Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[C:3]1[CH3:14].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:26][C@H:27]1[CH:32]2[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]2)[CH2:28]1>ClCCl>[N:29]12[CH2:34][CH2:33][CH:32]([CH2:31][CH2:30]1)[C@H:27]([NH:26][C:11]([C:4]1[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[C:3]=1[CH3:14])=[O:13])[CH2:28]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: Cc1c(C(=O)O)c2ccccc2n1C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N[C@@H]2CN3CCC2CC3)c2ccccc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
1,2-dimethylindole-3-carboxylic acid (1.05 g, 5.5 mmol) was dissolved with oxalyl chloride (0.55 ml, 6 mmol) and dimethylformamide (0.1 ml) in dichloromethane (30 ml) and stirred at room temperature for one hour. The mixture was then concentrated under reduced pressure, and the residue was dissolved in dichloromethane (20 ml). The resulting mixture was added dropwise at 0° C. to a solution of (S)-3-amino-1-azabicyclo[2.2.2]octane (0.7 g, 5.5 mmol) in dichloromethane (10 ml). The solution was stirred at room temperature for 30 minutes, after which the solvent was removed under vacuum. The residue was dissolved in water and washed with ethyl acetate. The aqueous layer was made basic with 10N aqueous sodium hydroxide, filtered and extracted with ethyl acetate. The organic layer was dried with anhydrous potassium carbonate, filtered, and then evaporated. Recrystallization from ethyl acetate afforded 0.7 g (46% yield) (S)-3-[(1-azabicyclo[2.2.2]oct-3-yl)aminocarbonyl]-1,2-dimethylindole, m.p. 176°-177° C.; [α]D25 -51.90 (c 0.92, CHCl3). Anal. for C18H23N3O: Calcd: C, 72.70; H, 7.79; N, 14.13. Found: C, 72.75; H, 7.89; N, 14.15.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[C:9]([C:26]#[N:27])=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][C:36]1([CH3:42])[CH3:41]>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:38]5[CH2:39][CH2:40][N:35]([CH3:34])[C:36]([CH3:42])([CH3:41])[CH2:37]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[C:9]([C:26]#[N:27])=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(c2)c(C#N)nn3Cc2ccc(Cl)cc2C(F)(F)F)S1
Reactant: CN1CCNCC1(C)C
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(c3)c(C#N)nn4Cc3ccc(Cl)cc3C(F)(F)F)S2)CC1(C)C

Procedure:
1-[4-Chloro-2-(trifluoromethyl)benzyl]-5-{[4-oxo-2-(3,3,4-trimethylpiperazin-1-yl)-1,3-thiazol-5(4H)-ylidene]methyl}-1H-indazole-3-carbonitrile was prepared from 1-(4-Chloro-2-trifluoromethyl-benzyl)-5-(2-ethylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-1H-indazole-3-carbonitrile and 1,2,2-Trimethyl-piperazine following General Procedure C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[NH2:16][CH2:17][CH:18]([OH:20])[CH3:19]>CO.O>[OH:20][CH:18]([CH3:19])[CH2:17][NH:16][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9]
Reactant: CC(O)CN
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: O
Solvent: CO
Product: CC(O)CNC(c1ccccc1)C(O)c1ccccc1
Temperature: 125 °C
Reaction time: 18 h
Yield: 28.1 %

