Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH:15](=O)[C:16]([CH3:19])([CH3:18])[CH3:17].C(O)(=O)C.C([BH3-])#N>ClCCl>[CH3:13][CH:12]([CH3:14])[CH2:11][C@H:3]([NH:2][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)C[C@H](NCC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(S)-tert-Butyl 2-amino-4-methylpentanoate hydrochloride (1.022 g, 4.57 mmol) and pivalaldehyde (0.502 mL, 4.57 mmol) were combined in dichloromethane (25 mL). Acetic acid (1.0 mL) was added. The reaction was stirred at room temperature for 5 minutes, then PS-cyanoborohydride (3.90 g, 9.14 mmol) was added. The reaction was stirred at room temperature overnight, then filtered and the solvent was removed in vacuo. The crude material was diluted with dichloromethane and basified using saturated aqueous sodium bicarbonate to give (S)-tert-butyl 4-methyl-2-(neopentylamino)pentanoate: 1H NMR (300 MHz, CDCl3) δ ppm 3.04 (t, J=7.4, 1H), 2.40 (d, J=11.1, 1H), 2.09 (d, J=11.1, 1H), 1.86-1.70 (m, 1H), 1.46 (s, 10H), 1.40 (t, J=7.2, 3H), 0.95-0.89 (m, 6H), 0.89 (s, 9H), (S)-tert-butyl 4-methyl-2-(neopentylamino)pentanoate was dissolved in 10 mL of 4 N HCl in dioxane and stirred at room temperature overnight. The solvent was removed under a stream of nitrogen and under high vacuum to give (S)-4-methyl-2-(neopentylamino)pentanoic acid: 1H NMR (300 MHz, DMSO-d6) δ ppm 8.89-8.37 (m, 1H), 8.34-8.03 (m, 1H), 3.82 (t, J=6.5, 1H), 2.88 (d, J=12.3, 1H), 2.62 (d, J=12.2, 1H), 1.83-1.67 (m, 2H), 1.67-1.56 (m, 1H), 1.00 (s, 9H), 0.97-0.88 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[SH:10].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1.Cl>N1C=CC=CC=1>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][S:10][C:3]2[C:4](=[O:9])[O:5][C:6]([CH3:8])=[CH:7][C:2]=2[OH:1])=[CH:14][CH:13]=1
Reactant: Cc1cc(O)c(S)c(=O)o1
Reactant: Fc1ccc(CCl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(O)c(SCc2ccc(F)cc2)c(=O)o1
Reaction time: 4 h

