Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)=[C:14]([O:31][CH3:32])[CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCCl>[CH3:32][O:31][C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:17]=[CH:16][C:15]=1[CH:18]1[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]1
Reactant: COc1cc(NC(=O)OCc2ccccc2)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NC(=O)OCc2ccccc2)ccc1C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A mixture of tert-butyl 4-(4-{[(benzyloxy)carbonyl]amino}-2-methoxyphenyl)piperidine-1-carboxylate (Preparation Example 454) (4.92 g), trifluoroacetic acid (10 mL) and 1,2-dichloroethane (50 mL) was stirred at room temperature for 1 hour. The reaction solvent was concentrated under reduced pressure, and after addition of saturated aqueous sodium hydrogen carbonate, the residue was extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was solidified by addition of diethyl ether to give benzyl (3-methoxy-4-piperidin-4-ylphenyl)carbamate (3.24 g) as a white solid.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[Cl:12]Cl>C(O)(=O)C>[Cl:12][C:10]1[CH:11]=[C:3]([CH:4]=[C:5]([O:6][CH3:7])[C:8]=1[OH:9])[CH:2]=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: ClCl
Solvent: CC(=O)O
Product: COc1cc(C=O)cc(Cl)c1O
Reaction time: 0.5 h

Procedure:
Compound 12 was prepared according to the procedure of Hann et al. (J. Am. Chem. Soc. 1927, 49, 535-7). To a solution of 2.50 g (16.4 mmol) of vanillin in 15 mL of glacial acetic acid was added chlorine gas through a glass tubing over 30 minutes (with a slow gas flow) at 25° C. White solid product was collected by filtration, washed with 50 mL of hexane, and dried in vacuo to give 2.033 g of 12. The acetic acid filtrate was again treated with chlorine gas as above for 30 minutes to give another 0.659 g of 12. A total of 2.691 g (88% yield) of 12 was obtained. The white solids were used in next step without purification. 1H NMR (CDCl3) δ 10.04 (s, 1H, OH), 9.76 (s, 1H, CHO), 7.56 (d, J=1.6 Hz, 1H, Ar), 7.37 (d, J=1.6Hz, 1H, Ar), 3.91 (s, 3H, OMe); 13C NMR (CDCl3) δ 190.5 (C═O), 149.0 (s, 2C), 128.2 (s), 125.6 (d), 120.1 (s), 109.2 (d), 56.3 (q).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[BH3-]C#N.[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH2:18][C:19]([N:21]2[CH:30]3[CH:25]([CH2:26][CH2:27][CH2:28][CH:29]3[N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[NH:24][CH2:23][CH2:22]2)=[O:20])[CH:14]=[CH:15][C:16]=1[Cl:17].C([O-])([O-])=O.[Na+].[Na+]>CO.C(O)(=O)C>[CH2:1]([N:24]1[CH:25]2[CH:30]([CH:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:28][CH2:27][CH2:26]2)[N:21]([C:19](=[O:20])[CH2:18][C:13]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([Cl:10])[CH:12]=2)[CH2:22][CH2:23]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Reactant: CCCC=O
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCN1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C2C(N3CCCC3)CCCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Butyraldehyde (93 mg, 1.3 mmol) was dissolved in 5 ml of MeOH and NaBH3CN (82 mg, 1.3 mmol) was added. The pH was adjusted to 5 with concentrated acetic acid. 2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (101 mg, 0.25 mmol), dissolved in MeOH (15 ml), was then added to the mixture and the mixture was stirred at room temperature overnight. After addition of saturated Na2CO3 solution (15 ml), the mixture was stirred at room temperature for 15 minutes. The precipitate formed was filtered off. The aqueous phase of the filtrate was extracted three times with CH2Cl2 and the combined organic phases were dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 9.5:0.5:0.1, l=15 cm, V=5 ml). A colorless resin was isolated.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[NH:3]1.[OH-].[Ca+2].[OH-].[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>C(O)(C)C>[CH3:1][N:2]1[C:6]([OH:7])=[C:5]([C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:13]=2[Cl:12])[C:4]([CH3:8])=[N:3]1
Reactant: Cc1cc(=O)n(C)[nH]1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 66.7 %

