Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH:24]=[CH:23][CH:22]=[CH:21]3)[C:17]([I:25])=[CH:16][C:15]=2[N+:26]([O-])=O)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].O.O.Cl[Sn]Cl>CCO>[I:25][C:17]1[C:18]([N:20]2[CH:24]=[CH:23][CH:22]=[CH:21]2)=[CH:19][C:14]2[NH:13][C:11](=[O:12])[CH2:10][C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[C:1]#[N:2])=[N:26][C:15]=2[CH:16]=1
Reactant: N#Cc1cccc(C(=O)CC(=O)Nc2cc(-n3cccc3)c(I)cc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: N#Cc1cccc(C2=Nc3cc(I)c(-n4cccc4)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from 3-(3-cyano-phenyl)-N-(4-iodo-2-nitro-5-pyrrol-1-yl-phenyl)-3-oxo-propionamide (Example M9) by reductive cyclization with SnCl2.2H2O in EtOH at 70° C. according to the general procedure J (method b). Obtained as a yellow solid (344 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](O)[CH2:20][OH:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:12]1([CH2:11][CH2:10][C:9]2([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:21][CH2:20][CH2:19][O:18]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCCO
Reactant: O=C(CCc1ccccc1)CCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: c1ccc(CCC2(CCc3ccccc3)OCCO2)cc1

Procedure:
A solution of 135 mg (0.6 mmol) of 1,5-diphenyl-3-pentanone, 0.2 ml of ethylene glycol, and 10 mg of p-toluene sulfonic acid monohydrate was refluxed with azeotropic removal of water. After separation of water was completed, the solution was diluted with ethyl acetate, washed sequentially with aqueous NaHCO and water, dried over Na2SO4, and concentrated to provide the desired compound. 1H NMR (CDCl3) δ2.0 (m, 4H), 2.71 (m, 4H), 4.03 (s, 4H), 7.15-7.3 (m, 10H). Mass spectrum: (M+H)+ =283.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6](Cl)(Cl)=[O:7].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]1[NH:23][C:22]([NH2:24])=[N:21][C:20]2[C:16]=1[N:17]=[CH:18][N:19]=2.CCN(CC)CC>C1(C)C=CC=CC=1.O>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]1[N:23]=[C:22]([NH2:24])[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[C:6]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:7]
Reactant: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Reactant: C1CCNC1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1nc(-c2ccco2)c2ncn(C(=O)N3CCCC3)c2n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
A solution of pyrrolidine (50 mL, 0.6 mmol) in toluene (2 mL) was treated with a solution of phosgene in toluene (0.31 mL, 1.93-M, 0.6 mmol), heated at 80° C. for 30 mins, cooled and concentrated in vacuo. The residue was dissolved in THF (2 mL) and added to a solution of 6-(2-furyl)-1H-purine-2-amine (100 mg, 0.5 mmol) and Et3N (83 mL, 0.6 mmol) in DMP (0.5 mL), stirred at 60° C. for 16 h, poured into water and extracted with EtOAc. The combined organic phase was dried (MgSO4), concentrated in vacuo and the resulting solid triturated with EtOAc/heptane and filtered to give the title compound (92 mg, 62%) as a cream solid.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:69])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH:66]([CH3:68])[CH3:67])[N:64]=[CH:65][C:52]3=[CH:51][CH:50]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:78]>CO.O>[ClH:78].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:69])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH:66]([CH3:67])[CH3:68])[N:64]=[CH:65][C:52]3=[CH:51][CH:50]=4)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)n1ncc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: CC(C)n1ncc2ccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc3c21
Yield: 81 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(1-isopropyl-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (3 mL), water (7 mL) and 1 M HCl (0.2 mL) and chromatographed on a 5 g C18 cartridge {gradient 30 to 70% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound (26.5 mg, 81%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.55 (br s, 3H), 8.33 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.53-7.39 (m, 7H), 7.32 (d, J=8.2 Hz, 2H), 5.46 (septet, J=6.6 Hz, 1H), 2.62-2.49 (m, 4H), 2.23-2.13 (m, 1H), 1.86-1.74 (m, 1H), 1.59 (d, J=6.6 Hz, 6H). LCMS (Method E): RT=3.81 min, [M+H]+=450.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[C:15]=1[OH:16])[C:5]([CH2:7][C:8](OCC)=[O:9])=O.O.[NH2:21][NH2:22]>C(O)C>[OH:9][C:8]1[NH:22][N:21]=[C:5]([C:4]2[CH:3]=[C:2]([OH:1])[C:15]([OH:16])=[C:14]([N+:17]([O-:19])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: CCOC(=O)CC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(-c2cc(O)[nH]n2)cc(O)c1O
Reaction time: 0.08 h

