Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[N+:18]([O-])([OH:20])=[O:19]>C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>[N+:18]([C:17]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[NH:7][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: CCCCC(=O)Nc1cccc(C(=O)OC)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CCCCC(=O)Nc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 36 %

Procedure:
To a solution of methyl 3-valerylaminobenzoate (2.3 g) in acetic anhydride (12 ml) was added dropwise fuming nitric acid (1.4 ml) while stirring under ice-cooling. To the mixture was added one drop of conc. sulfuric acid and the mixture was stirred for two hours. To the reaction mixture was added ice-water and it was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium bicarbonate and water and then dried. The solvent was evaporated to dryness, and the residue was purified by column chromatography on silica gel to afford a brown oil (1.0 g, 36%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C@@H:13]1[CH2:18][NH:17][CH2:16][C@H:15]([CH3:19])[NH:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:17]2[CH2:16][C@H:15]([CH3:19])[NH:14][C@H:13]([CH3:12])[CH2:18]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@@H]1CN(Cc2ccc([N+](=O)[O-])cc2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
A mixture of 4-nitrobenzaldehyde (6.612 g, 43.8 mmol) and (2R,6S)-2,6-dimethylpiperazine (5 g, 43.8 mmol) in 1,2-DCE (100 mL) was stirred at room temperature for 2 h. Sodium tri(acetoxy)borohydride (13.92 g, 65.7 mmol) was added and the reaction was stirred at room temperature over-weekend. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3 solution. The aqueous wash was extracted with 10% MeOH/DCM and the combined organics were dried and concentrated. Column chromatography eluting with 0-10% MeOH/DCM gave the title compound as a cream solid (4.278 g). δH (CDCl3, 400 MHz) 8.18 (2H, d), 7.51 (2H, d), 3.57 (2H, s), 2.97 (2H, m), 2.72 (2H, m), 1.72 (2H, m), 1.06 (6H, d). MS (ES+): MH+ 250.2.
Reaction SMILES: [C:1]([C:4]1[C:8]([O:9][C:10]([F:15])([F:14])[CH:11]([Cl:13])[F:12])=[CH:7][N:6]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[Cl:27])[N:5]=1)(=O)[NH2:2].P(Cl)(Cl)(Cl)=O.O>ClCCl>[Cl:13][CH:11]([F:12])[C:10]([F:15])([F:14])[O:9][C:8]1[C:4]([C:1]#[N:2])=[N:5][N:6]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:24])[F:25])=[CH:18][C:17]=2[Cl:27])[CH:7]=1
Reactant: NC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1OC(F)(F)C(F)Cl
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1OC(F)(F)C(F)Cl
Temperature: 80 °C
Yield: 55.5 %

Procedure:
A mixture of (RS)-3-carbamoyl-4-(2-chloro-1,1,2-trifluoroethoxy)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.75g) and phosphorus oxychloride (15ml) was heated at 80° C. for 6 hours. Water (100ml) and dichloromethane (50ml) were added to the cooled mixture and the layers were separated. The aqueous layer was extracted with dichloromethane (2x50ml) and the combined organic layers were washed with aqueous sodium hydrogen carbonate solution (1M; 30ml), dried over magnesium sulfate, and evaporated to give (RS)-4-(2-chloro-1,1,2-trifluoroethoxy)-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyanopyrazole (0.4g) as an off-white crystalline solid, m.p. 99°-101° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH2:35][CH3:36])[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH2:35][CH3:36])[C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[CH:23][CH:22]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: CCCN(c1ccc(I)cc1)c1ncccn1
Product: CCCN(c1ccc(/C=C/CC(NC(=O)c2c(Cl)cccc2Cl)C(=O)OC)cc1)c1ncccn1
Yield: 71.9 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (171 mg) was reacted with N-(4-iodophenyl)-N-propylpyrimidin-2-amine (192 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(propyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (209 mg). Column chromatography (silica gel, eluent: cyclohexane/chloroform=4/1-3/1) was used for purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([C:15](=[O:22])[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:10]=[CH:11][C:12]=1[O:13]C)[CH3:2].Cl.N1C=CC=[CH:27][CH:26]=1>O>[CH2:26]([O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:15](=[O:22])[C:9]1[CH:10]=[CH:11][C:12]([OH:13])=[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:23])[CH:8]=1)[CH3:27]
Reactant: c1ccncc1
Reactant: CCOC(=O)CCc1cc(C(=O)CCCC(=O)O)ccc1OC
Agent: Cl
Solvent: O
Product: CCOC(=O)CCCC(=O)c1ccc(O)c(CCC(=O)OCC)c1
Temperature: 240 °C
Yield: 77.3 %

