Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[S-:11][C:12]#[N:13].[NH4+]>CO>[CH3:8][C:7]1[C:2]([CH3:1])=[C:3]([OH:10])[C:4]([CH3:9])=[CH:5][C:6]=1[S:11][C:12]#[N:13]
Reactant: N#C[S-]
Reactant: Cc1ccc(C)c(O)c1C
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(SC#N)c(C)c(C)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
2,3,6-trimethylphenol (1.6 g, 11.8 mmol) was dissolved in 50 mL of anhydrous methanol which had been deoxygenated by bubbling with nitrogen. Ammonium thiocyanate (2.2 g, 28.9 mmol) was added to this solution which was then cooled to 0° C. and bubbled with chlorine gas. The initially colorless homogeneous solution becomes pink and then green with the formation of a white precipitate. The solution was stirred for 1 h at 0° C. and then for a further hour at 20° C. The dissolved chlorine was removed by bubbling with nitrogen and the precipitate removed by filtration. Evaporation of the filtrate under reduced pressure followed by drying under high vacuum (0.1 torr) yielded 2.20 g (97%) of 2,3,5-Trimethyl-4-hydroxyphenylthiocyanate in a form pure enough for the next step in the synthesis. An analytical sample was recrystallized from hexanes:white crystals, mp 100.3° C. 1H NMR (CDCl3) δ 7.2 (s, 1H), 5.0 (s, 1H) 2.4 (s, 3H), 2.2 (s, 6H).
Reaction SMILES: [OH-].[Na+].[CH2:3]1[O:7][C:6]2[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:5]=2[O:4]1.[Br:13][CH2:14][CH2:15]Br>O>[CH2:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([O:12][CH2:15][CH2:14][Br:13])=[CH:8][C:6]=2[O:7]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCOc1ccc2c(c1)OCO2

Procedure:
Sodium hydroxide 0.15 g was dissolved in water 6 ml, and Sesamol 0.50 g and 1,2-dibromoethane 0.37 ml were added thereto and heated under reflux for 12 hours. After cooling, water was added thereto, and the product was extracted with ethyl acetate and further washed with brine. The product was dried over magnesium sulfate anhydride and evaporated. The residue was purified by (NH) silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound 0.30 g, 34% was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:29][O:30][C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:29][O:30][C:31](=[O:32])[C:33]1[CH:38]=[CH:37][C:36]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])[CH:4]=2)=[CH:35][CH:34]=1
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(Cl)c(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c2)cc1

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 1, step 4) was reacted with 4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless solid. MS (m/e)=550.2 [M+H+].
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[N:31][CH:30]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:8](=[O:10])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:31][CH:30]=1
Reactant: O=C(O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1ccc(N)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid (prepared as in Example 22A, 526 mg, 2.0 mmol) in methylene chloride (20 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (1.2 mL, 2.4 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 15 min and at 25° C. for 30 min. The reaction mixture was then treated with a solution of 6-amino-nicotinic acid methyl ester (532 mg, 3.5 mmol) in tetrahydrofuran (10 mL) and N,N-diisopropylethylamine (0.84 mL, 4.8 mmol). This solution was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 80/20 hexanes/ethyl acetate) afforded 6-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-nicotinic acid methyl ester (353.9 mg, 44.6%) as a pale orange glass: EI-HRMS m/e calcd for C21H23N3O5 (M+) 397.1637, found 397.1631.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[N:2]=1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti](Cl)(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:7][C:3]2[N:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:12][CH:11]=1
Reactant: Nc1cccnn1
Reactant: COc1ccc(C=O)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: ClCCl
Product: COc1ccc(CNc2cccnn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.5 %

