Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:28])[C:15]([O:18][C:19]1[C:24]([CH:25]=O)=[CH:23][C:22]([Cl:27])=[CH:21][N:20]=1)([CH3:17])[CH3:16].N1CCCC1>CO>[CH3:12][O:13][C:14](=[O:28])[C:15]([O:18][C:19]1[C:24](/[CH:25]=[C:6]2\[C:7](=[O:11])[NH:8][C:9]3[C:5]\2=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)=[CH:23][C:22]([Cl:27])=[CH:21][N:20]=1)([CH3:17])[CH3:16]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: COC(=O)C(C)(C)Oc1ncc(Cl)cc1C=O
Solvent: C1CCNC1
Solvent: CO
Product: COC(=O)C(C)(C)Oc1ncc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 78.9 %

Procedure:
To the mixture of 6-chlorooxindole (4.9 g, 29.3 mmol) and 2-(5-Chloro-3-formyl-pyridin-2-yloxy)-2-methyl-propionic acid methyl ester (7.2 g, 28 mmol) in methanol (50 mL) was added pyrrolidine (2.3 mL, 28 mmol) dropwise. The mixture was then heated at 70° C. for 1 h. After cooled to room temperature, the mixture was filtered and the precipitate was collected, dried to give title compound as a yellow solid (9 g).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=O)[CH2:11][CH2:10][C@H:9]1[C:14]([NH2:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>O1CCCC1>[CH2:1]([NH:8][CH2:12][CH:11]1[CH2:10][CH2:9][CH2:14][NH:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H]1CCC(=O)N1Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc(CNCC2CCCN2)cc1
Yield: 122.7 %

Procedure:
Benzyl-(-)-pyroglutamide (60 g.) was suspended in one liter of tetrahydrofuran (THF) and stirred under nitrogen. The mixture was cooled to below 10° C. in an ice bath and one liter of 1 M BH3THF complex was slowly added. The mixture was stirred for 20 hours at room temperature and then refluxed for 28 hours. The reaction mixture was then cooled and 200 milliliters of methanol was added dropwise. The solvent was then removed and the residue dissolved in 2 N HCl and warmed in a steam bath for one hour. The solution was then cooled and filtered through Cellite®, basified with 50 percent NaOH, extracted with diethyl ether and the extract was washed with brine. The solution was dried and the solvent was removed to afford 2-benzylaminomethylpyrrolidine (64.2 g.) as a viscous oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2Cl)=[CH:4][CH:3]=1.[NH:13]1[C:21]2[C:16](=[CH:17][C:18](B(O)O)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([C:9]3[C:10]4[C:5](=[CH:4][CH:3]=[C:2]([C:18]5[CH:17]=[C:16]6[C:21](=[CH:20][CH:19]=5)[NH:13][CH:14]=[CH:15]6)[CH:11]=4)[CH:6]=[CH:7][N:8]=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: Clc1nccc2ccc(Br)cc12
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cc2ccc(-c3ccc4[nH]ccc4c3)cc2c(-c2ccc3[nH]ccc3c2)n1
Temperature: 25 °C
Yield: 38.4 %