Procedure:
In 65 ml. of isopropanol are suspended 4.48 g. of 1,3-dimethyl-5-pyrazolone and 3 g. of calcium hydroxide and the resulting suspension is heated under reflux for 30 minutes with stirring. After cooling, 8.4 g. of 2,4-dichlorobenzoyl chloride is added dropwise thereto. After completion of the dropwise addition, the mixture is heated under reflux for 2 hours. The solvent is distilled off from the reaction mixture and 15 ml. of water is added to the residue. The mixture is made acidic with 23 ml. of a 2 N hydrochloric acid solution and extracted with 60 ml. of chloroform. The chloroform layer is washed with water and the organic phase is separated and dried. The chloroform is distilled off. The residue is recrystallized from ethanol to give 7.6 g. of the desired product as colorless prisms of mp. 165°-166° C. Yield 66.7%
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@H:11]1[C:34]1[Se:35][CH:36]=[C:37]([C:39]([O:41][CH2:42]C)=[O:40])[N:38]=1)(=O)C1C=CC=CC=1.C[O-].[Na+]>>[C@@H:11]1([C:34]2[Se:35][CH:36]=[C:37]([C:39]([O:41][CH3:42])=[O:40])[N:38]=2)[O:12][C@H:13]([CH2:24][OH:25])[C@@H:14]([OH:15])[C@H:10]1[OH:9]
Reactant: CCOC(=O)c1c[se]c([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n1
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)c1c[se]c([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1

Procedure:
reacting said ethyl 2-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)selenazole-4-carboxylate with sodium methoxide to produce methyl 2-β-D-ribofuranosylselenazole-4-carboxylate; and
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](I)=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[N:10]1.[C:19]([Cu])#[N:20]>CN1C(=O)CCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:19]#[N:20])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[N:10]1
Reactant: FC(F)(F)c1cc(I)n(-c2cccc(Cl)c2Cl)n1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: N#Cc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1Cl
Temperature: 200 °C
Yield: 59.5 %

Procedure:
To a stirred solution of 1-(2,3-dichlorophenyl)-5-iodo-3-(trifluoromethyl)-1H-pyrazole (11.1 g, 27.58 mmol, 1.0 eq) in NMP (50 mL) was added CuCN (2.39 g, 27.58 mmol, 1.0 eq.) and heated to 200° C. for 2 h. The reaction mixture was passed through a celite pad and washed with excess of ethyl acetate. The filtrate was washed with water and the ethyl acetate layer was separated, dried (Na2SO4), and the solvent evaporated. The resulting residue was purified by CC using ethyl acetate/PE (1:9) to get 1-(2,3-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonitrile (5.02 g, crude, yellow solid).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[F:10][C:11]([F:28])([F:27])[S:12]([O:15][C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=2)(=[O:14])=[O:13].FC(F)(F)S(OC1N=CC2C(C=1)=CC=CC=2Br)(=O)=O>>[Cl:26][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[N:17][C:16]([NH:1][C:2]1[N:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1)=[CH:25]2.[F:28][C:11]([F:10])([F:27])[S:12]([O:15][C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=2)(=[O:14])=[O:13]
Reactant: N#Cc1cnc(N)cn1
Agent: O=S(=O)(Oc1cc2cc(Cl)ccc2cn1)C(F)(F)F
Agent: O=S(=O)(Oc1cc2cccc(Br)c2cn1)C(F)(F)F
Product: N#Cc1cnc(Nc2cc3cc(Cl)ccc3cn2)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Synthesis 5-1 using 2-amino-5-cyanopyrazine in place of (R)-5-amino-3-(pyrrolidin-3-yloxy)pyrazine-2-carbonitrile and 6-chloroisoquinolin-3-yl trifluoromethanesulfonate in place of 3,8-dichloroisoquinoline. 6-Chloroisoquinolin-3-yl trifluoromethanesulfonate was prepared using methods analogous to those described in Synthesis 11-1 for 8-bromoisoquinolin-3-yl trifluoromethanesulfonate. 1H NMR (DMSO, 400 MHz) δ 11.11 (s, 1H), 9.24 (s, 1H), 8.82 (d, 1H, J=1.3 Hz), 8.74 (d, 1H, J=1.3 Hz), 8.47 (s, 1H), 8.13 (d, 1H, J=8.6 Hz), 8.09 (d, 1H, J=1.8 Hz), 7.55 (dd, 1H, J=8.8, 2.0 Hz). LCMS (2) Rt=3.04 min, m/z (ESI+) 282 & 284 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:13][OH:14])[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:5][C:4]=2[N:3]=1.Cl[CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[CH:33].[H-].[Na+].CN(C)CCCON=C1CC(C2C=C(F)C=CC=2C2C=CC=CC=2)CC2N=C(N)N=C(C)C1=2>O>[CH2:33]([O:14][N:13]=[C:8]1[CH2:7][CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][C:4]2[N:3]=[C:2]([NH2:1])[N:11]=[C:10]([CH3:12])[C:9]1=2)[CH2:32][CH2:31][CH2:30][C:29]#[CH:28]
Reactant: C#CCCCCCl
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccccc1)C2
Agent: Cc1nc(N)nc2c1C(=NOCCCN(C)C)CC(c1cc(F)ccc1-c1ccccc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C#CCCCCON=C1CC(c2ccccc2-c2ccccc2)Cc2nc(N)nc(C)c21

