Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].Cl.[S:15]([O:20][CH3:21])([O:18][CH3:19])(=[O:17])=[O:16].[OH-].[Na+].[C:24]1(C)C(C)=CC=CC=1>>[S:15]([O:20][CH3:21])([O:18][CH3:19])(=[O:17])=[O:16].[CH3:24][O:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([O:20][CH3:21])=[O:6]
Reactant: O=C(O)c1cc(F)c(F)c(O)c1F
Reactant: Cc1ccccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc(F)c(F)c(OC)c1F

Procedure:
The reaction proceeds according to the following reaction scheme: ##STR5##299 g of an aqueous solution which contains 15.6 g (81 mmol) of 3-hydroxy-2,4,5-trifluorobenzoic acid (B) are initially introduced into a glass flask with stirring and are treated with 10 g of xylene instead of the water-insoluble trialkylamine or amine mixture. A 30% strength by weight aqueous hydrochloric acid is added up to a pH of 7 and the pH is checked by means of a calibrated pH electrode which dips into the aqueous phase. A total of 156.8 g (1.41 mol) of dimethyl sulfate are then added dropwise at a temperature of 40° C. over a period of 3.5 hours and the pH is kept constant at 7 by addition of a total of 46.6 g of a 10% strength by weight aqueous sodium hydroxide solution. Despite a considerable excess of dimethyl sulfate, the dimethylated product, namely methyl 3-methoxy-2,4,5-trifluorobenzoate, is only formed in small amounts.3-Hydroxy-2,4,5-trifluorobenzoic acid (B) corresponding to a yield of 8.6%,methyl 3-hydroxy-2,4,5-trifluorobenzoate corresponding to a yield of 67% and methyl 3-methoxy-2,4,5-trifluorobenzoate (C) corresponding to a yield of only 8.7% are found, in each case based on 3-hydroxy-2,4,5-trifluorobenzoic acid employed.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][C:8]([C:10]2[C:11]3[CH:23]=[CH:22][Se:21][C:12]=3[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1)=O.C(OCC)(=O)C.CCCCCC>O>[OH:2][CH2:3][C:5]1[O:9][C:8]([C:10]2[C:11]3[CH:23]=[CH:22][Se:21][C:12]=3[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(-c2nn(-c3ccccc3)c3[se]ccc23)o1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: OCc1ccc(-c2nn(-c3ccccc3)c3[se]ccc23)o1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
1.98 g (0.018 mole) of granular anhydrous calcium chloride, 1.377 g (0.036 mole) of sodium brorhydride and 100 ml of anhydrous THF were reacted at room temperature for 4 h to form a white dispersion of calcium borohydride (Ca(BH4)2). To the dispersion compound 78 (0.744 g, 0.002 mole) was added and was reduced by heating under refluxing for 24 h. The progress of the reduction reaction was monitored by TLC with ethyl acetate (EA):n-hexane=3:2. When the reaction was completed, the reaction mixture was cooled to room temperature, and THF was evaporated under a reduced pressure. The remaining reaction mixture was poured into water to stop the reaction, and then was extracted with chloroform. The organic layer was recovered, dried over MgSO4 and filtered. The solvent of the filtrate was evaporated under a reduced pressure, and the residue was subjected to a column chromatography with EA:n-hexane=3:2, and then recrystallized from EA to afford compound 80 in white crystals (0.612 g). Yield: 88.9%;
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][S:6][C@H:5]2[CH2:9][CH2:10][CH2:11][CH2:12][N:4]2[C:3]1=[O:13].F[C:15](F)(F)C(O)=O.N[C@H](C)CCCCO>>[NH2:1][C@H:2]1[CH2:8][CH2:7][S:6][C@H:5]2[CH2:9][CH2:10][CH2:11][C@@H:12]([CH3:15])[N:4]2[C:3]1=[O:13]
Reactant: O=C(O)C(F)(F)F
Reactant: N[C@H]1CCS[C@H]2CCCCN2C1=O
Agent: C[C@@H](N)CCCCO
Product: C[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12