Procedure:
A mixture of 1.61 g (5.0 mmol) of 3-(3-ethoxy-3-oxopropyl)-4-methoxy-δ-oxobenzenepentanoic acid and 11.56 g (0.1 mol) of pyridine hydrochloride was heated at ca. 240° C. for 1.33 hr. After being cooled to room temperature, the reaction mixture was treated with 100 mL of water and extracted twice with ether and once with ethyl acetate. The organic extracts were processed in the usual manner to give 1.30 g of a tan solid which was dissolved in 120 mL of ethanol. To this solution was slowly added 30 drops of thionyl chloride. The resulting solution was heated at reflux for 7 hr and then kept at room temperature for ca. 65 hr. The solvent was removed in vacuo and the residue was purified by flash chromatography on 100 g of silica gel, eluting with 3:1 hexane-ethyl acetate, to give 1.44 g (85.6%) of the title compound as a light-tan solid, mp 68°-69° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[N:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)=[C:26]=[O:27]>N1C=CC=CC=1>[F:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[NH:25][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:30][CH:29]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
To a solution of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.290 mmol) produced in Example 16(vi) in pyridine (3 mL) was added 1-isocyanato-4-(trifluoromethyl)benzene (50 μL, 0.348 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=5/95→10/90). The obtained solution was concentrated under reduced pressure to give the title compound (58 mg, 37%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([CH3:28])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[CH:27]=[C:26]([CH3:28])[S:25][C:15]=2[N:16]=1
Reactant: Cc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3-nitrobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([NH:11][CH2:12][C:13](=[O:33])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC1C=CC=CC=1)=[O:24])=[O:17])(OCC1C=CC=CC=1)=O.[ClH:34]>[Pd].CC(O)C>[ClH:34].[NH2:11][CH2:12][C:13](=[O:33])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:17]
Reactant: O=C(CCC(=O)OCCCCC(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: NCC(=O)CCC(=O)OCCCCC(=O)O
Yield: 92.2 %

