[CH2:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][C:22]([CH:26]=[O:27])=[CH:23][CH:24]=3)=[C:16]([F:25])[CH:15]=2)=[CH:12][CH:13]=1)[CH3:7]
Reactant: O=CN1CCOCC1
Reactant: CCc1ccc(-c2ccc(-c3ccc[se]3)c(F)c2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1ccc(-c2ccc(-c3ccc(C=O)[se]3)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
27.5 ml (0.16 mol) of TMP are initially introduced at −20° C. in 100 ml of THF, and 100 ml (0.16 mol, 15% soln. in hexane) of n-BuLi are metered in. After 30 min at this temperature, a solution of 50.2 g (0.15 mol) of 2-(4′-ethyl-3-fluorobiphenyl-4-yl)selenophene in 400 ml of THF is added. When the addition is complete, the batch is warmed to RT and left at this temperature for 30 min. The solution is cooled to −70° C., and 17.0 ml (0.17 mol) of N-formylmorpholine are added. The reaction mixture is warmed to RT and stirred for 1 h. the solution is diluted with a lot of dichloromethane, and 2 N hydrochloric acid is added. The mixture is washed with water, and the organic phase is separated off. The aqueous phase is extracted with dichloromethane, and the combined organic phases are washed with sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is taken up in dichloromethane and purified by column chromatography (SiO2, toluene). The further purification is carried out by recrystallisation from toluene. 5-(4′-Ethyl-3-fluorobiphenyl-4-yl)selenophene-2-carbaldehyde is obtained as a brown solid.
Reaction SMILES: C([C:9]1[C:13]([NH:14][C:15](=[O:28])[CH2:16][N:17]2[C:21](=O)[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3C2=O)=[CH:12][N:11](C)[CH:10]=1)(=O)C1C=CC=CC=1.NN.[CH3:32]O>>[CH3:32][C:10]1[NH:11][CH:12]=[C:13]2[C:9]=1[C:21]([C:20]1[CH:19]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N:17][CH2:16][C:15](=[O:28])[NH:14]2
Reactant: Cn1cc(NC(=O)CN2C(=O)c3ccccc3C2=O)c(C(=O)c2ccccc2)c1
Reactant: CO
Agent: NN
Product: Cc1[nH]cc2c1C(c1ccccc1)=NCC(=O)N2

Procedure:
3-Benzoyl-1-methyl-4-(phthalimidoacetamido)pyrrole (38 g.) is reacted with 6 g. of anhydrous hydrazine in 300 ml. of methanol according to the procedure of the foregoing example. After evaporation of the solvent and refluxing the residue with concentrated hydrochloric acid, the reaction mixture is filtered and the filtrate is alkalinized with dilute sodium hydroxide. The precipitate is crystallized from methanol. Yield 19 g. The compound decomposes at 400° C. without melting.