Procedure:
(4S,7R,10aS)-4-Amino-7-methylhexahydro-2H-pyrido[2,1-b][1,3]thiazepin-5(7H)-one (135 mg, 0.599 mmol) was synthesized as described for the preparation of Intermediate 40 using (R)-5-aminohexan-1-ol trifluoroacetate in step A. Anal. Calcd. for C10H18N2O5 m/z 214.3. found: 215.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 5.40-5.28 (m, 1H), 4.70-4.55 (m, 1H), 4.00 (ddd, J=14.7, 9.6, 5.2 Hz, 1H), 2.98-2.83 (m, 1H), 2.71-2.56 (m, 1H), 2.29-2.13 (m, 1H), 2.03-1.45 (m, 7H), 1.57-1.45 (m, 1H), 1.39-1.31 (m, 1H), 1.31 (d, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][CH:19]=1>>[C:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:16])[N:2]([NH:1][C:25](=[O:26])[CH2:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)[N:11]=1)([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1nn(N)c(=O)c2ccccc12
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: CC(C)(C)c1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product from Example 62A and 2-(4-chlorophenyl)acetyl chloride were treated using a method similar to that described in Example 1C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.54 (s, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.37 (dd, J=7.7, 1.6 Hz, 1H), 7.94-8.00 (m, 1H), 7.84-7.90 (m, 1H), 7.41 (s, 4H), 3.68 (s, 2H), 1.47 (s, 9H); MS (ESI+) M/Z 370 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17]>>[C:1]1([S:7]([N:10]2[C:16](=[O:17])[C:15]3[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:13][C:11]2=[O:12])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C=NS(=O)(=O)c1ccccc1
Product: O=c1[nH]c2ccccc2c(=O)n1S(=O)(=O)c1ccccc1
Yield: 72.4 %

Procedure:
3.00 g (16.4 mmol) of benzenesulfonylisocyanate and 2.04 g (14.9 mmol) of 2-aminobenzoic acid were treated in the same way as in Example 1 to obtain 3.26 g of the above-identified compound (yield 72.4%). Properties: colorless crystal, Melting point: 211°-213° C., PMR (δppm, DMSO-d6): 7.13 (1H,d), 7.20 (1H,t), 7.61-7.70 (3 H,m), 7.78 (1H,t), 7.87 (1H,d), 8.17 (2H,d), 11.51 (1H,br).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].C(Cl)(=O)C(Cl)=O.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.CN(C=O)C>[CH2:14]([O:6][C:1](=[O:7])[CH2:2][CH2:3][C:4]#[CH:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C#CCCC(=O)O
Reactant: OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C#CCCC(=O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 134.9 %

Procedure:
To a solution in dichloromethane (25 mL) containing a few drops DMF of 4-pentynoic acid (2.49 g, 23.4 mmol) was added oxalyl chloride (2.2 mL, 25 mmol). The reaction mixture was stirred for 1.5 hours and benzyl alcohol (3.9 mL, 38 mmol) was added via syringe. The reaction mixture was stirred for 6 hours and then was extracted with saturated aqueous sodium carbonate. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give 4-pentynoic acid benzyl ester (5.94 g) as a yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29]S(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:34]1(O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Br)cc2)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2ccccc2)NS(=O)(=O)c2ccc(Br)cc2)cc1
Yield: 85.3 %

Procedure:
The procedure described in Example 125 was repeated, except that ((RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (500 mg) was reacted with phenol (167 mg) to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenoxypropanamide (425.22 mg).
Reaction SMILES: [C:1]([C:4]1[CH:42]=[CH:41][C:7]([O:8][C:9]([C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[C:10]([N:24]2[C@H:27](SCC)[C@@H:26]([C@H:31]([OH:33])[CH3:32])[C:25]2=[O:34])[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[S:12])=[CH:6][CH:5]=1)([OH:3])=[O:2].[Cl:43]Cl>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[C:1]([C:4]1[CH:42]=[CH:41][C:7]([O:8][C:9]([C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[C:10]([N:24]2[C@@H:27]([Cl:43])[C@@H:26]([C@H:31]([OH:33])[CH3:32])[C:25]2=[O:34])[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[S:12])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: ClCl
Reactant: CCS[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(C(=O)O)cc1)C(=O)C(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C[C@@H](O)[C@H]1C(=O)N(C(C(=S)OCc2ccc([N+](=O)[O-])cc2)=C(Oc2ccc(C(=O)O)cc2)C(=O)C(C)(C)C)[C@H]1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a stirred solution of 10 g of 4-nitrobenzyl 3-(4-carboxyphenoxy)-2-(4(R)-ethylthio-3(S)- [1(R)-hydroxyethyl]azetidin-2-on-1-yl)-3-trimethylacetylthiopropenoate in 60 ml of chloroform at -60° C. was added a solution of 192 mmoles of chlorine in 17.8 ml of carbon tetrachloride. After 30 minutes, the reaction mixture was left to warm to room temperature, and the solvent was then removed in vacuo. Chromatography over silica gel using hexane-ethyl acetate-formic acid mixtures afforded 7.3 g of the title compound as a pale yellow foam.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:7]=[C:8]([N:20]2[CH2:24][C@H:23]([CH2:25]OS(C)(=O)=O)[O:22][C:21]2=[O:31])[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[CH2:13]1>CN(C=O)C.C(OCC)(=O)C>[N:1]([CH2:25][C@@H:23]1[O:22][C:21](=[O:31])[N:20]([C:8]2[CH:9]=[CH:10][C:11]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[CH2:13]3)=[C:6]([F:5])[CH:7]=2)[CH2:24]1)=[N+:2]=[N-:3]
Reactant: CN1CCN(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1=O
Temperature: 75 °C