Procedure:
To a stirred solution of 10.5 g. (0.0664 mole) of 4-hydroxy-6-methyl-3-mercapto-2-pyrone in 50 ml. of pyridine was added 9.60 g. (0.0664 mole) of p-fluorobenzyl chloride in one portion. The reaction was slightly exothermic, the temperature rising from 25° to 34°C. The reaction mixture was then allowed to stand at room temperature for four hours and at the end of this period was poured into a mixture of ice and 100 ml. of concentrated hydrochloric acid. The gummy precipitate was extracted with methylene chloride and the extract dried over anhydrous magnesium sulfate. The solvent was removed by evaporation in vacuo, leaving a light yellow oil, which crystallized upon cooling, weight 12.5 g. (71 percent). This was recrystallized from a solvent system of methylcyclohexane, benzene and ethanol to give light yellow crystals, m.p. 114.5°-118.5°C.; weight 7.20 g. Recrystallization from benzene gave the pure 3-(p-fluorobenzylthio)-4-hydroxy-6-methyl-2-pyrone as a pale yellow, crystalline solid, m.p. 118°-122°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][NH:39][CH2:40][C:41]#[CH:42]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:39]([CH3:38])[CH2:40][C:41]#[CH:42])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: C#CCNC
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: C#CCN(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and methyl-prop-2-ynylamine according to conditions described in general procedure C. Mp: 116-117° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.58-1.61 (m, 6 H), 2.85 (m, 3 H), 3.27-3.30 (m, 5 H), 4.22 (s, 2 H), 6.30 (d, J=5.5 Hz, 1 H), 6.94-6.98 (m, 1 H), 7.15 (d, J=8.8 Hz, 1 H), 7.43 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.55-7.60 (m, 3 H), 7.82-7.84 (m, 1 H), 7.98 (d, J=7.4 Hz, 1 H), 8.30 (d, J=5.5 Hz, 1 H), 10.44 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:18])[CH:15]=2)[NH:10][C:9]1=[O:19])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:18])[CH:15]=2)[N:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]1=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1Cc2cc(Br)ccc2NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC1Cc2cc(Br)ccc2N(Cc2ccccc2)C1=O
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A stirring mixture of 3B (0.60 g, 1.76 mmol), K2CO3 (0.49 g, 3.52 mmol), and benzyl bromide (0.36 g, 2.11 mmol) in acetone (15 mL) was heated to reflux under argon for 16 h. The mixture was then cooled to RT and the solvent was evaporated under vacuum. The resulting residue was partitioned between water and EtOAc. The EtOAc layer was washed with brine, dried (Na2SO4), and evaporated. The resulting crude product was chromatographed on silica gel eluted with 10-20% EtOAc in hexane (step-wise gradient) to obtain the title compound (0.72 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[C:9](=[CH:16][N:17]([CH3:19])[CH3:18])[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)CC(=O)c1ccccc1Cl
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CC(=O)C(=CN(C)C)C(=O)c1ccccc1Cl
Yield: 51 %

Procedure:
A mixture of crude 1-(2-chlorophenyl)butane-1,3-dione from the previous step and 1,1-dimethoxy-N,N-dimethylmethanamine (2.042 g, 17.14 mmol) in toluene (20 mL) was heated to reflux for 2 h and concentrated. Silica gel chromatography, using 70 to 100% ethyl acetate in hexanes gradient, gave 1-(2-chlorophenyl)-2-((dimethylamino)methylene)butane-1,3-dione as a red, viscous oil (2.20 g, 51% yield for 2 steps). MS (ES+) m/z: 252 (M+H); HPLC retention time: 2.51 min (Analytical HPLC Method D).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]=O.[N+:15]([CH3:18])([O-:17])=[O:16].[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]=[CH:18][N+:15]([O-:17])=[O:16]
Reactant: COc1ccc2ccccc2c1C=O
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2ccccc2c1C=C[N+](=O)[O-]
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of 2-methoxy-1-naphthaldehyde (1862 mg, 10 mmol) and nitromethane (610 mg, 10 mmol) in methanol (200 ml) is stirred at room temperature until the solids dissolved. The solution is cooled to about 0° C. and a 30% NaOH solution (2 ml, 20 mmol) is added dropwise over 30 min. The resulting solution is added slowly at 60° C. to a 35% HCl solution (200 ml). The amorphous solid that formed is filtered and washed with water. The crude product is recrystallized from ethanol to give pure title compound in 80% yield (1835 mg).
Reaction SMILES: [H-].[Na+].[C:3]([SH:7])([CH3:6])([CH3:5])[CH3:4].[F:8][CH:9]([F:31])[C:10]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12](Br)[C:11]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(OCC)C>C1COCC1>[C:3]([S:7][C:12]1[C:11]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:10]([CH:9]([F:31])[F:8])[N:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[C:13]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1Br
Reactant: CC(C)(C)S
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1SC(C)(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
A mixture of 0.44 g (0.011 mol) of 60of NaH in mineal oil dispersion was washed twice with 10 ml portions of dry THF. To the resulting oil free NaH was added 30 ml of dry THF followed by 1.08 g (1.4 ml, 0.012 mol) of t-butylmercaptan. The resulting mixture was heated up to 50° C. for 20 minutes and a white precipitate was formed. This suspension was added dropwise at room temperture to a solution of 4.20 g (0.01 mol) of product of Example 106 in 40 ml of dry THF. The reaction temperature rose to 35° C. After stirring at room temperature for 3 hours, the reaction mixture was poured into 3.7HCl. The aqueous layer was extractad twice with diethyl ether, dried (MgSO4) and concentrated to give 4.23 g of a light yellow oil. The crude product was purified by HPLC using 2EtOAC/cyclohexane as eluting solvent followed by kugelrohr distillation at 100°-110 ° C./100 Pa to give 2.86 g (67) of product as a colorless oil, nD25 1.4678.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.[K].[I-].[Na+]>CN(C=O)C>[OH:5][C:3]([CH3:6])([CH3:4])[CH2:2][C:9]12[CH:13]=[CH:14][CH:15]=[CH:16][CH:8]1[C:7]([NH:11][C:10]2=[O:12])=[O:17]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(O)CCl
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(O)CC12C=CC=CC1C(=O)NC2=O
Yield: 37 %