Procedure:
To a solution of pyridazin-3-ylamine (105 g, 1.1 mol, 1 eq) and 4-methoxybenzaldehyde (150 g, 1.1 mol, 1 eq) in DCM (3 L), was added titanium(IV) chloride triisopropoxide (572 g, 2.2 mol, 2 eq). The reaction mixture was stirred at RT for 8 h. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride (933 g, 4.4 mol, 4 eq) was added. The reaction mixture was allowed to stir at RT 5 h. After completion of the reaction, the reaction mixture was cooled to 0° C., quenched with ice water and the solid was filtered through celite pad. The layers were separated and the aqueous layer extracted with DCM (1 L). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude mass was dissolved in minimum amount of DCM and the product was extracted in 1.5 N HCl thrice. The aqueous layer was basified with saturated NaHCO3 solution; the precipitated product was filtered and dried. Then the solid obtained was washed with minimum amount of diethyl ether and dried to get 60 g of the title compound as pale pink solid (0.27 mol, 25% yield). MS (ESI pos. ion) riVz: (M+2)+=216.7. 1H NMR (400 MHz, Chloroform-d) δ 8.56 (dd, J=1.20, 4.60 Hz, 1H), 7.31 (dd, J=2.80, 11.60 Hz, 2H), 7.15 (dd, J=4.40, 9.00 Hz, 1H), 6.89 (dd, J=2.80, 5.80 Hz, 2H), 6.63 (dd, J=1.20, 9.20 Hz, 1H), 5.15 (br. s, 1H), 4.55 (d, J=5.60 Hz, 2H), 3.81 (s, 3H).
Reaction SMILES: C([O:5][C:6]([N:8]1[C:12]2[C:13](=[O:24])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:15][CH2:16][C:11]=2[C:10]([NH2:25])=[N:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].ClC[CH2:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][C:44]=2[CH3:50])[CH2:39][CH2:38]1)=O>>[NH2:25][C:10]1[C:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:13](=[O:24])[C:12]=2[N:8]([C:6](=[O:5])[CH2:34][CH2:35][N:37]2[CH2:42][CH2:41][N:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][C:44]=3[CH3:50])[CH2:39][CH2:38]2)[N:9]=1
Reactant: Cc1ccc(N2CCN(C(=O)CCCl)CC2)c(C)c1
Reactant: Cc1ccc(N2CCc3c(N)nn(C(=O)OC(C)(C)C)c3C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(N2CCc3c(N)nn(C(=O)CCN4CCN(c5ccc(C)cc5C)CC4)c3C2=O)cc1

Procedure:
A target compound (102.8 mg, 0.211 mmol, 55.7%) was yielded as white solid in the same manner as Example 1 by reacting 1-N-t-butoxycarbonyl-3-amino-4,5,6,7-tetrahydro-6-N-(p-tolyl)pyrazolo[3,4-c]pyridin-7-one (130 mg, 0.379 mmol) with potassium carbonate (57.6 mg, 0.417 mmol) and 3-chloro-1-{4-(2,4-dimethylphenyl)piperazin-1-yl}propan-1-one (111.7 mg, 0.398 mmol).
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1>>[CH3:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:18][C:17]=1[CH2:16][NH:15][CH:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]1
Reactant: Brc1cccnc1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2cccnc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (500 mg, 1.27 mmol) is coupled to 3-bromopyridine (202 mg, 1.27 mmol) using Method A to afford the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[N:14]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:13](=[O:23])[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.CO.[ClH:28]>FC(F)(F)C(O)=O>[ClH:28].[CH3:22][O:21][C:19]([CH2:18][O:17][N:14]1[C:13](=[O:23])[CH2:12][C:11]2([CH2:24][CH2:25][NH:8][CH2:9][CH2:10]2)[C:15]1=[O:16])=[O:20]
Reactant: COC(=O)CON1C(=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COC(=O)CON1C(=O)CC2(CCNCC2)C1=O
Reaction time: 0.17 h

Procedure:
In trifluoroacetic acid (3 ml) was dissolved 8-tert-butyloxycarbonyl-2-methoxycarbonylmethyloxy-2,8-diazaspiro[4,5]decane-1,3-dione (0.5 g), and the solution was left standing at room temperature for 10 minutes. To the solution was added methanol (20 ml), to which was added 2 ml of a methanol solution of 1N hydrogen chloride. The solvent was evaporated off under reduced pressure, and the residual oil was crystallized from ether-methanol to obtain 0.32 g of a coloress solid, m.p. 174° to 178° C.
Reaction SMILES: FC(F)(C(F)F)COC1C=CC(C=O)=CC=1.C(CC(O)=O)#N.N1CCCCC1.[F:29][C:30]([F:46])([CH:43]([F:45])[F:44])[CH2:31][O:32][C:33]1[CH:42]=[CH:41][C:36](/[CH:37]=[CH:38]\[C:39]#[N:40])=[CH:35][CH:34]=1.FC(F)(C(F)F)COC1C=CC(/C=C/C#N)=CC=1>N1C=CC=CC=1>[F:29][C:30]([F:46])([CH:43]([F:44])[F:45])[CH2:31][O:32][C:33]1[CH:42]=[CH:41][C:36]([CH:37]=[CH:38][C:39]#[N:40])=[CH:35][CH:34]=1
Reactant: N#C/C=C\c1ccc(OCC(F)(F)C(F)F)cc1
Agent: N#C/C=C/c1ccc(OCC(F)(F)C(F)F)cc1
Agent: N#CCC(=O)O
Agent: O=Cc1ccc(OCC(F)(F)C(F)F)cc1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: N#CC=Cc1ccc(OCC(F)(F)C(F)F)cc1
Yield: 78 %