Procedure:
Sodium azide (924 mg) was added to a solution of (5R)-3-(3-fluoro-4-{4-methyl-3-oxopiperazin-1-yl}phenyl)-5-(methanesulfonyloxymethyl)oxazolidin-2-one (950 mg) in dry DMF (50 ml), and the mixture heated at 75° C. for 2 hours. The mixture was diluted with ethyl acetate and washed with three portions of water. The aqueous layer was then back-extracted with two portions of ethyl acetate, and the combined organic extracts dried over MgSO4. Evaporation gave (5R)-5-azidomethyl-3-(3-fluoro-4-{4-methyl-3-oxopiperazin-1-yl}phenyl)oxazolidin-2-one product which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([NH2:14])[CH3:13]>C(O)C>[CH2:12]([NH:14][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:13]
Reactant: CCN
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CCO
Product: CCNCc1ccc([N+](=O)[O-])cc1

Procedure:
6.0 g of 4-nitrobenzyl bromide are dissolved in 25 ml of ethanol, combined with 25 ml of 10% ethanolic ethylamine solution and refluxed for 2 hours. Then the solution is concentrated by rotary evaporation, the residue is taken up with methylene chloride and washed with dilute sodium hydroxide solution. Finally the organic phase is evaporated down.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:18]([OH:21])([CH3:20])[CH3:19])[CH2:4][CH2:3]1.[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH:23]1[CH:31]=O>>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C@H:5]3[CH2:4][CH2:3][C@@H:2]([NH:1][CH2:31][CH:23]4[CH2:22][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24]4)[CH2:7][CH2:6]3)[C:9]([C:18]([OH:21])([CH3:19])[CH3:20])=[N:10][C:11]=2[CH:16]=1
Reactant: O=CC1Cc2ccccc2C1
Reactant: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](N)CC1
Product: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](NCC2Cc3ccccc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of cis-2-[1-(4-amino-cyclohexyl)-5-chloro-1H-benzoimidazol-2-yl]-propan-2-ol and indan-2-carbaldehyde. 1H-NMR is consistent with the assigned structure, LC-MS showed a single peak, C26H32ClN3O (m/e) calcd 437.2234, obsd 438.2 (M+H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2].[N+:16]([C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([O:14][C:22]2[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2[C@H](O)C[C@@H]1C
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: CC(=O)N1c2ccccc2[C@H](Oc2ccc([N+](=O)[O-])cc2)C[C@@H]1C
Yield: 72.4 %

Procedure:
[Step 1] Reactions and treatments were carried out in the same manner as in Step 2 of Example 117, using 102.6 g of (2S,4R)-1-acetyl-4-hydroxyl-2-methyl-1,2,3,4-tetrahydroquinoline instead of ethyl (2S,4R)-1-acetyl-4-hydroxyl-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate, and using 4-nitrophenol instead of benzoic acid. Thus, 118.2 mg (72.4%) of (2S,4R)-1-acetyl-2-methyl-4-(4-nitrophenoxy)-1,2,3,4-tetrahydroquinoline was obtained as a pale yellow amorphous substance.
Reaction SMILES: [C:1]1([S:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O-:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].[C:30]1([I+]C2C=CC=CC=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCOCC>O>[O-:25][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:24])=[O:22].[C:1]1([S+:11]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc([I+]c2ccccc2)cc1
Reactant: c1ccc2c(Sc3cccc4ccccc34)cccc2c1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O
Solvent: CCOCC
Product: c1ccc([S+](c2cccc3ccccc23)c2cccc3ccccc23)cc1
Reaction time: 24 h
Yield: 90 %