Procedure:
A mixture of trans-stilbene oxide (3.93 g, 0.20 mole) and 1-amino-2-propanol (4.51 g, 0.060 mole) was heated in an oil bath at 125° C. for 1 hour. After standing at ambient temperature for 18 hours, the viscous oil was dissolved in 20 ml of methanol and diluted with water causing a white solid to precipitate. The solid was collected, washed with water, and dried under ambient conditions to give 4.57 g (84%) of the product which was recrystallized from toluene to give 3.65 g solids; m.p. 116°-118° C.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12](=[S:16])[NH:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:17][CH3:18])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19]N(C=O)C.C([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([S:16][CH3:19])=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:17][CH3:18])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C=O
Reactant: CCc1[nH]n(C2CCCC2)c2nc(=S)[nH]c(=O)c1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(SC)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-6-(thioxo) pyrazolo[3,4-d]pyrimidin-4-one (5.2 g, 19.6 mmol), DMF (50 mL) and K2CO3 (2.76 g, 20 mmol) was stirred at ambient temperature for 25 minutes and then dimethyl sulfate (3.88 mL, 40 mmol) was added. The reaction mixture was stirred for 2 hours, then was poured into cold water. The product was collected by filtration, washed with water, recrystallized from cyclohexane/ether and dried at 70-75° C. in vacuo to afford 4.6 g of 1-cyclopentyl-3-ethyl-6-(methylthio) pyrazolo[3,4-d]pyrimidin-4-one, m.p.200-202° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:12]=1)[C:7]([OH:9])=O.[CH3:20][C:21]1[N:26]=[CH:25][C:24]([C@H:27]([NH2:29])[CH3:28])=[CH:23][N:22]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:12]=1)[C:7]([NH:29][C@@H:27]([C:24]1[CH:23]=[N:22][C:21]([CH3:20])=[N:26][CH:25]=1)[CH3:28])=[O:9]
Reactant: Cc1ncc([C@@H](C)N)cn1
Reactant: COCc1cc(C(=O)O)cc(-c2ccc(C)cn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1cc(C(=O)N[C@H](C)c2cnc(C)nc2)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(methoxymethyl)-5-(5-methylpyridin-2-yl)benzoic acid (30 mg, 0.12 mmol) in N,N-dimethylformamide (1.5 mL) were added (R)-1-(2-methylpyrimidin-5-yl)ethanamine (40 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (100 μL, 0.57 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product.
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:10]2=[O:19])[CH2:5][CH2:4]1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:22].C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[OH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]4[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=4)=[O:22])[CH2:14]3)[C:10]2=[O:19])[CH2:5][CH2:4]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C1N([C@H]2CC[C@H](O)CC2)CCC12CCCNC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCC2(CCN([C@H]3CC[C@H](O)CC3)C2=O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one hydrochloride (0.30 g, 0.0010 mol), p-nitrophenyl chloroformate (0.25 g, 0.0012 mol), and N,N-diisopropylethylamine (540 μL, 0.0031 mol) in methylene chloride (4 mL, 0.06 mol) was stirred at rt for 16 h. The crude reaction mixture was purified by flash column chromatography to afford 120 mg of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>ClCCl>[Si:23]([O:13][C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-methoxycarbonylpyrrolidine (21.46 g) and imidazole (7.74 g) in dichloromethane (150 ml) was added dropwise a solution of tert-butyldimethylsilyl chloride (14.67 g) in dichloromethane (30 ml) at room temperature. After two hours, resultant precipitate was filtered off, and the filtrate was washed in turn with water and brine. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (500 ml) eluting with a mixture of hexane and ethyl acetate (2:1, V/V) to give (2S,4R)-4-(tert-butyldimethylsilyloxy)-1-(tert-butoxycarbonyl)-2-methoxycarbonylpyrrolidine (32.3 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH2:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:3]1=[O:28].Cl[C:30]1[C:31]2[CH:43]=[C:42]([Cl:44])[CH:41]=[N:40][C:32]=2[N:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[N:35]=1>>[C:22]1([S:19]([CH2:18][C@@H:8]2[CH2:9][C@H:10]([N:13]([CH:15]([CH3:16])[CH3:17])[CH3:14])[CH2:11][CH2:12][C@@H:7]2[N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:30]3[C:31]4[CH:43]=[C:42]([Cl:44])[CH:41]=[N:40][C:32]=4[N:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[N:35]=3)[C:3]2=[O:28])(=[O:21])=[O:20])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1nc(Cl)c2cc(Cl)cnc2n1
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](Nc3nc(C(F)(F)F)nc4ncc(Cl)cc34)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1