Procedure:
2.0 g of ethyl (3,4-dihydroxy-5-nitrobenzoyl)acetate are suspended in 50 ml of ethanol. After treatment with 0.4 g of hydrazine hydrate the mixture is held at the reflux temperature for 16 hours. After distillation of the solvent, the residue is held at the boiling temperature for 5 minutes with 50 ml of ethyl acetate. The separated precipitate is filtered under suction and the filtrate is concentrated to 10 ml. The crystals, which separate in the cold, are filtered under suction. There is obtained 5-(5-hydroxypyrazol-3-yl)-3-nitropyrocatechol in form of orange crystals of m.p. 228° (dec.).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10]2=[O:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:26][C:27](OC1C=CC([N+]([O-])=O)=CC=1)=[O:28].Cl.[NH2:40][C@H:41]([C:46]([NH2:48])=[O:47])[C@H:42]([CH2:44][CH3:45])[CH3:43]>ClCCl>[ClH:26].[NH2:48][C:46]([C@@H:41]([NH:40][C:27]([N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:9]([CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:10]1=[O:18])=[O:28])[C@@H:42]([CH3:43])[CH2:44][CH3:45])=[O:47]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC[C@H](C)[C@H](N)C(N)=O
Reactant: O=c1[nH]c2ccccc2n1CCN1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)n1c(=O)n(CCN2CCOCC2)c2ccccc21)C(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(2-morpholin-4-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one (530 mg, 2.1 mmol) in dichloromethane (8 mL) were added triethylamine (1.0 mL, 7.0 mmol) and 4-nitrophenyl chloroformate (470 mg, 2.3 mmol) at 0° C. and the mixture was stirred for 3 h at rt. Then to this mixture was added a mixture of L-isoleucinamide hydrochloride (430 mg, 2.6 mmol) and triethylamine (0.6 mL, 4.3 mmol) in dichloromethane (4 mL) at 0° C. and stirred rt. After 22 h, the reaction was quenched by addition of water (50 mL) and extracted with dichloromethane (50 mL×2). The combined organic layers were washed with water (20 mL×3), brine (20 mL) and dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1/4) to afford 600 mg (70%) of free form of the title compound. The obtained compound was dissolved in ethyl acetate (1 mL) and to this solution was added 4N HCl in ethyl acetate (0.4 mL) to form white solid which was filtered and dried in vacuo to give the title compound (600 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:22][OH:23])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:30].[Na+].OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:30])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:22][OH:23])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(C4(CO)CC4)cc3)cc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(CO)CC4)cc3)cc12
Temperature: 0 °C
Reaction time: 20 h
Yield: 30.5 %