Procedure:
A solution of 1-chloro-2-methyl-2-propanol (2.23 g, 97%, 0.02 mol), potassium phthalimide (3.780 g, 98%, 0.02 mol) and sodium iodide (60 mg, 4 mmol) in anhydrous DMF (40 mL) was heated to reflux overnight. The solvent was evaporated under reduced pressure. The resulting product was triturated with a mixture of 3:2 ethyl acetate/hexanes and the ensuing white precipitate was removed by filtration. The yellow filtrate was concentrated under reduced pressure and purified by flash chromatography in a mixture of 2:3 ethyl acetate/hexanes. The impure product thus isolated was triturated with hot hexanes (125 mL) and filtered to remove an insoluble white impurity. After evaporation of the solvent under reduced pressure, the obtained white solid was recrystallized in hexanes. The product was yielded as colorless crystals that were collected by filtration and dried under high vacuum (1.63 g, 37% yield). m.p.: 104-105° C.; TLC Rf 0.20 (2:3 ethyl acetate/hexanes); FTIR (KBr): 3524, 3456, 3097, 3031, 2973, 2930, 1773, 1698, 1611, 1466, 1427, 1389, 1319, 1190, 1076, 990, 965, 912, 890, 838, 766, 724, 712, 638 cm−1; 1H-NMR (500 MHz, CDCl3): δ 1.26 (s, 6H, 2 CH3), 2.74 (s, 1H, OH), 3.75 (s, 2H, CH2), 7.72 (dd, 2H, Jo=5.44 Hz, Jm=3.04 Hz, 2 Hc), 7.85 (dd, 2H, Jo=5.42 Hz, Jm=3.06 Hz, 2 Hh); 13C-NMR (126 MHz, CDCl3): δ 27.6 (2 CH3), 49.3 (CH2), 71.6 (CMe2), 123.6 (2 Cb), 132.0 (2 Ca), 134.3 (2 Cc), 169.3 (2 CO).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[N:19]=[C:18]([C:20]([NH2:22])=[O:21])[CH:17]=[CH:16][CH:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[N:19]=[C:18]([C:20]([NH2:22])=[O:21])[CH:17]=[CH:16][CH:15]=2)=[N:13]1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(C(N)=O)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: NC(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 71.7 %