Procedure:
A mixture of 7-bromo-1-chloroisoquinoline (0.20 g, 2.1 mmol), 5-indoleboronic acid (0.80 g, 5.0 mmol), tetrakis(triphenylphosphene)palladium (0.19 g, 0.16 mmol), potassium carbonate (2.1 mL, 2 M, 4.1 mmol), N,N-dimethylformamide (11 mL) was stirred while purging the headspace with argon for 30 min. The mixture was then brought to reflux for 16 h before being allowed to cool to RT. The mixture was filtered through a bed of silica gel, diluted with water (50 mL), and extracted with ethyl acetate (50 mL). The organic layer was separated and washed with NaOH (2×20 mL, 10% aq.), water (5×30 mL, until refractive changes were no longer seen at the organic-aqueous interface), and ammonium chloride (20 mL, sat.). The organic layer was then adsorbed onto silica gel and flash-chromatographed (ethyl acetate/hexanes) to afford 0.29 g (39%) of a yellow solid. MS (ESI): calculated for C25H17N3, 359.1. found 360.2 [M+H]+382.1 [M+Na]+, and 358.0 [M−H]−. 1H NMR (500 MHz, DMSO-d6) δ 6.46-6.50 (m, 1H) 6.52-6.59 (m, 1H) 7.34-7.36 (m, 1H) 7.36-7.41 (m, 2H) 7.42-7.52 (m, 3H) 7.58 (d, J=8.30 Hz, 1H) 7.81 (dd, J=5.49, 5.00 Hz, 2H) 7.92 (s, 1H) 8.08-8.17 (m, 2H) 8.33 (s, 1H) 8.54 (d, J=5.61 Hz, 1H) 11.18 (br. s., 1H) 11.30 (br. s., 1H) ppm.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C:2]1=[O:10].Cl[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:14][N+:13]=1[O-]>>[O:22]1[CH2:23][CH2:24][N:19]([CH2:18][C:15]2[CH:16]=[CH:17][C:12]([C:3]3[C:4]4[C:5](=[CH:6][N:7]=[CH:8][CH:9]=4)[NH:1][C:2]=3[OH:10])=[N:13][CH:14]=2)[CH2:20][CH2:21]1
Reactant: [O-][n+]1cc(CN2CCOCC2)ccc1Cl
Reactant: O=C1Cc2ccncc2N1
Product: Oc1[nH]c2cnccc2c1-c1ccc(CN2CCOCC2)cn1
Yield: 14 %

Procedure:
Prepared as described in examples 2.2 and 2.3 starting from 352 mg (2.62 mmol) of 1H-pyrrolo[2,3-c]pyridin-2(3H)-one and 500 mg (2.19 mmol of 2-chloro-5-(morpholinomethyl)pyridine 1-oxide). Amount 33 mg. Yield 14%.
Reaction SMILES: [OH:1][CH:2]([CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([N:30]=[C:31]=[O:32])=[CH:24][C:23]=2[O:22]1>>[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([NH:30][C:31]([O:1][CH:2]([CH3:20])[CH2:3][N:4]3[CH2:5][CH2:6][CH:7]([C:10]4[C:18]5[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=5)[NH:12][N:11]=4)[CH2:8][CH2:9]3)=[O:32])=[CH:24][C:23]=2[O:22]1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: CC(O)CN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Product: CC(CN1CCC(c2n[nH]c3cc(F)ccc23)CC1)OC(=O)Nc1ccc2c(c1)OCO2
Yield: 8.3 %

Procedure:
Starting from 3-[1-(2-hydroxyprop-1-yl)-4-piperidinyl]-6-fluoro-1H-indazole (300 mg, 1.1 mmol) and 3,4-methylenedioxyphenylisocyanate (380 mg, 2.2 mmol) using the procedure described in example 12A was prepared 40 mg (9%) of the title compound as an amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:21])[CH2:10][C:11]1[C:19]2[O:18][CH:17]=[CH:16][C:15]=2[CH:14]=[C:13]([F:20])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22]N1C(=O)CCC1=O>>[C:1]([O:5][C:6]([NH:8][CH:9]([CH3:21])[CH2:10][C:11]1[C:19]2[O:18][C:17]([Cl:22])=[CH:16][C:15]=2[CH:14]=[C:13]([F:20])[CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(Cc1cc(F)cc2ccoc12)NC(=O)OC(C)(C)C
Product: CC(Cc1cc(F)cc2cc(Cl)oc12)NC(=O)OC(C)(C)C
Yield: 42.7 %