Procedure:
A stirred mixture of the product from 8c (0.70 g; 1.54 mmol), 12 M HCl (0.13 mL; 1.54 mmol), 10% Pd/C (Degussa type E101 NE/W) (100 mg), and 2-propanol (25 mL) was hydrogenated at ambient temperature and 4 bars pressure overnight. The mixture was filtered through a Celite® 545 pad; the filtrate was evaporated and the residue was triturated with dry diethyl ether (3×5 mL). After drying of the residue at ambient temperature and 0.01 mm Hg, 0.38 g (97%) product was obtained (white solid).
Reaction SMILES: [CH2:1]([Zn]CC)C.C([Si]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:22])=[CH2:21])=[CH:16][CH:15]=1)(C)C)(C)(C)C.ICI.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>ClC(Cl)C>[CH3:1][C:20]1([C:17]2[CH:16]=[CH:15][C:14]([OH:13])=[CH:19][CH:18]=2)[CH2:21][CH2:22]1
Reactant: C=C(C)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reactant: CC[Zn]CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(Cl)Cl
Solvent: ICI
Product: CC1(c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
Diethylzinc (1.0 M in hexanes, 69 mL, 69 mmol) was added to a solution of tert-butyl-(4-isopropenyl-phenoxy)-dimethyl-silane (6.85 g, 27.6 mmol) in dichloroethane at 0° C. Diiodomethane (11.2 mL, 138 mmol) was then added dropwise to the solution and the resultant mixture was stirred at 0° C. for 0.5 h and allowed to warm to rt for 2 h. The opaque mixture was quenched with saturated aqueous NH4Cl. The aqueous phase was extracted with CH2Cl2 and the combined organic layers were washed with saturated aqueous NaHCO3. The organic layers were dried over sodium sulfate, filtered through celite, and concentrated. The crude TBS ether was dissolved in THF (50 mL) and TBAF (1.0 M in THF, 28 mL, 28 mmol) was added at rt. The solution was stirred for 2 h and then quenched with aqueous 1.0 M HCl. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with saturated NaHCO3. The organic layers were dried over sodium sulfate, filtered and concentrated. Purification by silica-gel chromatography (1% 2-propanol/12% ethyl acetate in hexanes) provided 4-(1-methyl-cyclopropyl)-phenol (2.77 g, 68%) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[N:9]1[C:14]2[NH:15][C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18](=[O:20])[NH:19][C:13]=2[CH:12]=[CH:11][CH:10]=1>C1(C)C(C)=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:15]1[C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18](=[O:20])[NH:19][C:13]2[CH:12]=[CH:11][CH:10]=[N:9][C:14]1=2)=[O:7]
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: O=C(Cl)CCCCCl
Solvent: Cc1ccccc1C
Product: O=C1Nc2cccnc2N(C(=O)CCCCCl)c2ccccc21

Procedure:
A solution of 5-chlorovaleryl chloride and 5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one in xylene was reacted to obtain 11-(5-chlorovaleryl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one which after crystallization from n-propanol melted at 170°-172° C.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.Cl.C([O:26][C:27](=[O:30])[CH2:28][NH2:29])C.C(N(CC)CC)C.[OH-].[K+]>C(O)C.O>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([NH:29][CH2:28][C:27]([OH:30])=[O:26])=[O:6]
Reactant: CCOC(=O)CN
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)NCC(=O)O
Yield: 85 %

Procedure:
The reaction of 6.1 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid with glycine ethyl ester hydrochloride was conducted in the same manner as described in Example 1 except that 6.5 ml of triethylamine was used. Then, a solution of 2.7 g of potassium hydroxide in ethanol was added. The mixture was heated under reflux for 30 minutes. After the completion of the reaction, water was added and the obtained aqueous solution was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate. The solvent was distilled off to afford 6.1 g (yield 85%) of the title compound as a pale brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([OH:14])[CH:5]=[CH:4][C:3]1=2.[F:16][C:17]([F:27])([F:26])[C:18](=O)[CH2:19][C:20](OCC)=[O:21].OS(O)(=O)=O>>[CH3:1][C:2]1([CH3:15])[C:3]2[CH:4]=[C:5]3[C:6](=[CH:7][C:8]=2[C:9]([CH3:13])([CH3:12])[CH2:10][CH2:11]1)[O:14][C:20](=[O:21])[CH:19]=[C:18]3[C:17]([F:27])([F:26])[F:16]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Agent: O=S(=O)(O)O
Product: CC1(C)CCC(C)(C)c2cc3c(C(F)(F)F)cc(=O)oc3cc21
Temperature: 100 °C
Yield: 38.2 %