Procedure:
The titled compound was prepared from (3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-one and 4,6-dichloro-2-trifluoromethyl-pyrido[2,3-d]pyrimidine using the conditions described in Example 106, part C. MS (ES+)=639 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH2:12]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@@H:20]([NH2:23])[CH2:19]1)=[O:17])[CH:13]=[CH2:14].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:12]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@@H:20]([NH:23][C:7]2[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=2[F:1])[CH2:19]1)=[O:17])[CH:13]=[CH2:14]
Reactant: C=CCOC(=O)N1CC[C@@H](N)C1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CC[C@@H](Nc2ccc([N+](=O)[O-])cc2F)C1

Procedure:
A solution of 5.01 g of 3,4-difluoro nitrobenzene, 5.1 g (3R)-1-allyloxycarbonyl-3-amino pyrrolidine (30 mmol) and 6.27 ml of triethylamine (31.5 mmol) in 100 ml of ethyl acetate was stirred at reflux. The reaction was monitored by HPLC. The reaction was diluted with ethyl acetate, washed with water and brine, the org. layer dried over Mg sulfate, filtered and evaporated. The residue crystallized from an ether/hexane mixture.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20](OC2C=CC([N+]([O-])=O)=CC=2)=[O:21])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.CCN(CC)CC>C1COCC1>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)=[O:21])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(Nc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCc1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1ccccn1)Nc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Yield: 45 %

Procedure:
2-{[(4-nitrophenoxy)carbonyl]amino}phenyl 4-(trifluoromethyl)-benzenesulfonate (0.25 mmol, 120 mg) is dissolved in THF, and 2-(aminomethyl)pyridine (0.25 mmol, 26 μl) and Et3N (0.3 mmol, 42 μl) are added to the solution. The reaction mixture is heated at 60° C. for overnight. After purification by preparative HPLC, 2-({[(pyridin-2-ylmethyl)amino]carbonyl}amino)phenyl 4-(trifluoromethyl)benzenesulfonate is obtained in 45% yield. 1H NMR (400 MHz, MeOD-d6) 8.54 (d, 1H), 8.01(d, 2H), 7.82(m, 4H), 7.42(d, 1H), 7.34(t, 1H), 7.26(m, 4H), 7.05(t, 1H), 4.41(s, 2H). ESI+ for C20H16F3N3O4S m/z=452, (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([S:7](Cl)(=[O:9])=[O:8])[N:3]=1.C(O)(=O)C.[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:17]=1[NH2:18]>>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([S:7]([NH:18][C:17]2[C:16]([F:15])=[CH:22][CH:21]=[CH:20][C:19]=2[F:23])(=[O:9])=[O:8])[N:3]=1
Reactant: Nc1c(F)cccc1F
Reactant: Nc1nc(S(=O)(=O)Cl)n[nH]1
Solvent: CC(=O)O
Product: Nc1nc(S(=O)(=O)Nc2c(F)cccc2F)n[nH]1

Procedure:
5-Amino-3-chlorosulfonyl-1,2,4-triazole (20 g of about 92 percent purity, 0.1 mole) was slurried in 168 g (2.8 moles) of acetic acid and 14.2 g (0.11 moles) of 2,6-difluoroaniline were added. The mixture was stirred and heated at 90° C. for 11 hours at which time analysis by HPLC a 76 percent conversion to the title compound and 9 percent conversion to its 5-acetylamino derivative. Water was added and the mixture cooled to 10° C. The solids were collected by filtration, washed with water, and dried at 60° C. to obtain 14.8 g (53 percent of theory) of the title compound as a 96 percent purity product. Analysis of the filtrate by HPLC showed that it contained another 26 percent of theory and the total yield was 79 percent of theory.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH2:14]([O:16][C:17]([C:19]1[CH:29]=[C:22]2[C:23]([CH2:27][OH:28])=[CH:24][CH:25]=[CH:26][N:21]2[N:20]=1)=[O:18])[CH3:15].CC(C)=O>C(O)(C)C>[CH3:15][CH2:14][O:16][C:17]([C:19]1[CH:29]=[C:22]2[C:23]([C:27]([OH:3])=[O:28])=[CH:24][CH:25]=[CH:26][N:21]2[N:20]=1)=[O:18]
Reactant: CCOC(=O)c1cc2c(CO)cccn2n1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CCOC(=O)c1cc2c(C(=O)O)cccn2n1
Reaction time: 0.33 h

