Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH2:6][CH2:7][C:8]([CH2:14][CH2:15][CH2:16][CH:17]([CH2:19][CH2:20][CH2:21][CH:22]([CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:23])[CH3:18])([CH3:13])[O:9]2)=[C:4]([CH3:30])[C:3]=1[OH:31].[C:32](O)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=1.C(OC(=O)C1C=CC=NC=1)(=O)C1C=CC=NC=1.C(Cl)(=O)C1C=CC=NC=1.Cl>N1C=CC=CC=1>[CH3:12][C:11]1[C:2]([CH3:1])=[C:3]([O:31][C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=2)=[O:39])[C:4]([CH3:30])=[C:5]2[CH2:6][CH2:7][C@:8]([CH2:14][CH2:15][CH2:16][C@@H:17]([CH2:19][CH2:20][CH2:21][C@@H:22]([CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:23])[CH3:18])([CH3:13])[O:9][C:10]=12
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Reactant: O=C(O)c1cccnc1
Agent: Cl
Agent: O=C(Cl)c1cccnc1
Agent: O=C(OC(=O)c1cccnc1)c1cccnc1
Solvent: c1ccncc1
Product: Cc1c(C)c2c(c(C)c1OC(=O)c1cccnc1)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2

Procedure:
More specifically, dl-α-tocopherol is reacted with a reactive derivative of nicotinic acid such as nicotinic anhydride or nicotinic chloride in the presence of a hydrochloride and pyridine, and the resulting reaction product is post-treated and purified by column chromatography, whereby pure dl-α-tocopheryl nicotinate is obtained.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C.O>[Cl:1][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1
Reactant: O=[N+]([O-])O
Reactant: ClCC1COc2ccccc2O1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)OC(CCl)CO2
Reaction time: 2 h

Procedure:
92 g of 2-chloromethyl 2,3-dihydro [4H] 1,4-benzodioxin are dissolved in 675 ml acetic acid. In this solution it is added a mixture of 500 ml acetic acid and 250 ml nitric acid while keeping the temperature below 20°. The mixture is kept at room temperature for 2 hours then heated at 90° for 1 hour. It is thereafter poured in water and extracted with methylene chloride. 102 g of the nitroderivative are obtained. It is in the form of yellow crystalls which melt at 60°-62°.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:16]C1C=CC(N)=CC=1>>[F:16][C:4]1[CH:3]=[CH:2][C:1]([NH:7][C:8]([C:10]2([C:13]([OH:15])=[O:14])[CH2:11][CH2:12]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(O)C1(C(=O)Nc2ccccc2)CC1
Reactant: Nc1ccc(F)cc1
Product: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Yield: 57 %

Procedure:
Following the procedure described above for the compound 161 (scheme 45), but replacing aniline for 4-fluoroaniline, title compound 181 was obtained in 57% yield. MS (m/z): 224.0 (M+H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[I:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:14]C(=O)O[C:11](=[O:16])[C:10]=2[CH:17]=1>N1C=CC=CC=1>[NH2:14][C:9]1[CH:8]=[CH:7][C:6]([I:5])=[CH:17][C:10]=1[C:11]([NH:4][CH2:1][CH2:2][CH3:3])=[O:16]
Reactant: O=c1[nH]c2ccc(I)cc2c(=O)o1
Reactant: CCCN
Solvent: c1ccncc1
Product: CCCNC(=O)c1cc(I)ccc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.1 %

Procedure:
Propylamine (1.2 g, 20.3 mmol) and 6-iodo-2H-3,1-benzoxazine-2,4(1H)-dione (5.0 g, 17.3 mmol) were combined in pyridine (85 mL) and stirred at room temperature for 24 h. The reaction was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate (200 mL) and 5% hydrochloric acid (200 mL). The phases were separated and the organic phase was washed with 1N sodium hydroxide, water, and brine. Drying over anhydrous sodium sulfate and evaporation under reduced pressure afforded 3.9 g of the title compound, 1H NMR (300 MHz, CDCl3): δ0.99 (t,3H1); 1.63 (m,2H); 3.35 (m,2H); 5.52 (br s,2H); 5.95 (br s,1H); 6.47 (d, 1H); 7.42 (dd,1H); 7.55(d,1H).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH3:5][N:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]([OH:14])[CH2:8][C:7]1([CH3:16])[CH3:15].[OH-].[K+]>C1C=CC=CC=1>[C:1]([CH2:2][CH2:3][O:14][CH:9]1[CH2:8][C:7]([CH3:15])([CH3:16])[N:6]([CH3:5])[C:11]([CH3:13])([CH3:12])[CH2:10]1)#[N:4]
Reactant: C=CC#N
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CN1C(C)(C)CC(OCCC#N)CC1(C)C
Reaction time: 16 h