Procedure:
A mixture of methyl thiosalicylate (1.1 g, 6.4 mmol), 6-cyano-2-pyridinecarboxamide (0.47 g, 3.1 mmol), triethylamine (1.0 ml, 7.1 mmol) and toluene (3 ml) was refluxed for 6 hrs as described in Example. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-ethanol to give the titled compound (0.63 g, 70%).
Reaction SMILES: CN(C)CCCN=C=NCC.[OH:12][CH2:13][CH:14]1[CH2:22][CH:21]2[CH:17]([CH2:18][NH:19][CH2:20]2)[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])([OH:23])[CH2:15]1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C@H:40]([CH3:44])[C:41](O)=[O:42]>ClCCl.O.OC1C2N=NNC=2C=CC=1>[OH:12][CH2:13][CH:14]1[CH2:22][CH:21]2[CH:17]([CH2:18][N:19]([C:41](=[O:42])[C@H:40]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[O:33][CH3:32])[CH3:44])[CH2:20]2)[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])([OH:23])[CH2:15]1
Reactant: COc1ccccc1[C@H](C)C(=O)O
Reactant: COc1ccccc1C1(O)CC(CO)CC2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1[C@H](C)C(=O)N1CC2CC(CO)CC(O)(c3ccccc3OC)C2C1
Temperature: 20 °C
Reaction time: 20 h
Yield: 82 %

Procedure:
2.1 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide are added to a solution of 2.77 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol, 1.80 g of (S)-2-(2-methoxyphenyl)propionic acid and 30 mg of hydroxybenzotriazole hydrate in 80 cm3 of dichloromethane. After stirring at 20° C. for 20 hours, the reaction mixture is washed with 40 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.06-0.20 mm, height 40 cm) in a mixture of cyclohexane and ethyl acetate (30:70 by volume) and then in a mixture of ethyl acetate and methanol (90:10 by volume). Evaporation of the eluent and drying. I under reduced pressure (2.7 kPa) give 3.6 g of 6-hydroxymethyl-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol (mixture of the 2 diastereoisomers, 3aR,4R,6S,7aS,S and 3aS,4S,6R,7aR, S) in the form of a white solid. M.p.K =178° C.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:9]([N:12]([CH3:14])[CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=O.[CH3:15][N:16]([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:23])[C:17]1[CH:22]=[CH:21][C:20]([CH:1]([C:3]2[CH:11]=[CH:10][C:9]([N:12]([CH3:14])[CH3:13])=[CH:8][CH:4]=2)[C:3]2[CH:11]=[CH:10][C:9]([N:12]([CH3:14])[CH3:13])=[CH:8][C:4]=2[C:5]([OH:7])=[O:6])=[CH:19][CH:18]=1
Reactant: CN(C)c1ccc(C=O)c(C(=O)O)c1
Reactant: CN(C)c1ccccc1
Product: CN(C)c1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2C(=O)O)cc1

Procedure:
In another known process for the preparation of CVL there are three steps. The first step comprises the interaction of the methyl ester of 2-formyl-5-dimethylaminobenzoic acid with two equivalents of N,N-dimethylaniline to obtain the methyl ester of 2-[bis(4-dimethylaminophenyl)-methyl]-5-dimethylaminobenzoic acid. After isolation, this benzoic acid is oxidized in the second step and finally in the third step the oxidized product is saponified and the lactone ring is closed to obtain the 3,3-bis(4-dimethylaminophenyl)-6-dimethylaminophthalide (CVL).
Reaction SMILES: [OH-].[K+].C([NH:8][O:9][CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=1[CH3:19])(OCC)=O>>[CH3:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[CH2:10][O:9][NH2:8]
Reactant: CCOC(=O)NOCc1c(C)cc(C)cc1C
Agent: [K+]
Agent: [OH-]
Product: Cc1cc(C)c(CON)c(C)c1
Reaction time: 12 h
Yield: 71.4 %