Procedure:
To a mixture of 6-chloro-5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1H-indole-3-carbaldehyde (80 mg, 0.24 mmol) in acetonitrile (3 mL) and tert-butanol (3 mL) was added 2-methyl-2-butene (3 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (420 mg, 4.80 mmol) and sodium phosphate monobasic (650 mg, 4.80 mmol) in water (3 mL) dropwise via addition funnel. The reaction mixture was warmed to room temperature and stirred for 20 hours. The solvent was removed in vacuo to give a residue, which was purified by prep-HPLC (Column: Boston Symmetrix ODS-H 150*30 mm*5 μm Mobile phase: from 36% MeCN in water (0.1% TFA) to 36% MeCN in water (0.1% TFA); Wavelength: 220 nm Flow rate: 30 mL/min) to give 6-chloro-5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1H-indole-3-carboxylic acid (25 mg, 32% yield) as a white solid. MS (ES+) 364.0 (M+Na)+. 1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 11.96 (s, 1H), 8.07 (d, 1H), 7.92 (s, 1H), 7.62 (s, 1H), 7.38-7.32 (m, 4H), 4.73-4.71 (m, 1H), 3.58-3.57 (m, 2H), 0.88-0.77 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.N1C=CC=CC=1.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>C(Cl)Cl>[OH:20][C:17](=[C:6]1[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:5])[CH2:18][CH3:19]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(O)=C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of Meldrum's acid (10 g, 69.4 mmol) in CH2Cl2 (170 mL) was cooled to 0° C. Pyridine (11.2 ml, 138.8 mmol) and propanoyl chloride (10.1 mL, 76.3 mmol) were added via syringe. The resulting solution was stirred at 0° C. for 1 hour, then warmed to room temperature and stirred for 1 hour. The reaction was diluted with CH2Cl2 and washed with aq HCl (15 mL conc HCl in 200 mL water, 1×) and water (1×). The organic solution was dried over Na2SO4 and concentrated to give a dark red solid.
Reaction SMILES: C(=N[C@H](C)C(C1C=CC=CC=1OC)(C1C=CC=CC=1OC)O)C1C(=CC=CC=1)O.[CH3:30][C:31](=[CH:33][CH:34]=[C:35]([CH3:37])[CH3:36])[CH3:32].C1(NN)C=CC=CC=1.[N+](=[CH:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[N-]>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:53][CH2:52][O:51][C:49]([CH:48]1[C:35]([CH3:37])([CH3:36])[CH:34]1[CH:33]=[C:31]([CH3:32])[CH3:30])=[O:50]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)=CC=C(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: COc1ccccc1C(O)(c1ccccc1OC)[C@@H](C)N=Cc1ccccc1O
Solvent: O
Solvent: NNc1ccccc1
Product: CCOC(=O)C1C(C=C(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
22.6 mg (0.05 mmol) of copper complex prepared from 9.98 mg (0.05 mmol) of copper acetate-mono hydrate and 21.5 mg of (R)-N-salicylidene-2-amino-1,1-di(2-methoxyphenyl)propanol, and 6.0 g (55 mmol) of 2,5dimethyl-2,4-hexadiene were charged in a 50 ml Schlenk's tube wherein the atmosphere is substituted with nitrogen, followed by the addition of 5.4 mg of phenylhydrazine, and 1.14 g (10 mmol) of ethyl diazoacetate was added dropwise at 80° C. over 2 hours. After the completion of the dropwise addition of ethyl diazoacetate, the mixture was further stirred at 25° C. for 1 hour. The amount of chrysanthemic acid ethyl ester formed was determined by gas chromatography. As a result, it was 1.76 g and the yield was 90.0% based on ethyl diazoacetate and, furthermore, the trans/cis ratio was 58/42. After 2,5-dimethyl-2,4-hexadiene (boiling point: 51° C./30 mmHg) was distilled off from the reaction mixture, 1 g of the concentrated solution was taken out. Then, 10 ml of an aqueous 1N sodium hydroxide solution and 5 ml of ethanol were added and alkali hydrolysis was performed by stirring at 100° C. for 1 hour. The resulting chrysanthemic acid was reacted with I-menthol and the formed diastereomer was analyzed by gas chromatography. As a result, the optical purity of the (+)-trans isomer was 63% e.e., whereas, the optical purity of the (+)-cis isomer was 63% e.e.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.I[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:13][CH3:14])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1cc(Cl)ccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOc1ccc(Cl)cc1C(N)=O
Yield: 36.6 %