Procedure:
A mixture of 500 g of 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde, 183 g of cyanoacetic acid, 250 ml of pyridine and 250 ml of piperidine are heated with stirring and allowed to react for 1 hour at 110° C. A further 36.6 g of cyanoacetic acid are then added and the mixture is allowed to react for a further 30 minutes at 110° C. The reaction mixture is cooled, distilled under reduced pressure and 433.1 g of 4-(2,2,3,3-tetrafluoropropoxy)cinnamonitrile are obtained (yield: 78%; purity 95%) in the form of a mixture of isomers which contains cis-4-(2,2,3,3-tetrafluoropropoxy)cinnamonitrile and trans-4-(2,2,3,3-tetrafluoropropoxy)cinnamonitrile in a molar ratio cis:trans of approximately 1.35 to 1.8:1 (corresponding to a weight ratio of about (58 to 64):(42 to 36)) and in addition up to about 3% by weight of piperidine and 2% by weight of unidentified impurities and resins.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][N:11](C(OCC2C=CC=CC=2)=O)[C:12]([NH:14]C(OCC2C=CC=CC=2)=O)=[NH:13])[CH2:4][CH2:3]1.[H][H]>[Pd].C(O)C>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]([NH2:14])=[NH:13])[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: CN1CCC(CCCN(C(=N)NC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCC(CCCNC(=N)N)CC1
Temperature: 50 °C

Procedure:
To a 1-L round bottom flask were added N-[3-(1-methyl-piperidin-4-yl)-propyl]-N,N′-di-cbz-guanidine (140.6 g, 0.301 moles) and ethanol (500 mL, 200 proof). The flask was equipped with a heating mantle and warmed to 50° C. Once a yellow homogeneous solution was obtained, the heating mantle was exchanged for an ice bath and the mixture cooled to an internal temperature of 10° C. The resultant cold mixture was transferred to a 2.25 liter Parr bottle equipped with a thermocouple probe, and 10% Pd on Carbon (10 wt. %) in one portion. The bottle was charged with H2(g) (60 psi). The Parr bottle was kept pressurized with hydrogen gas for 15 minutes, then evacuated, re-pressurized with H2(g) (60 psi) and allowed to shake for an additional hour. The catalyst was removed by filtration (Zap-Cap) and washed with ethanol (300 ml, 200 proof). The solvent was removed under pressure to yield the title compound.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6](=[N:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)SC)(=[O:4])=[O:3].S(Cl)([Cl:21])(=O)=O>C(OCC)(=O)C>[CH3:1][S:2]([NH:5][C:6]([Cl:21])=[N:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)(=[O:4])=[O:3]
Reactant: CSC(=Nc1ccc(Cl)c(Cl)c1)NS(C)(=O)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC(Cl)=Nc1ccc(Cl)c(Cl)c1

Procedure:
The N-methylsulphonyl-N'-(3,4-dichlorophenyl)-S-methylisothiourea (150 g) obtained in the manner described was suspended in 250 ml of ethyl acetate, and 45 ml of sulphonyl chloride (0.55 mole) was added dropwise to the suspension at a temperature of 50° C. The solvent as well as the formed methanesulphonyl chloride and unreacted sulphonyl chloride was distilled off in the Rotovap, and the crystallising residue was taken up in hexane. After filtration with suction, the resulting N-methylsulphonyl-N'-(3,4-dichlorophenyl)-chloroformamidine had a melting oint of 154° - 156° C.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](Cl)=[N:18][OH:19])=[CH:12][CH:11]=1.CN(C)C=O.[C:26]([C:28]1[C:29]([NH2:35])=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=1)#[CH:27].C(N(CC)CC)C>C(OCC)(=O)C.O>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[CH:27]=[C:26]([C:28]3[C:29]([NH2:35])=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=3)[O:19][N:18]=2)=[CH:12][CH:11]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(CCc2ccccn2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2cc(Cc3ccc(CCc4ccccn4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.9 %