Procedure:
Beginning with 0.29 gm (1.0 mMol) N-tert-butoxycarbonyl 1-(5-fluorobenzofur-7-yl)-2-aminopropane and 0.16 gm (1.20 mMol) N-chlorosuccinimide, 0.14 gm (43%) of the desired compound were prepared essentially as described in EXAMPLE 16.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1>>[C:17]1([CH3:21])[CH:18]=[CH:19][CH:20]=[C:15]([NH:14][S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH:16]=1
Reactant: Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: Cc1cccc(NS(=O)(=O)c2ccc(C(=O)O)cc2)c1

Procedure:
4-(chlorosulfonyl)benzoic acid (500 mg, 2.27 mmol) was treated with m-toluidine (729 mg, 6.8 mmol) using method A to give 4-(N-m-tolylsulfamoyl)benzoic acid as an off white solid. Yield: 463 mg (70%). 1H-NMR: 8.10 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H), 7.22 (t, J=8.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.95 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 3.14 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:23]([O:22][C:20]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:21])[CH3:24]
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Nc1ccc2[nH]cc(C3=CCN(CC)CC3)c2n1

Procedure:
Beginning with 0.015 gm (0.062 mMol) 5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.068 mMol) ethyl chloroformate, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[CH:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:29][C:28]([C:27]3[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:31][CH:30]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1)([CH3:20])[CH3:19]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(OC(C)C)cc1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(OC(C)C)cc1
Yield: 19.8 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-isopropoxyphenyl)-3-oxopropionate (15.0 g) and 4-nitrobenzylamine (11.2 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-isopropoxyphenyl)-2-(4-nitrophenyl)imidazole-4-carboxylate (4.2 g).
Reaction SMILES: C=O.[CH2:3]([O:6][CH2:7][CH2:8][CH2:9]C=O)[CH2:4][CH3:5].[CH2:12]([O:15]CCCC=O)C=C>>[CH2:7]([O:6][CH:3]([CH2:4][CH3:5])[CH:12]=[O:15])[CH2:8][CH3:9]
Reactant: CCCOCCCC=O
Reactant: C=CCOCCCC=O
Agent: C=O
Product: CCCOC(C=O)CC

Procedure:
Conversion of formaldehyde was essentially complete. The crude product contained 4-propoxy-n-butyraldehyde and 4-allyloxy-n-butyraldehyde in a mol ratio of about 13:1, respectively.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15]C)=O.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>C(O)C.O>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:13]([C:3]2[C:4](=[O:12])[NH:5][C:6]3[C:11]([C:2]=2[OH:1])=[N:10][CH:9]=[CH:8][CH:7]=3)=[O:15])=[CH:20][CH:19]=1
Reactant: COC(=O)c1c(O)c2ncccc2[nH]c1=O
Reactant: NCc1ccc(F)cc1
Solvent: CCO
Solvent: O
Product: O=C(NCc1ccc(F)cc1)c1c(O)c2ncccc2[nH]c1=O
Temperature: 100 °C

Procedure:
A mixture of methyl 4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.2 g, 0.91 mmol) and 4-fluorobenzyl amine (Aldrich, 0.31 mL, 2.72 mmol) in absolute ethanol (5 mL) was heated to 100° C. for 6 hours. A thick paste formed. The reaction was diluted with water and the solids collected. The crude material was purified by preparative reverse phase HPLC eluting with a gradient of 5-95% acetonitrile/water (0.1% TFA). The product precipitated from the column fractions was collected to afford the desired product as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15](OCC)=[O:16])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].O>C(O)C>[Si:1]([O:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH2:15][OH:16])[CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(CO[Si](C)(C)C(C)(C)C)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1cc(CO)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
23.82 g of ethyl 5-(t-butyldimethylsilanyloxymethyl)-isoxazole-3-carboxylate was dissolved in 100 ml of ethanol, and 3.16 g of sodium borohydride was then added. The mixture was stirred at room temperature for 4 hours. After 50 ml of water was added, the reaction mixture was concentrated to 50 ml under reduced pressure. The concentrated solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 18.74 g of [5-(t-butyldimethylsilanyloxymethyl)isoxazol-3-yl]methanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1
Yield: 97.4 %