Procedure:
2.65 parts of acrylonitrile was added dropwise with stirring to a solution of 8.55 parts of 1,2,2,6,6-pentamethylpiperidin-4-ol and 0.30 parts of 40% potassium hydroxide solution in 80 parts of benzene. Stirring was continued at room temperature for 16 hours after which time the solution was washed with water, dried and the benzene solvent removed by distillation under reduced pressure. Fractional distillation of the residue, under reduced pressure gave 1.70 parts of 4-(2'-cyanoethoxy)-1,2,2,6,6-pentamethylpiperidine having a boiling point of 105°-6° C. at 0.1 mm of Hg and the following elemental analysis by weight:
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+].Br[CH2:8][CH:9]1[CH2:11][CH2:10]1>O>[CH:9]1([CH2:8][S:1]([O-:4])(=[O:3])=[O:2])[CH2:11][CH2:10]1.[Na+:5]
Reactant: O=S([O-])[O-]
Reactant: BrCC1CC1
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CC1CC1
Temperature: 100 °C
Yield: 128.9 %

Procedure:
Sodium sulfite (1.43 g, 11.3 mmol) was dissolved in water (8.00 mL). To this, (bromomethyl)cyclopropane (1.00 mL, 10.3 mmol) was added and the mixture was stirred with heat at 100° C. for 24 hours. The solvent in the reaction mixture was evaporated off under reduced pressure, and the residue was subjected to slurry purification using diisopropyl ether, to give sodium cyclopropanemethanesulfonate (2.10 g, yield: 99%).
Reaction SMILES: C(N1CCC(CO)CC1)(OC(C)(C)C)=O.OC1C=C(C(OC)=O)ON=1.[N].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C([NH:43][C:44](=[N:47]C(OCC1C=CC=CC=1)=O)SC)(OCC1C=CC=CC=1)=O>>[C:44]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)(=[NH:43])[NH2:47]
Reactant: C1CCNCC1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: COC(=O)c1cc(O)no1
Agent: [N]
Product: N=C(N)N1CCCCC1

Procedure:
Scheme XIXb outlines the synthesis of the analogous compounds where R1 is 4-(1-amidinopiperidinyl) instead of 4-amidinophenyl. After initial condensation of N-BOC-4-piperidinylcarbinol with methyl 3-hydroxyisoxazole-5-carboxylate under Mitsunobu conditions, the intermediate ester is saponified and condensed with a 1,3-diaminpropionate using conditions described above. The piperidine nitrogen is deprotected and treated with N,N'-diCBz-S-methylisothiourea to give a protected amidinopiperdine. Hydrogenation gives the amidinopiperidine compounds as the methyl esters. ##STR76##
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[N:8][C:9]=1[NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.CCN(CC)CC.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>ClCCl>[C:30]([N:13]1[CH2:14][CH2:15][C@@H:11]([NH:10][C:9]2[N:8]=[CH:7][C:6](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][C:4]=2[Cl:3])[CH2:12]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCNC2)c(Cl)c1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(C(=O)c3ccccc3)C2)c(Cl)c1
Temperature: 23 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To an ice-cooled solution of ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridyl}acrylate dihydrochloride (330 mg) and Et3N (0.437 ml) in dichloromethane (8 ml) was added benzoyl chloride (132 mg), the mixture was stirred at 23° C. for 1 hour. The mixed solution was poured into a mixture of water (20 ml) and DCM (15 ml). The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (12 g) using a mixed solvent of dichloromethane and MeOH (100:1 to 40:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. ethyl (2E)-3-(6-{[(3R)-1-benzoyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)acrylate (245 mg) was obtained as colorless syrup.
Reaction SMILES: C([O:5][C:6](=[O:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[S:20][CH:21]=2)=[O:16])=[CH:10][CH:9]=1)(C)(C)C.Cl.[O:28]1CCOC[CH2:29]1>C(Cl)(Cl)Cl>[S:20]1[CH:21]=[C:17]([C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:7][C:6]([OH:5])=[O:26])=[CH:9][C:10]=2[O:28][CH3:29])=[O:16])[C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]1=2
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)Cc1ccc(NC(=O)c2csc3ccccc23)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(CC(=O)O)ccc1NC(=O)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
4-[(Benzo[b]thiophen-3-ylcarbonyl)amino]phenylacetic acid tert-butyl ester (2.12 g, 5.33 mmol) and a 4N—HCl-dioxane solution (20 mL) were mixed, and the mixture was stirred for hours at room temperature, and for 8 hours at 70° C. After cooling the mixture naturally, the mixture was diluted with chloroform (200 mL), washed with water (100 mL) and saturate brine (100 mL), and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified with a column (40S) of Biotage AB (5% methanol-chloroform), to obtain the title compound (3.47 g, 94%) as a crystalline powder.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][C@H:11]([C@@H:20]([C@H:29]([CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[O:30][S:31]([CH3:34])(=[O:33])=[O:32])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)=O>CN(C)C=O>[N:1]([CH2:10][C@H:11]([C@@H:20]([C@H:29]([CH2:35][O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[O:30][S:31]([CH3:34])(=[O:33])=[O:32])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[N+:2]=[N-:3]
Reactant: CS(=O)(=O)OC[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](COCc1ccccc1)OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)O[C@@H](COCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H](CN=[N+]=[N-])OCc1ccccc1
Temperature: 60 °C
Yield: 68.2 %