Procedure:
To a mixture of (4-(2-pyridin-2-yl-ethyl)-phenyl)-acetohydroximoyl chloride hydrochloride (780 mg, 2.51 mmol) described in Manufacturing Example 93-1-8 and dimethylformamide (10 mL) were added 3-ethynyl-pyridin-2,6-diamine (96 mg, 0.721 mmol) described in Manufacturing Example 13-1-3 and triethylamine (1.05 mL, 7.53 mmol), which was stirred for 3 hours at room temperature. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. This organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=4:6 then ethyl acetate) to obtain the title compound (80 mg, 30%).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:32][CH2:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[N:38]([CH:44]1[CH2:49][CH2:48][C:47](=[O:50])[NH:46][C:45]1=[O:51])[CH2:37]2.Cl>CN(C=O)C>[O:51]=[C:45]1[CH:44]([N:38]2[CH2:37][C:36]3[C:40](=[CH:41][CH:42]=[C:34]([CH2:33][NH:32][C:10](=[O:12])[C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:14][CH:13]=4)[CH:35]=3)[C:39]2=[O:43])[CH2:49][CH2:48][C:47](=[O:50])[NH:46]1
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(C(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
A mixture of 4-(ethylsulfonyl)benzoic acid (0.30 g, 1.4 mmol) and CDI (0.24 g, 1.5 mmol) in DMF (30 ml) was stirred at 40° C. for 4 hours. 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.50 g, 1.4 mmol) was added and the mixture was stirred at 40° C. for 2 h. 4% Aqueous HCl (30 mL) was added and the resulting precipitate was filtered, washed with water (30 mL) and dried in vacuo providing N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-ethanesulfonyl-benzamide as a white solid, (0.39 g, 66% yield); mp 222-224° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 6.39 (98.78%); 1H NMR (DMSO-d6) δ 1.11 (t, J=7.3 Hz, 3H, CH3), 1.92-2.09 (m, 1H, CHH), 2.28-2.46 (m, 1H, CHH), 2.54-2.67 (m, 1H, CHH), 2.82-3.02 (m, 1H, CHH), 3.37 (q, 2H, CH2), 4.31 (d, 1H, CHH), 4.42 (d, 1H, CHH), 4.62 (d, J=5.3 Hz, 2H, CHH), 5.11 (dd, J=4.8, 13.1 Hz, 1H, CH), 7.48 (d, 1H, Ar), 7.57 (s, 1H, Ar), 7.71 (d, 1H, Ar), 8.02 (s, 2H, Ar), 8.15 (d, J=8.1 Hz, 2H, Ar), 9.45 (t, 1H, NH), 10.96 (s, 1H, NH); 13C NMR (DMSO-d6) δ 7.05, 22.49, 31.20, 42.89, 47.13, 49.01, 51.58, 122.15, 122.97, 127.13, 127.94, 128.31, 130.46, 138.75, 140.71, 142.42, 143.45, 165.06, 167.89, 170.98, 172.85; LCMS: MH=470; Anal. Calcd for C23H23N3O6S+0.3 CH2Cl2: C, 56.54; H, 4.81; N, 8.49. Found: C, 56.51; H, 4.90; N, 8.84.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]2[O:20][CH2:19]2)[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:21]([NH:25][CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[N:29]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:28]([CH3:42])([CH3:41])[CH2:27]1)[CH2:22][CH2:23][CH3:24]>C(O)C>[OH:1][C:2]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]([OH:20])[CH2:19][N:25]([CH2:21][CH2:22][CH2:23][CH3:24])[CH:26]2[CH2:31][C:30]([CH3:32])([CH3:33])[N:29]([O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:28]([CH3:42])([CH3:41])[CH2:27]2)[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: O=C(c1ccccc1)c1ccc(OCC2CO2)cc1O
Reactant: CCCCNC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Solvent: CCO
Product: CCCCN(CC(O)COc1ccc(C(=O)c2ccccc2)c(O)c1)C1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Yield: 91.9 %

Procedure:
A mixture of 4.0 g (14.8 g mmol) of 2-hydroxy-4-(2,3-epoxypropoxy)benzophenone, 6.9 g (22.2 mmol) of 4-butylamino-1-cyclohexyloxy-2,2,6,6-tetramethylpiperidine, and 40 ml of ethanol is heated at reflux for 4 hours. Ethanol is evaporated, and the residue is purified by flash chromatography on silica gel (4:1 heptane: ethyl acetate) to afford 7.9 g (92% yield) of the title compound, a yellow oil.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[CH2:14][C:15]#[N:16])([O-])=O>CCO.O.C(O)(=O)C.[Pd]>[F:13][C:10]([F:11])([F:12])[C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[NH:16][CH:15]=[CH:14]2
Reactant: N#CCc1cc(C(F)(F)F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1ccc2[nH]ccc2c1
Yield: 61.4 %