Procedure:
A mixture of 5-chlorosalicylamide (16.0 g., 0.093 mole), iodoethane (31.8 g., 0.204 mole), and potassium carbonate (13.1 g., 0.095 mole) in ethanol (225 ml.) was heated under reflux for 20 hours. The hot mixture was filtered. The filtrate was reduced to dryness. The residue was triturated with water. The mixture was filtered and the collected solid recrystallized from acetonitrile to give 5-chloro-2-ethoxybenzamide (6.8 g., 36.6%) m.p. 136°-139°.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:8][CH2:7][NH:6][C@@H:5]([C:9]([OH:11])=[O:10])[CH2:4]1.[N:12]([O-])=O.[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>O.CCOCC>[CH3:2][C@@H:3]1[CH2:8][CH2:7][N+:6]2=[N:12][O:10][C:9]([O-:11])=[C:5]2[CH2:4]1
Reactant: C[C@@H]1CCN[C@@H](C(=O)O)C1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: C[C@@H]1CC[n+]2noc([O-])c2C1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
Concentrated hydrochloric acid (6.0 ml) was added to a suspension of (2R,4R)-4-methyl-2-piperidinecarboxylic acid (Biochem. Biophys. Res. Commun. 1981; 101(2); 440) (10 g, 7.03 mmol), in water (30 ml) and this solution cooled to −5° C. A solution of sodium nitrite (5.3 g, 7.7 mmol), in water (20 ml) was then added, and this solution stirred at room temperature for 2 hours. The mixture was extracted with dichloromethane, twice, and the combined organic extracts were dried (MgSO4) and evaporated under reduced pressure to give a white solid. Trifluoroacetic anhydride (11 ml, 7.70 mmol) was added to a cooled (−3° C.) solution of the intermediate product in ether (200 ml) and the reaction stirred overnight at room temperature. The mixture was evaporated under reduced pressure, and the residue purified by column chromatography using ethyl acetate as the eluant. The title compound was obtained as a brown crystalline solid, 7.1 g.
Reaction SMILES: C(=O)([O-])O.[Na+].[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[C:9]([NH2:24])=[N:8]1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>O1CCCC1.O>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:14]=2)[C:9]([NH:24][C:26](=[O:27])[O:28][CH2:29][CH3:30])=[N:8]1
Reactant: CCOC(=O)Cl
Reactant: Cn1nc(N)c2ccc(OCc3ccccc3)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Nc1nn(C)c2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
9.8 g of sodium hydrogen carbonate (0.117 mol) are added to a solution of 19.7 g (0.078 mol) of 1-methyl-6-(phenylmethoxy)-1H-indazol-3-amine in 200 ml of a 9:1 mixture of tetrahydrofuran/water, and then 8.9 ml (0.093 mol) of ethyl chloroformate are added dropwise while maintaining the temperature at 25° C. A milky suspension is obtained which is left with stirring for 30 minutes, and then the solvent is evaporated off under reduced pressure. The residue is treated with dichloromethane and water. The organic phase is decanted off, dried over sodium sulphate and concentrated under reduced pressure. The product is crystallized from diisopropyl ether. 20.1 g of product are obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].Cl[C:12]([CH3:20])([CH2:14][CH2:15][C:16](Cl)([CH3:18])[CH3:17])[CH3:13].C1(O)C=CC=CC=1>>[CH:1]([C:4]1[C:5]([OH:10])=[CH:6][C:7]2[C:12]([CH3:20])([CH3:13])[CH2:14][CH2:15][C:16]([CH3:18])([CH3:17])[C:8]=2[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: CC(C)c1ccccc1O
Solvent: Oc1ccccc1
Product: CC(C)c1cc2c(cc1O)C(C)(C)CCC2(C)C

Procedure:
In a manner similar to Example 7(a) above, by the reaction of 30 g (0.22 mol) of 2-isopropylphenol with 40.3 g (0.22 mol) of 2,5-dichloro-2,5-dimethylhexane, 48.9 g (90%) of the expected phenol of melting point 79-80° C. were obtained after chromatography on a silica column eluted with a mixture of dichloromethane and hexane (40/60).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.O=S(Cl)[Cl:12]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([Cl:12])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnccn1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnccn1
Temperature: 60 °C
Reaction time: 0.03 h

Procedure:
To a solution of pyrazine-2-carboxylic acid (1.36 g, 10.9 mmol, 1 eq.) in SOCl2 (20 mL) was added DMF (2 drops). The mixture was stirred at 60° C. for 2.0 min. The volatiles were removed in vacuo to give crude pyrazine-2-carbonyl chloride, which was used in the next step directly. TO a suspension of 2-amino-5-nitrobenzoic acid (2.00 g, 10.9 mmol, 1.0 eq.) in THF (50 mL) was added Et3N (1.09 g) and pyrazine-2-carbonyl chloride in anhydrous THF (50 mL) dropwise. The resulting mixture was stirred at room temperature for 18 h. After the reaction was completed, the volatiles were removed. The residue was suspended in H2O (10 mL) and the pH was adjusted to 5 by slow addition of 2N HCl in water. The resulting solid was collected and dried in vacuo to give 3.12 g of 5-nitro-2-(pyrazine-2-carboxamido)benzoic acid as a brown solid (99%). LCMS m/z=289.0 (M+1) (Method B) (retention time=1.24 min),
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[NH2:15][C:16]1[NH:20][N:19]=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[C:17]=1[C:34]([NH2:36])=[O:35]>>[NH2:12][C:10]1[CH:11]=[C:2]2[C:3]([C:4](=[O:6])[NH:15][C:16]3[N:20]2[N:19]=[C:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:25][CH:26]=2)[C:17]=3[C:34]([NH2:36])=[O:35])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1[nH]c(=O)c1ccc(N)cc12