Procedure:
A mixture of sodium azide (1.72 g, 26.4 mmol) and 1,4-di-O-methanesulfonyl-2,3,5-tri-O-benzyl-L-xylitol (13.9 g, 24 mmol) in dimethylformamide (500 mL) is heated overnight at 60° C. under stirring. Dimethylformamide is evaporated under reduced pressure. The residue is dissolved in ethyl acetate and washed with water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure, yielding an oil. Flash chromatography on silica gel and elution with a 7:3 mixture of cyclohexane and ethyl acetate yield 1-azido-1-deoxy-4-O-methanesulfonyl -2,3,5-tri-O-benzyl-L-xylitol (8.6 g, 63%) as an oil.
Reaction SMILES: [CH2:1]([N:3](CC)[C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11](O)[C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][CH:13]=1)[CH3:2].[CH2:27]([N:29](CC)[CH2:30][CH2:31]N)[CH3:28]>[Cl-].[Zn+2].[Cl-]>[CH2:27]([N:29]([CH2:30][CH3:31])[CH2:2][CH2:1][N:3]1[CH:11]([C:12]2[CH:13]=[CH:14][C:15]([N:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:16][CH:17]=2)[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:4]1=[O:24])[CH3:28]
Reactant: CCN(CC)C(=O)c1ccccc1C(O)c1ccc(N(CC)CC)cc1
Reactant: CCN(CC)CCN
Agent: [Cl-]
Agent: [Zn+2]
Product: CCN(CC)CCN1C(=O)c2ccccc2C1c1ccc(N(CC)CC)cc1

Procedure:
Using 3.54 g of Compound C, 0.15 g of anhydrous zinc chloride and 5 ml of N,N-diethylethylenediamine, the same procedures as in Example 16 were repeated. The crude crystals obtained were crystallized from hexane to give 2.38 g of 2-(2-diethylaminoethyl)-3-(4-diethylaminophenyl)isoindolin-1-one (Compound 19).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([N:22]([C:32]4[CH:36]=[CH:35][O:34][N:33]=4)CC4C=CC(OC)=CC=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:37])=[C:4]([O:38][CH2:39][C:40]#[N:41])[CH:3]=1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:32]4[CH:36]=[CH:35][O:34][N:33]=4)(=[O:20])=[O:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:37])=[C:4]([O:38][CH2:39][C:40]#[N:41])[CH:3]=1
Reactant: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(Br)cc3OCC#N)c2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCOc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 0.33 h