Procedure:
A mixture of 2-fluoro-4-nitrophenol (15 gr, 95.5 mmol) and benzyl bromide (18 g, 105 mmol) in acetone (125 ml) containing potassium carbonate (26.5 gr, 190 mmol) was heated at reflux for 2 hours. The volatiles were removed and the residue was partitioned between 2N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water, brine, dried (MgSO4) and the volatiles were removed under vacuum. The solid was triturated with petroleum ether to give 2-fluoro-4-nitro-benzyloxybenzene (23 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[C:31]#[N:32])[O:5][CH2:6][C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:22][O:23]S(C)(=O)=O.C[O-].[Na+].[C:36](OCC)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][C:7]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH2:22][O:23][CH3:36])[CH:28]=[CH:29][C:30]=1[C:31]#[N:32]
Reactant: CS(=O)(=O)OCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(Cl)c1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(Cl)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
120 mg Methanesulfonic acid 5-(3-chloro-4-cyano-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl ester were dissolved in 5 ml methanol. 12.9 mg sodium methoxide were added and the mixture stirred at 50° C. for one hour. The reaction mixture was diluted by addition of 50 ml ethyl acetate, washed with one molar hydrochloric acid then dried over MgSO4. The solvent was removed in vacuo and the residue purified by RP-HPLC to provide 30 mg of 2-chloro-4-[4-methoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzonitrile as lyophilisate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].Cl[CH2:12][C:13](Cl)=[O:14].C([O-])([O-])=O.[K+].[K+]>>[F:8][C:6]1[C:5]([F:9])=[CH:4][C:3]2[O:10][CH2:12][C:13](=[O:14])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(F)c(F)cc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2cc(F)c(F)cc2N1
Yield: 63.7 %

Procedure:
A crude of 2-amino-4,5-difluorophenol (2.67 g, 18.4 mmol), 2-chloroacetyl chloride (2.28 g, 20 mmol) and K2CO3 (5.34 g, 38.6 mmol) were mixed according to GP1. Purified by column chromatography (SiO2; heptanes/EtOAc 4:1 to 1:1) to give the title compound (2.17 g, 64%). Rf=0.43 (heptanes/EtOAc 1:1); Mp=214.5-219.2° C.; 1H NMR (CD3OD) δ 6.90 (dd, J=11.4 Hz, J=7.2 Hz, 1H), 6.80 (dd, J=11.0 Hz, J=7.7 Hz, 1H), 4.56 (s, 2H); 13C NMR (CD3OD) δ 167.0, 147.0 (dd, J=243.5 Hz, J=13.8 Hz), 146.9 (dd, J=240.0 Hz, J=13.8 Hz), 141.2 (dd, J=9.8 Hz, J=3.0 Hz), 124.8 (dd, J=8.7 Hz, J=3.0 Hz), 106.9 (dd, J=22.0 Hz, J=6.9 Hz), 105.5 (dd, J=23.1 Hz, J=4.6 Hz), 68.1 (t, J=6.5 Hz).
Reaction SMILES: [C:1]([CH:3]1[O:7]C(=O)[NH:5][C@@:4]1([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=1)[CH3:9])#[CH:2].[OH-].[Na+].CCOC(C)=O.C([O-])(O)=O.[Na+]>C(O)C>[NH2:5][C:4]([CH3:9])([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:16][CH:17]=1)[C@H:3]([OH:7])[C:1]#[CH:2]
Reactant: C#CC1OC(=O)N[C@]1(C)CCc1ccc(OCCCCCCC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C#C[C@@H](O)C(C)(N)CCc1ccc(OCCCCCCC)cc1