Procedure:
A 2.65 M solution of the Jones reagent (28 mL) is added dropwise over 40 min to a solution of 4-hydroxymethylpyrazolo[1,5-a]pyridine-2-carboxylic acid ethyl ester (5.30 g, 24.1 mmol) and acetone (240 mL) under air cooled by a water bath. After 20 min, isopropanol (3 mL) is added dropwise. After stirring for 30 min, the blue-green mixture is filtered (acetone rinse). The organics are concentrated under reduced pressure. The residue is dissolved in water. Et2O is added and the mixture is stirred for 15 min. The resulting solid is collected by filtration. The filtrate is dried to afford the title compound as a tan solid. LC-MS m/z (M+Na+): 257.02§.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][NH+:7]=1.[C:16](=[C:19]1[CH2:23][CH2:22][CH2:21][C:20]1=O)([CH3:18])[CH3:17]>CN(C)C=O.CO>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:18][C:16]1[C:19]2[C:23]([CH:22]=[CH:21][CH:20]=2)=[N+:7]2[C:6]([CH:17]=1)=[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=[CH:9][CH2:8]2
Reactant: c1ccc2c[nH+]ccc2c1
Reactant: CC(C)=C1CCCC1=O
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc2[n+](c3c1=CC=C3)CC=c1ccccc1=2

Procedure:
Isoquinolinium perchlorate (2.3 g) and 2-isopropylidene cyclopentanone (1.5 g) in dimethylformamide (5 ml) were refluxed for 18 hours. The reaction mixture was cooled, diluted with methanol and filtered. Purification was effected by recrystallization from acetonitrile (norite). Yield 1.5 g, m.p. > 300°,
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:15][Si:16]([CH3:33])([CH3:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br>>[CH3:15][Si:16]([CH3:32])([CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCBr
Reactant: CCOC(=O)CCc1ccc(N)cc1
Product: CCOC(=O)CCc1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1

Procedure:
In a manner directly analogous to that described in Example 6, ethyl 4-aminohydrocinnamate is alkylated with 14-(trimethylsilyl)tetradecyl bromide to form ethyl 4-[14-(trimethylsilyl)tetradecylamino]hydrocinnamate. Subsequently, in a manner directly analogous to that described in Example 9, ethyl 4-[14-(trimethylsilyl)tetradecylamino]hydrocinnamate is hydrolyzed to 4-[14-(trimethylsilyl)tetradecylamino]hydrocinnamic acid.
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]([OH:2])=[O:11])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccccc1N
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(CNc2ccccc2C(=O)O)cc1

Procedure:
Prepared by a similar procedure as described for preparation 1J, starting from anthranilic acid methyl ester and 4-methoxybenzaldehyde. 13C-NMR (DMSO-d6) δ 169.9, 158.2, 150.6, 134.2, 131.6, 131.0, 128.3, 114.3, 113.9, 111.6, 110.2, 54.9, 45.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][N:12]=[C:11]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.O>[CH2:1]([O:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(-n2cccn2)nc1OCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(-n2cccn2)nc1OCc1ccccc1
Yield: 29 %