Procedure:
To a solution of 1-(4-bromo-2-(cyanomethoxy)-5-fluorophenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.80 g, 1.251 mmol) in DCM (12.51 ml) at room temperature was added trifluoromethanesulfonic acid (0.333 ml, 3.75 mmol). The resulting solution was stirred for 20 minutes and LCMS indicated that the reaction was complete. The reaction mixture was concentrated and loaded directly onto an silica column and purified by ISCO MPLC (100% heptanes to 75% 3:1 EtOAc:EtOH). The product eluted at 75% 3:1 EtOAc:EtOH. m/z (ESI) 522.9 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH:18]1([CH2:21][CH2:22][NH:23][C:24]([C:26]2[N:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:30][CH:31]=2)=[O:25])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][CH2:22][NH:23][C:24]([C:26]2[N:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][N:35]([C:5](=[O:6])[C:4]4[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:3]=4[C:2]([F:17])([F:16])[F:1])[CH2:34][CH2:33]3)=[CH:30][CH:31]=2)=[O:25])[CH2:20][CH2:19]1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3cc(C(F)(F)F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2,5-bis-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (50% yield). 1H NMR (400 MHz, CDCl3) δ 8.08, 7.99, 7.92-7.9, 7.85-7.84, 7.65, 7.02, 4.13-4.08, 3.95-3.71, 3.57-3.55, 3.38-3.36, 1.57-1.44, 0.8-0.7, 0.48-0.46, 0.16-0.08.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12]O>OS(O)(=O)=O>[C:1]1([CH:7]([CH3:11])[C:8]([O:10][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(=O)O)c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)c1ccccc1
Temperature: 25 °C

Procedure:
2-Phenylpropionic acid (8.4 g, 56 mmol) in methanol (180 ml) and concentrated H2SO4 (2 ml) were heated at reflux for 4 hours. The reaction was cooled down to room temperature and concentrated in vacuo (~30 ml), which was poured into ice water (~100 ml). The products were extracted with Et2O (150 ml×3), which was washed with saturated NaHCO3, H2O and dried over MgSO4. Filtration and evaporation of solvent yielded a yellow oil (8.9 g), which was distilled to give a colorless oil (8.34 g, 51 mmol, 91%, b.p. 73° C./1.5 mm Hg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20].[C:21]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)#[N:22].CCN(C(C)C)C(C)C.C(OC1C=CC(/C=C2/C(=O)N(CCNC(=O)C)C(=O)S/2)=CC=1)C>>[C:21]([C:23]1[CH:24]=[CH:25][C:26]([S:29]([NH:1][CH2:2][CH2:3][N:4]2[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=3)/[S:6][C:5]2=[O:20])(=[O:31])=[O:30])=[CH:27][CH:28]=1)#[N:22]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Agent: CCOc1ccc(/C=C2\SC(=O)N(CCNC(C)=O)C2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(/C=C2\SC(=O)N(CCNS(=O)(=O)c3ccc(C#N)cc3)C2=O)cc1

Procedure:
The title compound 27b was prepared from compound 76 (101 mg, 0.25 mmol), 4-cyano-benzenesulfonyl chloride (55 mg, 0.28 mmol) and DIPEA (131 μL, 0.75 mmol) in a manner similar to that described for 25a in 92.0% (105 mg) yield as a light-yellow solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[OH-].[Na+].[I:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>O.O1CCCC1>[I:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](=[O:13])[NH:2][CH2:3][C:4]([NH2:6])=[O:5]
Reactant: NCC(N)=O
Reactant: O=C(Cl)c1ccccc1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)CNC(=O)c1ccccc1I
Reaction time: 0.03 h
Yield: 21.9 %

Procedure:
A solution of 5.0 g of glycinamide hydrochloride in 10 ml of water was cooled in an ice bath during the addition of 30 ml of 6 N sodium hydroxide. To the resulting mixture was added a solution of 8.0 g o-iodobenzoyl chloride in 20 ml of tetrahydrofuran and the mixture was shaken vigorously for 2 minutes. The mixture was then stirred for 21/2 hours. The tan solid which formed was filtered by suction and washed with water until the washings were neutral. The residue was then dried on a rotary evaporator for 5 hours at 60° and 80 mm Hg. There was thus obtained a crude product which was recrystallized from ethanol to yield 2.0 g of o-iodohippuramide as buff colored crystals, m.p. 183°-185°, Rf 0.64.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[CH:10]=2)[NH:5][C:4](=[O:25])[CH:3]=1.[CH:26](/B(O)O)=[CH:27]\[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH:12]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[NH:5][C:4](=[O:25])[CH:3]=[C:2]3/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:19][CH:20]=1
Reactant: O=c1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc2[nH]1
Reactant: OB(O)/C=C/c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1cc(/C=C/c2ccccc2)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc2[nH]1
Reaction time: 2 h