Procedure:
A mixture of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Intermediate 2, 4.12 g, 20.2 mmol), ethyl trifluoroacetoacetate (7.4 mL, 50.4 mmol), and H2SO4 (8 mL, 75%) was heated at 100° C. for 4 h. The mixture was poured onto ice, quenched with NaHCO3 and extracted with Et2O. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was dissolved in Et2O, a readily crystalline side product precipitated and was removed by filtration. The filtrate was concentrated to give a residue. Recrystallization of the residue gave the title compound as white crystals (2.5 g, 38%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[CH3:12].[CH:13]([Mg]Br)=[CH2:14].O>C1COCC1>[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([F:11])=[C:6]2[C:7]=1[CH:13]=[CH:14][NH:8]2
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1Br
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(F)c2[nH]ccc2c1Br
Temperature: -78 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
To a solution of 1-bromo-4-fluoro-2-methyl-5-nitro-benzene (20 g, 0.086 mol) in THF (250 mL) at −78° C. was added vinylmagnesium bromide (300 ml, 0.3 mol) dropwise, then the mixture was stirred at −78° C. for 2 h. Water was added and the reaction allowed to warm slowly to rt. The mixture was extracted with EtOAc, dried over Na2SO4, and concentrated. The crude product was purified by silica gel column chromatography to afford 4-bromo-7-fluoro-5-methylindole (3.2 g, 16.4%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].[Br:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:21]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:18]2[CH:19]=[C:20]([O:22][CH2:23][CH:24]([CH3:25])[CH3:26])[CH:21]=[C:16]([Br:15])[CH:17]=2)=[CH:8][C:7]=1[CH3:13]
Reactant: COC(=O)COc1ccc(O)cc1C
Reactant: CC(C)COc1cc(Br)cc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(Oc2cc(Br)cc(OCC(C)C)c2)cc1C

Procedure:
(4-Hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (215 mg; 1.1 mmol), 3-Bromo-5-isobutoxy-phenylboronic acid (523.4; 1.9 mmol), copper(II) acetate (199 mg; 1.1 mmol), crushed molsieves (about 1 g) and triethylamine (0.46 ml; 3.3 mmol) was dissolved in dichloromethane (40 ml) and stirred over night. The reaction mixture was filtered through celite and evaporated to dryness. The crude product was purified by preparative HPLC (method B). Yield: 300 mg; 65%. HPLC-MS: m/z: 423.5 (M+); Rt: 2.71 min
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[CH:12]([CH:13]=[CH2:14])[O:11]C(=O)[NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>O1CCOCC1.O>[OH:11][C@H:12]([C@@H:8]([NH2:9])[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:13]=[CH2:14]
Reactant: C=CC1OC(=O)N[C@H]1CC1CCCCC1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=C[C@H](O)[C@@H](N)CC1CCCCC1

Procedure:
To the resultant 5S-diastereomer from Example 4 (2.06 g, 9.84 mmol) in dioxane (180 ml) and water (120 ml) was added barium hydroxide octahydrate (6.24 g, 19.8 mmol). The mixture was refluxed for 18 h, cooled, filtered, concentrated, taken up in water and extracted with ethyl acetate which was dried over Na2SO4 and evaporated to afford 1.64 9 (91%) of the desired product, m.p.: 59°-61° C.
Reaction SMILES: [Mg].[CH3:2]I.[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([Cl:14])[C:12]=1[Cl:13])[CH:8]=[O:9].[Cl-].[NH4+].Cl>CCOCC>[Cl:4][C:5]1[CH:6]=[C:7]([CH:8]([OH:9])[CH3:2])[CH:10]=[C:11]([Cl:14])[C:12]=1[Cl:13]
Reactant: CI
Reactant: O=Cc1cc(Cl)c(Cl)c(Cl)c1
Agent: Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: CC(O)c1cc(Cl)c(Cl)c(Cl)c1
Reaction time: 8 h

Procedure:
To a suspension of magnesium turnings (0.55 g.) in dry ether (20 ml.) was added dropwise a solution of methyl iodide (3 g.) in dry ether (10 ml.) at such a rate that the reaction refluxed. After the addition was complete, 3,4,5-trichlorobenzaldehyde (see Process B) (4 g.) was added in dry ether (10 ml.) at a rate that maintained reflux. The reaction was stirred overnight. Saturated ammonium chloride solution was added, followed by dilute hydrochloric acid. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated to give 1-(3,4,5-trichlorophenyl)ethanol. Nuclear Magnetic Resonance Spectrum (NMR) was as follows; 1.2, 3H, d; 4.2, 1H, s; 4.8, 1H, m; 7.3, 2H, s.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:18][N:19]([CH2:21][CH2:22][CH2:23]Cl)[CH3:20]>>[CH3:18][N:19]([CH3:20])[CH:21]([C:14]1[C:13]([CH3:16])=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[N:8][NH:9]2)[CH2:22][CH3:23]
Reactant: Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Reactant: CN(C)CCCCl
Agent: Cl
Product: CCC(c1c(C)ccc2[nH]nc(-c3ccccc3)c12)N(C)C
Yield: 59.6 %