Procedure:
The title compound was prepared from 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime, compound 66, (50 mg, 0.145 mmol), 6-chloro-1-hexyne (21 μl, 0.174 mmol) and sodium hydride (60% dispersion in oil) (11 mg, 0.465 mmol), following the same procedure used for 2-amino-7-(4-fluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-(3-dimethylamino-propyl)-oxime (compound 88), except after addition of water the solvent was removed under reduced pressure. The crude material was taken up in methanol (20 ml) and the resulting solution was filtered. The solvent was removed under reduced pressure. The title compound was purified by preparative HPLC (mass directed fraction collection).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][CH:9]([CH2:13][CH2:14][C:15]([OH:17])=O)[C:10](O)=[O:11].[NH4+:18].[OH-]>>[CH3:8][CH:9]1[CH2:13][CH2:14][C:15](=[O:17])[NH:18][C:10]1=[O:11]
Reactant: CC(CCC(=O)O)C(=O)O
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: CC1CCC(=O)NC1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
Acetic anhydride was added to commercially available 2-methylglutaric acid (1 g, 6.8 mmol) at room temperature, and the mixture was stirred at 60° C. for 8 hours under reflux. After completion of the reaction was confirmed by TLC, the remaining acetic anhydride was removed under reduced pressure. The concentrated compound was dissolved in tetrahydrofuran and an ammonia aqueous solution (1.7 mL, 14.6 mmol) was slowly added thereto at 0° C., followed by stirring for 8 hours at room temperature. After the reaction was complete, the remaining ammonia aqueous solution was removed under reduced pressure and an acetic anhydride was added, followed by reflux at 60° C. for 8 hours. The residual acetic anhydride was removed under reduced pressure. The concentrate was purified by column chromatography (ethyl acetate:hexane=1:1) to afford 682 mg (yield: 78%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:45])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:45])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([C:41]([F:42])([F:43])[F:44])[CH:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C(F)(F)F)c2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J19) (218 mg, 0.70 mmol) and 3-oxo-3-[3-(2-trifluoromethyl-pyridin-4-yl)-phenyl]-propionic acid tert-butyl ester (Example K38) (256 mg, 0.70 mmol) according to the general procedure M. Obtained as a light brown solid (260 mg, 62%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:9]=[C:10]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([Cl:14])=[N:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1.N1C=CC=CC=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>C1COCC1.CN(C=O)C>[C:30]1([O:29][C:27](=[O:28])[NH:1][C:2]2[S:3][C:4]([C:8]3[CH:13]=[N:12][C:11]([Cl:14])=[C:10]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:9]=3)=[C:5]([CH3:7])[N:6]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1nc(N)sc1-c1cnc(Cl)c(NS(C)(=O)=O)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)Oc2ccccc2)sc1-c1cnc(Cl)c(NS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-[5-(2-Amino-4-methyl-1,3-thiazol-5-yl)-2-chloropyridin-3-yl]methanesulfonamide (63 mg, purity 88%, 0.17 mmol) was dissolved in a mixture of THF (1 mL) and DMF (1 mL) and cooled to 0° C. Pyridine (0.103 mL, 1.27 mmol) was added followed by phenyl chloroformate (0.027 mL, 0.2 mmol). The stirring was continued for 25 minutes at 0° C. and at room temperature