Procedure:
To a stirred solution of (R)-5-Ethynyl-4-[2-(4-heptyloxy-phenyl)-ethyl]-4-methyl-oxazolidin-2-one in ethanol (1 ml) is added NaOH (1 ml, 1M aqueous solution). The mixture is heated at reflux temperature for 20 hours. The reaction mixture is then poured onto a biphasic mixture of AcOEt and NaHCO3 (saturated aqueous solution). The aqueous phase is extracted with AcOEt (3 times). The combined organic layers are dried (Na2SO4) and concentrated under reduced pressure. The product is purified by RP-HPLC (ZORBAX Extend C-18) eluting with 5%→95% CH3CN in H2O (+0.1% TFA) to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[SH:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[S:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:20][CH:21]=1)([O-:14])=[O:13]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Sc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
The title compound was prepared from 1-Chloro-2-nitro-4-trifluoromethyl-benzene (250 mg, 1.10 mmol), N-(4-Mercapto-phenyl)-acetamide (185 mg, 1.10 mmol), and K2CO3 (268 mg, 1.94 mmol) heated in DMF at 100° C. for 16 hrs. Reaction mixture was then cooled to room temperature and diluted with water and extracted with ethyl acetate (350 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[NH2:15][C:16]1[CH:17]=[C:18]([C:23]2[NH:28][C:27](=[O:29])[C:26]([CH3:30])=[N:25][N:24]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:15][C:16]1[CH:17]=[C:18]([C:23]2[NH:28][C:27](=[O:29])[C:26]([CH3:30])=[N:25][N:24]=2)[CH:19]=[CH:20][C:21]=1[Cl:22])=[O:8])=[O:5]
Reactant: Cc1nnc(-c2ccc(Cl)c(N)c2)[nH]c1=O
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Solvent: CC#N
Product: Cc1nnc(-c2ccc(Cl)c(NC(=O)NC(=O)c3cc(F)c(F)cc3Cl)c2)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The solution of equivalent amounts of 2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the solution of 60 mg of 3-(3-amino-4-chlorophenyl)-6-methyl-4H-[1,2,4]triazin-5-one in 8 ml of acetonitrile and the mixture was stirred at room temperature for 30 minutes. The solid was filtered off with suction and dried under reduced pressure.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[CH2:3][OH:4].[Br:16][CH2:17][CH:18]=O.B(F)(F)F>[N+](C)([O-])=O>[CH3:1][C:2]1([CH3:15])[C:5]2[C:10](=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=2)[CH:18]([CH2:17][Br:16])[O:4][CH2:3]1
Reactant: COc1ccc(C(C)(C)CO)cc1OC
Reactant: O=CCBr
Agent: FB(F)F
Solvent: C[N+](=O)[O-]
Product: COc1cc2c(cc1OC)C(C)(C)COC2CBr

Procedure:
A 2,2-Dimethyl-2-(3,4-dimethoxyphenyl)ethanol (0.95 g, 0.0045 m) is stirred with 1.07 g (0.0054 m) of the ethyl acetal of bromoacetaldehyde and 0.19 g (0.0014 m) of BF3 .etherate in 25 ml of nitromethane for 15 hours. The mixture is partitioned between methylene chloride and aqueous sodium carbonate. The organic phase is dried over sodium sulfate and concentrated to yield 1.52 g of 4,4-dimethyl-6,7-dimethoxy-1-bromomethylisochroman. The nmr is consistent with the assigned structure.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6](=[NH:10])[O:7][CH2:8][CH3:9].C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Cl:21][CH2:22][C:23](/[N:10]=[C:6](\[O:7][CH2:8][CH3:9])/[C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([F:2])[CH:4]=1)=[O:24]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=N)c1cccc(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCO/C(=N\C(=O)CCl)c1cccc(F)c1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
To a suspension of ethyl 3-fluorobenzimidate hydrochloride (400 mg, 1.96 mmol) in dichloromethane (15 mL) was added triethylamine (497 mg, 684 μL, 4.91 mmol) at RT. The reaction mixture was cooled to 0-5° C. and 2-chloroacetyl chloride (333 mg, 234 μL, 2.95 mmol) was added dropwise over a period of 5 min. After 20 min the ice bath was removed and the mixture was stirred at RT for 2 h. The reaction mixture was poured into KHSO4 (10% aqueous solution, 25 mL) and extracted with dichloromethane (3×50 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give the product as light brown oil (537 mg, 1.98 mmol, 101%) which was used without further purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[CH2:13])[C:11]3([CH2:18][CH2:17][N:16]([C:19](OC4C=CC=CC=4)=[O:20])[CH2:15][CH2:14]3)[O:10][C:9]2=[O:28])=[CH:4][CH:3]=1.[OH:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[CH2:13])[C:11]3([CH2:14][CH2:15][N:16]([C:19]([N:35]4[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][OH:29])[CH2:33][CH2:34]4)=[O:20])[CH2:17][CH2:18]3)[O:10][C:9]2=[O:28])=[CH:6][CH:7]=1
Reactant: OCCN1CCNCC1
Reactant: C=C1N(c2ccc(Cl)cc2)C(=O)OC12CCN(C(=O)Oc1ccccc1)CC2
Solvent: Cc1ccccc1C
Product: C=C1N(c2ccc(Cl)cc2)C(=O)OC12CCN(C(=O)N1CCN(CCO)CC1)CC2
Yield: 67 %