Procedure:
200 ml of an aqueous solution of 45 g (0.8 mole) of potassium hydroxide was added to 47.5 g (0.2 mole) of the N-carboethoxy-O-(2,4,6-trimethylbenzyl)hydroxylamine prepared as described in Reference Example 1, and the mixture was heated under refluxing for 5 hours. The reaction mixture was allowed to stand for 12 hours, the precipitated crystals were collected by filtration and washed with water to obtain 23.6 g (70.6% yield) of O-(2,4,6-trimethylbenzyl)hydroxylamine. Recrystallization from diethyl ether-petroleum ether (1:3 by volume) yielded a product having a melting point of 54 - 55° C which was subjected to elementary analysis.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[C:8]([CH2:11][C@@H:12]([NH:18][S:19]([C:22]1[S:23][C:24]([C:27]#[C:28][C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:26]=1)(=[O:21])=[O:20])[CH2:13][N+:14]([CH3:17])([CH3:16])[CH3:15])([OH:10])=[O:9]>CO.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[C:8]([CH2:11][C@@H:12]([NH:18][S:19]([C:22]1[S:23][C:24]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=2)=[CH:25][CH:26]=1)(=[O:20])=[O:21])[CH2:13][N+:14]([CH3:17])([CH3:15])[CH3:16])([OH:10])=[O:9]
Reactant: Cc1cccc(C#Cc2ccc(S(=O)(=O)N[C@H](CC(=O)O)C[N+](C)(C)C)s2)c1
Agent: [Pd]
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Product: Cc1cccc(CCc2ccc(S(=O)(=O)N[C@H](CC(=O)O)C[N+](C)(C)C)s2)c1
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of (R)-3-carboxy-N,N,N-trimethyl-2-(5-(m-tolylethynyl)thiophene-2-sulfonamido)propan-1-aminium 2,2,2-trifluoroacetate (7 mg, 0.013 mmol) in MeOH (3 mL) was purged with nitrogen and Pd/C (10 mg) was added and the flask was purged with hydrogen and stirred for 1 h. The mixture was filtered through celite and concentrated. The residue was dissolved into H2O and lyophilized to give the title compound as a white solid (7 mg, 100%). 1H NMR (400 MHz, D2O) δ 7.42 (d, 1H, J=3.8 Hz), 7.08 (t, 1H, J=7.4 Hz), 6.97-6.94 (m, 2H), 6.88 (d, 1H, J=7.1 Hz), 6.74 (d, 1H, J=3.9 Hz) 4.14-4.11 (m, 1H), 3.52-3.49 (m, 1H), 3.46-3.44 (m, 1H), 3.15-3.07 (m, 2H), 3.10 (s, 9H), 2.84 (m, 2H) 2.32-2.25 (m, 1H) 2.15 (s, 3H), 2.01-1.96 (m, 1H); MS ESI 425.2 [M+H]+, calcd for [C20H29N2O4S2+H]+ 425.16.
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[CH2:11]1[O:29][C:28]2[CH:27]=[CH:26][C:15]([CH2:16][C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH:18]=3)=[CH:14][C:13]=2[O:12]1>>[CH2:11]1[O:29][C:28]2[CH:27]=[CH:26][C:15]([CH2:16][C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[S:6]([Cl:10])(=[O:8])=[O:7])=[CH:14][C:13]=2[O:12]1
Reactant: O=S(=O)(Cl)Cl
Reactant: c1ccc2sc(Cc3ccc4c(c3)OCO4)cc2c1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1c(Cc2ccc3c(c2)OCO3)sc2ccccc12

Procedure:
2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonyl chloride was prepared by the method of Example 40B using DMF (9.1 mmoles, 0.70 ml), sulfuryl chloride (7.7 mmoles, 0.62 ml) and 2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene (4.6 mmoles, 1.2 g). Flash chromatography (5% ethyl acetate/hexanes) provided 0.71 g (42%) of a light yellow solid.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([OH:28])=[CH:8][C:9]([N+:25]([O-:27])=[O:26])=[C:10]([C:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=3)[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:37]([O:39][CH3:40])=[O:38]>ClCCl>[CH:1]1([C:6]2[C:7]([O:28][C:37]([O:39][CH3:40])=[O:38])=[CH:8][C:9]([N+:25]([O-:27])=[O:26])=[C:10]([C:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=3)[CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C3CCCC3)c(O)cc2[N+](=O)[O-])CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Oc1cc([N+](=O)[O-])c(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1C1CCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.5 %