Procedure:
By the procedure similar to that described in Example 1, 3-phenyl-5-methylindazole (4.17 g) and dimethylaminopropyl chloride hydrochloride (4.74 g) were treated to obtain an oily product. The product was purified through distillation under reduced pressure to obtain 3.5 g of 1-dimethylaminopropyl-3-phenyl-5-methylindazole (b.p. 185°C/0.5 mmHg).
Reaction SMILES: COC1C(OC)=NS(=O)(=O)N=1.CN.CO[C:16]1[C:20]([NH:21][CH3:22])=[N:19][S:18](=[O:24])(=[O:23])[N:17]=1.[NH:25]([C:29]1[S:30][CH:31]=[C:32]([CH2:34][S:35][CH2:36][CH2:37][NH2:38])[N:33]=1)[C:26]([NH2:28])=[NH:27]>>[NH:25]([C:29]1[S:30][CH:31]=[C:32]([CH2:34][S:35][CH2:36][CH2:37][NH:38][C:16]2[C:20]([NH:21][CH3:22])=[N:19][S:18](=[O:24])(=[O:23])[N:17]=2)[N:33]=1)[C:26]([NH2:28])=[NH:27]
Reactant: CNC1=NS(=O)(=O)N=C1OC
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Agent: CN
Agent: COC1=NS(=O)(=O)N=C1OC
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1csc(NC(=N)N)n1

Procedure:
Reaction of a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide with one equivalent of methylamine and treatment of the resultant 3-methoxy-4-methylamino-1,2,5-thiadiazole 1,1-dioxide with one equivalent of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine yields the title compound, which is identical to the product obtained in Example 31.
Reaction SMILES: C([O:4][CH:5]([CH2:19][N:20]([CH3:22])[CH3:21])[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)C>[OH-].[K+]>[CH3:22][N:20]([CH3:21])[CH2:19][CH:5]([OH:4])[CH:6]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)OC(CN(C)C)C(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: CN(C)CC(O)C(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 2.4 %

Procedure:
2-Acetoxy-3-dimethylamino- 1,1-diphenyl-propane 8200mg) was dissolved in methanolic potassium hydroxide (5% 10 ml) and the solution allowed to stand overnight. Solvent was evaporated and the residue dissolved in ether and water. The ether extract was dried and evaporated to give 3-dimethylamino-1,1- diphenyl-propan-2-ol (170 mg, 97%), m.p. 72°- 73°
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.075 mmol), glycine (745 mg, 9.9 mmol) and NaOMe solution (15 mL, 7.5 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and water (30 mL). 1 M HCl was added with vigorous stirring until pH was about 2. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (20-100% EtOAc/hexanes+2% AcOH) to give 19 mg of the title compound as an off-white solid. MS: (+) m/z 378.95 (M+1).
Reaction SMILES: C(O[C:4]([CH:6]([O:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1)[CH3:7])=[O:5])C.[CH3:20][NH2:21]>CN(C)C=O>[CH3:20][NH:21][C:4]([CH:6]([O:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:10]=1)[CH3:7])=[O:5]
Reactant: CCOC(=O)C(C)Oc1ncn(-c2ccccc2)n1
Reactant: CN
Solvent: CN(C)C=O
Product: CNC(=O)C(C)Oc1ncn(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
A 2.5 g portion of the compound of Example 1 was combined with 10 ml of 40% aqueous methylamine and 20 ml of dimethylformamide at room temperature, and the mixture was allowed to stand for 2 days. It was then poured into ice-water, and the solid was collected and air-dried to obtain 0.4 g of the desired product, m.p. 134°-135°.