for 1 hour. Additional phenyl chloroformate (0.013 mL, 0.1 mmol) was added and the stirring was continued for 45 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic phase was washed with saturated aqueous sodium hydrogen carbonate, twice with water and finally with brine. Evaporation of the organic solvent at reduced pressure gave N-[5-(6-chloro-5-methanesulfonylaminopyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]carbamic acid phenyl ester which was used without purification; Mass Spectrum: M+H+ 439 and 441.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.O[C@@H:14]1[CH2:18][CH2:17][O:16][CH2:15]1.[O:19]=[C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[N:21]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:29]=[C:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](=[O:19])[N:21]1[N:30]([C@H:14]1[CH2:18][CH2:17][O:16][CH2:15]1)[C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36]
Reactant: CC(C)(C)OC(=O)NN1C(=O)c2ccccc2C1=O
Reactant: O[C@@H]1CCOC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N([C@H]1CCOC1)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
DEAD (11.5 mL) was added dropwise to a solution of (R)-(−)-3-hydroxytetrahydrofuran (CAS No. 86087-24-3) (4.84 g), t-butyl (1,3-dioxoisoindolin-2-yl)carbamate (12 g) and triphenylphosphine (18.0 g) in THF (160 mL) under ice-cooling over five minutes. The reaction mixture was stirred at 0° C. for three minutes and then at room temperature for seven hours and 40 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 20%) to give the title compound (12.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](=[N:15]C)([NH:10][C:11](C)(C)C)=[O:9].B(F)(F)F.CCOCC.C1(OC)C=CC=CC=1.FC(F)(F)S(O)(=O)=O.C([O-])(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](=[N:10][CH3:11])([NH2:15])=[O:9]
Reactant: CN=S(=O)(NC(C)(C)C)c1ccccc1Br
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN=S(N)(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cleavage of the tert-butyl group from 2-bromo-N-(1,1-dimethylethyl)-N'-methylbenzenesulfonimidamide by use of trifluoroacetic acid with or without added boron trifluoride etherate was found to be slow at room temperature. 2-Bromo-N-(1,1-dimethylethyl)-N'-methylbenzenesulfonimidamide (0.9 g, 2.9 mmol) recovered from these cleavage experiments and anisole (0.6 g, 5.5 mmol) were dissolved in trifluoroacetic acid (25 mL). Trifluoromethanesulfonic acid (ca. 9 g, 60 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. Then sodium acetate (5.5 g, 67 mmol) was added and the solvent was evaporated to leave a solid residue. This was dissolved in a mixture of dichloromethane and a small amount of water. Potassium carbonate was added until the mixture became basic. The mixture was partially dried (Na2SO4), filtered through Celite®, redried (Na2SO4), and gravity filtered. Evaporation of the solvent left a slightly brownish oil (1.4 g). This was dissolved in dichloromethane and chromatographed on a column of silica gel using 40:1 CH 2 Cl2 -Et2O followed by 1:1 CH2Cl2 -Et2O as eluant. Fractions containing the product (Rf =0.44, 10:1 CH2Cl2 -Et2O, UV) were evaporated to leave 2-bromo-N'-methylbenzenesulfonimidamide as a colorless oil (0.7 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1>C(O)(C)C>[N+:8]([C:5]1[C:4]([N:12]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11]2)=[N:3][CH:2]=[CH:7][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccnc1N1CCc2ccccc2C1
Reaction time: 3 h