Procedure:
Di(1-naphthyl)sulfide (3 g, 0.0104 mole), diphenyliodonium triflate (5.8 g, 0.0135 mole) and copperbenzoate (0.08 g, 0.003 mole) are heated without solvent for 3 hours at 120-145° C. under a nitrogen atmosphere. After cooling down, 75 ml ether was added and the mixture vigorously stirred overnight to achive solidification. Filtration and washing with ether yielded a brown solid, which was dissolved in hot water, the solution filtered and the water removed in vacuo. The resulting white solid was stirred in 50 ml ethyl ether for 24 hours, the mixture filtered and the residue washed with ethyl ether, yielding 4.8 g (90%) of the title compound, di-(1-naphtyl)phenylsulfonium triflate. The structure was confirmed by 1H/13C NMR spectroscopy.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH3:21])[C:16]([O:18]CC)=O)[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[CH2:22]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:29]([N:28]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:16](=[O:18])[CH:15]([C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([OH:4])[CH:6]=1)[CH3:21])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCOC(=O)C(C)c1ccc(OC(C)=O)c(OC(C)=O)c1
Reactant: CCCCCCNCCCCCC
Product: CCCCCCN(CCCCCC)C(=O)C(C)c1ccc(O)c(O)c1

Procedure:
Ethyl 3,4-diacetoxyphenylpropionate and di-n-hexylamine were used to obtain N,N-Di-n-hexyl-3,4-dihydroxyphenylpropionamide by carrying out the same procedures as described in Example 1, as an oily product.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.Cl[C:27]1[N:32]=[CH:31][C:30]2[C:33]([C:55]3[CH:60]=[CH:59][N:58]=[C:57]([CH3:61])[CH:56]=3)=[N:34][N:35]([C:36]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:29]=2[CH:28]=1.[Li+].C[Si]([N-:67][Si](C)(C)C)(C)C.CO>C1COCC1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CCOC(C)=O>[CH3:61][C:57]1[CH:56]=[C:55]([C:33]2[C:30]3[CH:31]=[N:32][C:27]([NH2:67])=[CH:28][C:29]=3[N:35]([C:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[N:34]=2)[CH:60]=[CH:59][N:58]=1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(Cl)ncc23)ccn1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(N)ncc23)ccn1
Temperature: 65 °C
Yield: 99.8 %

Procedure:
Pd2(dba)3 (0.192 g, 0.209 mmol), biphenyl-2-yl(dicyclohexyl)phosphane (0.073 g, 0.209 mmol), and 6-chloro-3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.02 g, 2.094 mmol) were placed in a microwave vial under nitrogen and dissolved in THF (11 mL) The reaction mixture was degassed for 5 min, LiHMDS (2.51 mL, 2.51 mmol, 1M in THF) was added via syringe and then heated to 65° C. overnight. The mixture was cooled to RT and Pd2(dba)3 (0.096 g, 0.1 mmol), biphenyl-2-yl(dicyclohexyl)phosphane (0.036 g, 0.1 mmol) and LiHMDS (1.25 mL, 1.25 mmol, 1M in THF) were added again. The mixture was degassed for 5 min and heated to 80° C. for 3 h, cooled to RT and quenched with 1N HCl. The mixture was then concentrated and partitioned between DCM and 1N NaOH. The organic layer was extracted with DCM (3×) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel over a gradient of 0-100% EtOAc in hexanes and then over a gradient of 0-30% (1:2=MeOH:EtOAc) in DCM to yield 3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine (549 mg, 2.09 mmol, 56%) as a solid. MS ESI calc'd. for C31H26N5 [M+1]+468, found 468.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14]CC=C)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([Cl:10])=[CH:9][N:4]2[N:3]=1.C1([SiH3])C=CC=CC=1>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([Cl:10])=[CH:9][N:4]2[N:3]=1
Reactant: C=CCOC(=O)c1c(N)nn2cc(Cl)cnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Product: Nc1nn2cc(Cl)cnc2c1C(=O)O
Temperature: 25 °C
Reaction time: 7 h
Yield: 5131.4 %