Procedure:
(2-Nitro-5-trifluoromethylphenyl)acetonitrile (D4, 1.9 g, 0.0088 mole) in 90% EtOH/H2O (25 ml) and glacial acetic acid (0.25 ml) was hydrogenated at 50 psi in the presence of 10% Pd/C (1 g) at room temperature for 2 hours. After filtration of the catalyst through kieselguhr, the solvent was removed in vacuo. The residue was basified with saturated aqueous potassium carbonate solution, extracted into DCM, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 30% ethyl acetate/60-80° petroleum ether to afford the title compound (1.0 g, 65%) as an off white solid.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C([O-])(=O)C.[Na+].[NH2:13][CH2:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)=[O:16]>O>[N+:23]([C:20]1[N:19]=[CH:18][C:17]([C:15](=[O:16])[CH2:14][NH:13][C:5](=[O:7])[CH3:6])=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: NCC(=O)c1ccc([N+](=O)[O-])nc1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)NCC(=O)c1ccc([N+](=O)[O-])nc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
1.575 cm3 (16.66 mmol) of acetic anhydride and then 1.367 g (16.66 mmol) of sodium acetate in solution in 3 cm3 of water are added at a temperature in the region of 5° C. to 1.05 g (4.166 mmol) of 2-amino-1-(6-nitropyridin-3-yl)-ethanone in solution in 25 cm3 of water. After stirring for 3 hours at 5° C., the reaction mixture is extracted with three times 10 cm3 of ethyl acetate. All the organic phases are combined, washed with 30 cm3 of a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.618 g of N-[2-(6-nitropyridin-3-yl)-2-oxoethyl]acetamide, in the form of a yellow solid. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm) 1.90 (s, 3H); 4.66 (d, J=4.5 Hz, 2H); 8.37 (broad t, J=4.5 Hz, 1H); 8.43 (d, J=8.5 Hz, 1H); 8.68 (dd, J=2.0 and 8.5 Hz, 1H); 9.16 (d, J=2.0 Hz, 1H). 2-Amino-1-(6-nitropyridin-3-yl)ethanone may be prepared in the following manner:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=S)[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:7]=2[CH:20]=1.O.[NH2:22][NH2:23]>CO>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:22][NH2:23])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:7]=2[CH:20]=1
Reactant: CSc1ccc2c(c1)C(c1ccccn1)=NCC(=S)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: CSc1ccc2c(c1)C(c1ccccn1)=NCC(NN)=N2

Procedure:
According to the procedure of Preparation 1, 7-methylthio-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-thione is reacted with hydrazine hydrate in methanol to give 7-methylthio-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl hydrazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][NH:21][CH:22](C(OC(C)(C)C)=O)[CH2:23][CH3:24])[CH:16]=[CH:17][CH:18]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH3:24])[CH:16]=[CH:17][CH:18]=1)(=[O:10])=[O:9]
Reactant: CCC(NCCc1cccc(N)c1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1F
Product: CCCNCCc1cccc(NS(=O)(=O)c2ccccc2F)c1

Procedure:
Using procedure 4, 2-fluorobenzenesulfonyl chloride was added to 2-(3-aminophenyl)ethyl-1-(tert-butoxycarbonyl)propylamine (13) to give the title compound as a solid, m.p. 165-169° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]#[N:22])[CH:17]=[CH:18][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]([N:49]1[CH2:55][CH2:54][CH2:53][C@@H:50]1[CH2:51]O)([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>O1CCCC1>[C:21]([CH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][CH2:51][C@H:50]1[CH2:53][CH2:54][CH2:55][N:49]1[C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])#[N:22]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: N#CCc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.8 %

Procedure:
Diethyl azodicarboxylate (3.92 g, 22.5 mmol) was added dropwise to a solution of 3-hydroxyphenyl acetonitrile (3.0 g, 22.5 mmol), triphenylphosphine (5.90 g, 22.5 mmol) and Boc-(R)-prolinol (4.53 g, 22.5 mmol) in tetrahydrofuran (30 ml), and the reaction stirred at room temperature for 18 hrs. The mixture was evaporated under reduced pressure and the residue partitioned between dichloromethane and water. The layers were separated, the organic phase washed with water, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:pentane:methanol (80:20 to 100:0:0 to 95:0:5) to give the title compound, (2.69 g, 38%).