Procedure:
A suspension of 2-chloro-5-nitro-pyridine (1.58 g, 10 mmol) in isopropanol (30 ml) was treated at rt with 1,2,3,4-tetrahydro-isoquinoline (2.6 g, 20 mmol). The resulting mixture was stirred for 3 hr. The precipitate was filtered, partitioned (AcOEt/H2O) and the organic phase dried (Na2SO4). After evaporation of the solvent the title compound was obtained as a yellow solid mass (1.4 g, 55%), MS: m/e=256 (M+H+).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:16])=[C:5]([NH:12]C(=O)C)[C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)#[N:2].OS(O)(=O)=O>O>[NH2:12][C:5]1[C:4]([CH3:16])=[C:3]([CH:8]=[CH:7][C:6]=1[N+:9]([O-:11])=[O:10])[C:1]#[N:2]
Reactant: CC(=O)Nc1c([N+](=O)[O-])ccc(C#N)c1C
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C#N)ccc([N+](=O)[O-])c1N
Temperature: 100 °C

Procedure:
N-(3-cyano-2-methyl-6-nitrophenyl)acetamide (0.37 g, 1.7 mmol) was added to a 2N aq. H2SO4 solution (10 mL). The reaction was heated to 100° C. for 6 hr. The reaction mixture was cooled to rt and poured into iced water. The solid precipitate was collected by filtration, and then washed with water several times to give the title compound. MS (ESI−) m/z 176.1 (M−H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1)[CH3:2].[CH3:13][Mg]Br.[Cl-].[NH4+]>C(OCC)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([CH3:13])([OH:12])[CH3:11])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(CC(C)=O)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCc1ccc(CC(C)(C)O)cc1

Procedure:
14.8 g (90 mmol) of 1-(4-ethylphenyl)propan-2-one dissolved in diethyl ether is added dropwise to 39 mL of a 3 molar solution of methylmagnesium bromide in diethyl ether while being cooled with an ice bath in such a way that the temperature does not exceed 30° C. After the addition has ended, the reaction mixture is refluxed for 1.5 hours and then hydrolyzed with 10% ammonium chloride solution. After the removal of the organic phase, the aqueous phase is extracted with diethyl ether. The combined ether phases are washed with water, dried with sodium sulfate, and evaporated down. The oil thus obtained is further reacted directly. Yield: 15.5 g (90%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([OH:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>ClCCl.CCOCC>[CH:12](=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC=O
Reaction time: 2 h

Procedure:
21.5 g (100 mmol) of pyridinium chlorochromate are suspended in 200 ml of anhydrous dichloromethane. 16 g (66 mmol) of hexadecanol in 50 ml of anhydrous dichloromethane are added dropwise. After 2 hours, the mixture is diluted with 300 ml of anhydrous ether, and the solution is decanted off from the black residue. The residue is washed three times with about 50 ml of anhydrous ether. The organic phases are combined and the ether is evaporated off to dryness. The residue is chromatographed on silica gel using petroleum ether/ethyl acetate 9:1. Yield: 15 g (95%), melting point 33°-34° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:37][C:38]1[C:43]([NH2:44])=[CH:42][CH:41]=[CH:40][N:39]=1>C(Cl)Cl>[NH2:44][C:43]1[C:38]([NH:37][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:10])=[N:39][CH:40]=[CH:41][CH:42]=1
Reactant: Nc1cccnc1N
Reactant: O=C(O)CCCNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1cccnc1NC(=O)CCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[(phenylmethoxy)carbonylamino]butanoic acid (1.1 eq) was dissolved in methylene chloride (0.2M) followed by the addition of 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCA) (1.2 eq) and triethylamine (1.5 eq). The mixture was stirred at room temperature under nitrogen for 30 mins, followed by addition of 2,3-diaminopyridine. The mixture was then stirred at room temperature for 48 hrs., quenched with saturated sodium carbonate and extracted with ether. The organic phase was concentrated in vacuo and chromatographed on silica gel. (10% MeOH/CH2Cl2). EI-MS m/z 329 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=2)[O:24][C:25]=1[CH3:26]>>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([C:23]2[O:24][C:25]([CH3:26])=[C:21]([CH2:20][N:11]3[C:12]4[C:8](=[CH:7][C:6]([CH2:5][C@H:4]([O:15][CH2:16][CH3:17])[C:3]([OH:2])=[O:18])=[CH:14][CH:13]=4)[CH:9]=[CH:10]3)[N:22]=2)[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=1
Reactant: CCO[C@@H](Cc1ccc2[nH]ccc2c1)C(=O)OC
Reactant: COc1cc(OC)cc(-c2nc(CCl)c(C)o2)c1
Product: CCO[C@@H](Cc1ccc2c(ccn2Cc2nc(-c3cc(OC)cc(OC)c3)oc2C)c1)C(=O)O
Yield: 43 %

Procedure:
Starting from (S)-2-ethoxy-3-(1H-indol-5-yl)-propionic acid methyl ester and 4-chloromethyl-2-(3,5-dimethoxy-phenyl)-5-methyl-oxazole, the title compound was obtained in 43% yield as a pale red solid. MS: (M−H)− 463.2.