Procedure:
To a suspension of allyl 2-amino-6-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 4b (1 g, 3.96 mmol) in DCM (15 mL) was added phenylsilane (856.6 mg, 0.9756 mL, 7.916 mmol), followed by Pd(PPh3)4 (182.9 mg, 0.1583 mmol). The reaction was stirred at room temperature for 7 h. The reaction mixture was filtered and the solid was washed with DCM to give a light yellow solid (43.2 g). This solid was triturated further in DCM (225 mL) at RT for 45 min, then filtered and dried overnight under vacuum to provide 2-amino-6-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 5b as a yellow solid (791 m, 94% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]#[N:14])[CH2:9][CH2:8]1.[OH:15][NH:16][C:17](=N)[CH:18]([CH3:20])[CH3:19].CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH:18]([C:17]1[N:14]=[C:13]([N:10]2[CH2:9][CH2:8][CH:7]([C@H:5]3[CH2:6][C@H:4]3[CH2:3][CH2:2][OH:1])[CH2:12][CH2:11]2)[O:15][N:16]=1)([CH3:20])[CH3:19]
Reactant: CC(C)C(=N)NO
Reactant: N#CN1CCC([C@H]2C[C@H]2CCO)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCO)CC2)n1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
In a 500 ml RBF was added a solution of 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carbonitrile (15.3 g, 85 mmol) in 1:1 THF:EtOAc (150 ml). To this solution was added N-hydroxy-2-methylpropanimidamide (9.93 g, 97 mmol) as a solid and the resulting mixture was stirred to yield a clear solution. An addition funnel was added to the flask and the whole set up was set under nitrogen atmosphere. The solution was placed in an oil bath heated to 70° C. A 0.5M solution of zinc chloride (204 ml, 102 mmol) in THF was placed in the addition funnel and added over a 5 minute period to the reaction mixture. Upon complete addition, the resulting mixture was stirred at 70° C. for 2 hours. After 30 minutes the clear solution became cloudy. After 1 hour at 70° C., a thick white precipitate formed. TLC indicates consumption of the all starting material. The mixture was cooled to RT and the white solid was filtered off and washed with 1:1 THF:EtOAc (200 mL) and dried. The white solid in the fitted funnel was dissolved in 100 mL of DMF and drawn through by vacuum into a 250 ml RBF. To this solution was then added Tosic Acid (8.07 g, 42.4 mmol) and the resulting mixture stirred at 80° C. overnight. (LCMS after 2.5 hrs showed the reaction was ˜30-40% complete with no other by-products forming.) The mixture was allow to cool to room temperature and then was diluted with 150 mL of ethyl acetate. The mixture was placed in a separatory funnel and washed with sat'd sodium bicarbonate solution (150 mL). The aqueous was extracted once with ethyl acetate (100 mL) and the organics were combined. The organics were washed with 1M Na2CO3 (50 mL), followed by water (2×100 mL), and then brine (100 mL). The organics were dried over sodium sulfate, filtered, and the filtrate concentrated to dryness under reduced pressure. The residue was taken up in 50 mL DCM and loaded onto a Flash 75 system (silica gel column). Biotage Flash 75 purification was done eluting with 20-70% ethyl acetate/hexane for 4 column volumes followed by 70% ethyl acetate for 4 column volumes (total solvent 16 L). The fractions containing the product were collected and concentrated under reduced pressure to afford the pure product. LC/MS (m/z): 280 (M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15].[NH2:27][C@H:28]([C:39]([NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:40])[CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1>C1COCC1>[NH:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:14]([C:17]([NH:27][C@H:28]([C:39]([NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:40])[CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=[O:19])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.3 %

Procedure:
2.78 g (14.5 mmol) of EDCl was added to 40 ml of THF solution of 1.47 g (7.25 mmol) of Boc-Aib-OH (manufactured by Sigma-Aldrich Corporation), and 2.03 g (7.25 mmol) of H-Trp-NHPh obtained in Synthesis Example 4-2, followed by stirring for 16 hours at room temperature. After a reaction mixture was concentrated under reduced pressure, the concentrate was extracted by adding water and ethyl acetate. After an organic layer was washed sequentially with a diluted hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water (one time for each), it was concentrated under reduced pressure, thereby obtaining crude amide. The obtained amide compound was purified by a silica gel column chromatography (hexane/ethyl acetate=3/1 to 0/1 (volume ratio)), thereby obtaining 2.20 g of the product with a yield of 65.3%.