Procedure:
Ethyl 4-(benzyloxy)-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylate, 11-b, (150 g, 0.46 mol) in THF (1.5 L) was treated with LiOH monohydrate (58 g, 1.39 mol) in water (60 ml) at room temperature for 3 hours. The mixture was concentrated under vacuum and diluted with water (200 ml) followed by extraction with ethyl acetate. The aqueous layer was acidified to pH=2 with 10% HCl and solid crashed out from the solution which was then filtered and washed with water to afford the product, 11-c, (40 g, 29%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([NH:1][N:2]2[N:11]=[C:10]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:21])=[O:34])=[CH:28][CH:27]=1)(=[O:24])=[O:25]
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O
Product: CS(=O)(=O)c1ccc(CC(=O)Nn2nc(S(=O)(=O)c3ccccc3)c3ccccc3c2=O)cc1

Procedure:
The product from Example 68B and 2-(4-(methylsulfonyl)phenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.56 (d, J=8.2, 1H), 8.42-8.35 (m, 1H), 8.15-8.08 (m, 1H), 8.04-7.99 (m, 3H), 7.91 (d, J=8.3, 2H), 7.82-7.77 (m, 1H), 7.71-7.65 (m, 2H), 7.57 (d, J=8.3, 2H), 3.83 (s, 2H), 3.24 (s, 3H); MS (DCI+) M/Z 515 (M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.1 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (78 mg, 60%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1.Br[CH:17]([CH2:19][CH3:20])[CH3:18].O>CN(C=O)C>[CH3:18][CH:17]([S:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1)[CH2:19][CH3:20]
Reactant: COc1ccc(S)cc1
Reactant: CCC(C)Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)Sc1ccc(OC)cc1
Reaction time: 8 h

Procedure:
Potassium t-butoxide (30.6 g, 275.0 mmol) is added to a solution of 4-methoxybenzenethiol (30.0 ml, 250.0 mmol) in 250 ml of DMF. The mixture is heated at 80° until homogeneous, after which 2-bromobutane (30.0 ml, 275.0 mmol) in 30 ml of DMF is added dropwise over approx. 30 min. The mixture is stirred at 60° overnight after which it is cooled and is then poured into water and the aqueous phase is extracted with ether (3×). The combined ether extracts are washed with water, with 5% sodium hydroxide, with water and with brine, dried, and the solvent removed to give 4-(1-methylpropylthio)anisole.
Reaction SMILES: Cl.[OH:2][CH:3]1[O:18][C:6]2=[C:7]([O:16][CH3:17])[C:8]3[O:13][C:12](=[O:14])[CH:11]=[CH:10][C:9]=3[CH:15]=[C:5]2[CH2:4]1.[CH2:19](O)[CH3:20]>>[CH2:19]([O:2][CH:3]1[O:18][C:6]2=[C:7]([O:16][CH3:17])[C:8]3[O:13][C:12](=[O:14])[CH:11]=[CH:10][C:9]=3[CH:15]=[C:5]2[CH2:4]1)[CH3:20]
Reactant: CCO
Reactant: COc1c2c(cc3ccc(=O)oc13)CC(O)O2
Agent: Cl
Product: CCOC1Cc2cc3ccc(=O)oc3c(OC)c2O1
Reaction time: 2 h

Procedure:
Absolute ethanol was saturated with gaseous hydrogen chloride at 0°. To this solution, 5.0g. (0.214 mole) of 2-hydroxy-9-methoxy-2,3-dihydro-7H-furo[3,2-g][1]benzopyran-7-one was added, and the reaction was allowed to proceed at 25° for 2.0 hours. The solvent was evaporated, and the residue was passed through a column consisting of 150 g. silica (upper layer) and 50 g. of neutral alumina (lower layer) using benzene/ethyl acetate, 4:1. Fractions containing the product were combined and evaporated to afford pure 2-ethoxy-9-methoxy-2,3-dihydro-7H-furo[3,2-g][1]benzopyran-7-one as a white solid. Recrystallization from ethanol yielded an analytical sample, mp 119°-120°.