Procedure:
A mixture containing 4.0 g of 3-(4-chlorophenyl)-4-methylene-2-oxo-8-phenoxycarbonyl-1-oxa-3,8-diazaspiro[4,5]decane and 6.13 ml of N-(2-hydroxyethyl)piperazine in 20 ml of ortho-xylene is refluxed under nitrogen for 60 hours. After cooling down, the reaction mixture is diluted with 20 ml of xylene and the organic solution is washed first with an aqueous saturated sodium chloride solution containing 5% by weight of sodium hydroxide and then with aqueous saturated sodium chloride solution. After drying over anhydrous magnesium sulfate and then evaporating the solvent under reduced pressure the crude product obtained is recrystallized from a mixture of benzene and hexane under clarifying by activated carbon to give the title compound in 67% yield, m.p.: 185°-186° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[N-:9]=[N+:10]=[N-:11].[Na+]>CN(C=O)C.O>[N:9]([CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1)=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(CCl)no1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(CN=[N+]=[N-])no1
Yield: 73.7 %

Procedure:
3-Chloromethyl-5-methylisoxazole (500 mg, 3.8 mmol) and sodium azide (494 mg, 7.6 mmol) were heated in DMF (10 ml) at 60° C. for 6 hours. The reaction mixture was diluted with water then extracted with EtOAc. The organic extracts were dried (MgSO4) and the volatiles removed by evaporation to give the title compound (387 mg, 73%) as an oil. NMR (DMSO): 2.40 (s, 3H), 4.48 (s, 2H), 6.28 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15](=[O:20])[N:14]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)[CH:13]=[CH:12]2)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:30])[N:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15](=[O:20])[N:14]([C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=1)[CH:13]=[CH:12]2)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc([N+](=O)[O-])cc3)c(=O)c2cc1F
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc(N)cc3)c(=O)c2cc1F
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a suspension of [7-Fluoro-2-(4-nitro-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (0.33 g, 0.79 mmol) in ethyl acetate (6 mL) and ethanol (2 mL) under Ar was added 10% Pd/C (0.13 g, 0.12 mmol Pd). The mixture was hydrogenated under 1 atm H2 for 2 hr, filtered through Celite and concentrated to give 0.28 g (92%) of [2-(4-Amino-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester. RP-HPLC: 3.83 min; ES-MS (M+H)+=384.0; 1H-NMR (DMSO-d6) δ (ppm): 1.32 (s, 9), 3.17 (s, 3), 5.31 (br s, 2), 6.60 (m, 3), 7.00 (d, 2), 7.32 (d, 2), 7.75 (d, 1), 7.86 (d, 1).