Procedure:
Tert-butyl 4-(5-cyclopentyl-4-hydroxy-2-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (596 mg, 1.53 mmol) was dissolved in dichloromethane (5 mL) and triethylamine (388 mg, 535 μL, 3.84 mmol) then treated dropwise with methyl chloroformate (178 μL, 2.301 mmol). The reaction was stirred for 5 min at room temperature and then concentrated in vacuo to tert-butyl 4-(5-cyclopentyl-4-(methoxycarbonyloxy)-2-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (680 mg, 99% yield). The material was used without purification. LC/MS m/z 447.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:29]=O)=[C:26]([CH3:28])[CH:27]=2)=[O:22])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:29]=[C:10]3[C:3]4[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=4[NH:8][C:9]3=[O:11])=[C:26]([CH3:28])[CH:27]=2)=[O:22])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=O
Reactant: O=C1Cc2c(Cl)ncnc2N1
Product: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(Cl)c21
Yield: 25.5 %

Procedure:
4-Chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (80 mg, 0.47 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (124 mg, 0.47 mmol) at room temperature to give 50 mg (26%) of 5-(4-chloro-6-oxo-6,7-dihydro-pyrrolo[2,3-d]pyrimidin-5-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide as a yellow solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]#[C:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=2)[NH:14][N:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(OCC)(=O)C.CCO.[Pd]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([NH2:21])[CH:19]=2)[NH:14][N:13]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCC#Cc1n[nH]c2ncc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCc1n[nH]c2ncc(N)cc12
Reaction time: 8 h
Yield: 57.1 %

Procedure:
10% (wt.) Pd on activated carbon (0.017 g, 0.016 mmol) was added to a solution of 3-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (0.053 g, 0.160 mmol) in a mixture of ethyl acetate/EtOH (1:1, 6 mL). The reaction mixture was purged with nitrogen for 5 minutes and then stirred under a hydrogen balloon overnight. The reaction mixture was filtered through GF/F paper. The filter cake was rinsed with ethyl acetate, and the filtrate was concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (2:1), hexanes/ethyl acetate (1:1) to give 3-(3-(tert-butyldimethylsilyloxy)propyl)-1H-pyrazolo[3,4-b]pyridin-5-amine (0.028 g, 57%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:14]2[CH:19]=[CH:18][C:17]([C:20](=O)[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22]N(C)C)=[CH:16][CH:15]=2)[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:34]1([C:40]2[NH:41][C:42]([NH2:45])=[N:43][N:44]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(O)(=O)C.C(O)C>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:22][N:43]4[N:44]=[C:40]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:41]=[C:42]4[N:45]=3)=[CH:18][CH:19]=2)[CH2:9][C:10]([OH:13])([CH3:12])[CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CC(C)(O)C2)cc1)c1ccccc1
Reactant: Nc1nnc(-c2ccccc2)[nH]1
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(O)CC(NC(=O)OC(C)(C)C)(c2ccc(-c3nc4nc(-c5ccccc5)nn4cc3-c3ccccc3)cc2)C1

Procedure:
A mixture of 2 (270 mg, 0.6 mmol) and 5-Phenyl-4H-[1,2,4]triazol-3-ylamine (96 mg, 0.6 mmol) in acetic acid (1 mL) and ethanol (4 mL) was heated under reflux for 6 hours.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].C(=O)([O-])[O-].[K+].[K+].O>C1C=CC=CC=1>[CH3:8][C:2]1[CH:1]=[C:6]([CH:5]=[CH:4][CH:3]=1)[O:7][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1cccc(OCC(=O)c2ccccc2)c1

Procedure:
Using an alternative condensation, equimolar amounts of m-cresol and alpha-bromoacetophenone are refluxed in benzene in the presence of potassium carbonate with azeotropic removal of water to provide alpha-(3-methylphenoxy)acetophenone.