Procedure:
4-Bromo-6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinolin-2(1H)-one (50 mg, 0.116 mol, 1 equip), trans-beta-styreneboronic acid (35 mg, 0.232 mmol, 2 equip), SPhos (9.7 mg, 0.023 mmol, 0.2 equip), tripotassium phosphate (49.2 mg, 0.232 mmol, 2 equip), and palladium acetate (2.6 mg, 0.012 mmol, 0.1 equip) were added to 1,4-dioxane (5 mL) and the resulting mixture stirred for 2 h. Additional trans-beta-styreneboronic acid (35 mg, 0.232 mmol, 2 equip), SPhos (9.7 mg, 0.023 mmol, 0.2 equip), tripotassium phosphate (49.2 mg, 0.232 mmol, 2 equip), and palladium acetate (2.6 mg, 0.012 mmol, 0.1 equip) were added and the resulting mixture was stirred overnight. The reaction mixture was diluted with water and ethyl acetate and the layers were separated. The organic phase was washed with saturated sodium bicarbonate, then water, dried over Na2SO4, filtered and concentrated. The residue was purified by MPLC using a dichloromethane-methanol gradient to yield (E)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-4-styrylquinolin-2(1H)-one.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([CH3:23])=[CH:13][C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[CH2:36][NH2:37].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[CH:20]=[C:15]4[C:14]([CH2:21][N:37]([CH2:36][C:29]5[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:28]=5[O:27][CH3:26])[C:16]4=[O:17])=[CH:13][C:12]=3[CH3:23])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)cc1C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3cc(C)c(Cc4ccc(-n5cccn5)cc4)cc3C2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 460.8 %

Procedure:
A solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-2-formyl-4-methylbenzoate (0.30 g), (2,4-dimethoxyphenyl)methanamine (0.02 g) and anhydrous magnesium sulfate (0.21 g) in THF (6.00 mL) was stirred at room temperature for 1.5 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (6.00 mL) and THF (6.00 mL), sodium triacetoxyborohydride (0.38 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.25 g).
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:15](Cl)=[O:16].[NH2:22][C:23]1[CH:24]=[C:25]([CH:36]=[CH:37][N:38]=1)[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>>[CH2:29]([NH:28][C:26](=[O:27])[C:25]1[CH:36]=[CH:37][N:38]=[C:23]([NH:22][C:15](=[O:16])[C:14]2[CH:13]=[C:12]([F:11])[CH:20]=[C:19]([F:21])[CH:18]=2)[CH:24]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Agent: O=C(Cl)c1ccccc1F
Product: O=C(NCc1ccccc1)c1ccnc(NC(=O)c2cc(F)cc(F)c2)c1
Yield: 68 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 3,5-difluorobenzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(3,5-difluorobenzamido)isonicotinamide was obtained as a colorless solid in 68% yield: mp 185-187° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 11.16 (s, 1H), 9.35 (t, J=6.0 Hz, 1H), 8.54-8.50 (m, 2H), 7.75-7.71 (m, 2H), 7.58-7.47 (m, 2H), 7.31-7.21 (m, 5H), 4.46 (d, J=5.9 Hz, 2H); MS (ES+) m/z 368.5 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH2:20][CH3:21].[Br:22]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH:4]([Br:22])[CH:3]1[CH2:20][CH3:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CC)C2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CC)C2Br
Temperature: 25 °C

Procedure:
To a solution of ethyl (1-oxo-2-ethyl-6,7-dichloro-5-indanyloxy)acetate (19.8 g., 0.060 mole) in carbon tetrachloride (200 ml.) is added N-bromosuccinimide (11.32 g., 0.0636 mole) and α,α1 -azodiisobutyronitrile (425 mg.). The mixture is heated at reflux for 10 minutes, cooled to room temperature and filtered to remove succinimide. The filtrate is washed with water and then dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure to afford ethyl (1-oxo-2-ethyl-3-bromo-6,7-dichloro-5-indanyloxy)acetate which is dissolved in pyridine (40 ml.) and heated at 80° C. for 30 minutes. The solution is then cooled to room temperature and poured into 1.2 N hydrochloric acid (400 ml.). The product is extracted with chloroform and the combined extracts are washed with water and dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure to afford 16.8 g. of a crude product which is then recrystallized from methanol to afford substantially pure ethyl (1-oxo-2 -ethyl-6,7-dichloroinden-5-yloxy)acetate, m.p. 141°-143° C.