Procedure:
The desired product was prepared from methyl 2-chloro-4-nitrobenzoate and 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide using the procedures similar to those for compound 76 and 77. 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.44-7.36 (m, 2H), 7.19-7.02 (m, 6H), 6.64 (d, J=8.4 Hz, 1H), 6.55 (br s, 2H). MS (ESI, m/e) [M+1]+ 412.1.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:25])[N:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16](Cl)[N:15]=2)[CH:9]=1)[CH:2]=[CH2:3].Br.[NH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([Cl:37])[CH:31]=1>>[CH2:1]([O:4][C:5](=[O:25])[N:6]([C:21]([CH3:22])([CH3:24])[CH3:23])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([Cl:37])[CH:31]=3)[N:15]=2)[CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N(Cc1cccc(-c2ccnc(Cl)n2)c1)C(C)(C)C
Reactant: NCCc1ccc(O)c(Cl)c1
Agent: Br
Product: C=CCOC(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(C)(C)C
Yield: 79 %

Procedure:
tert-Butyl-[3-(2-chloro-pyrimidin-4-yl)-benzyl]-carbamic acid allyl ester was coupled with 4-(2-amino-ethyl)-2-chloro-phenol hydrobromide salt (intermediate 71) following procedure F to give the title product in 79% yield. LC-MS showed the product had the expected M+H+ of 495. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) 8.3 (d, 1H).) 7.9 (m, 2H) 7.4 (m, 1H) 7.3 (m, 1H) 7.2 (s, 1H) 7.0 (d, 1H) 6.9 (m, 2H) 5.9 (m, 1H) 5.2 (m, 2H) 5.1 (m, 2H) 4.7 (s, 2H) 4.6 (d, 2H) 3.7 (m, 2H) 2.9 (m, 2H) 1.41 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[Br:12]Br.[CH2:14]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])O.[K+]>CO.O.O1CCOCC1>[CH3:10][CH:9]([N:24]1[CH2:25][CH2:26][CH:21]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:22][CH2:23]1)[CH:8]([OH:11])[C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1.[BrH:12]
Reactant: BrBr
Reactant: c1ccc(Cc2ccncc2)cc1
Reactant: CCC(=O)c1ccc(O)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: Br
Product: CC(C(O)c1ccc(O)cc1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
To 4 ml of dioxane were added 6.0 g of 4'-hydroxypropiophenone. 6.4 Grams of bromine were added dropwise to the mixture with stirring at room temperature, and the reaction liquid was stirred for an additional 10 minutes. To the reaction liquid were then added 6.4 g of 4-benzylpyridine, 1 ml of water, 100 ml of methanol and 4.0 g of potassium hydrogen carbonate, and the mixture was refluxed under heating for 5 hours. The reaction mixture was then treated in the same manner as described in Example 26, whereby 10.6 g (66.4%) of ifenprodil hydrobromide were obtained as white crystals.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[N:11]=1.[N+](N[C:24]1[NH:29][C:28](=[O:30])[C:27]([CH3:31])=[CH:26][N:25]=1)([O-])=O.[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36]>N1C=CC=CC=1.CC(C)=O>[CH3:31][C:27]1[C:28](=[O:30])[NH:29][C:24]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([NH:6][C:5]([NH2:17])=[N:4][CH2:3][C:2]([F:1])([F:18])[F:19])[S:8][CH:9]=2)=[N:25][CH:26]=1.[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36]
Reactant: Cc1cnc(N[N+](=O)[O-])[nH]c1=O
Reactant: NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: Cc1cnc(NCCCCc2csc(NC(N)=NCC(F)(F)F)n2)[nH]c1=O

Procedure:
A mixture of 2-[2-(2,2,2-trifluoroethyl)-guanidino]-4-(4-aminobutyl)thiazole (0.7 g.) and 2-nitroamino-5-methyl-4(3H)-pyrimidone (0.3 g.) was heated under reflux in pyridine (3 ml.) for 3.5 hours. The mixture was then evaporated to dryness and the residue purified by preparative thin layer chromatography using ethyl acetate/methanol 6:1:1 v/v/v for development. The appropriate band was extracted with chloroform/ethanol 1:1 v/v (200 ml.). Evaporation of the solvent to dryness gave a red gum which was treated in acetone with excess maleic acid to give 5-methyl-2-(4-[(-2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]butylamino)pyrimid-4-one containing 1.75 equivalents of maleic acid. The n.m.r. of this compound in d6 dimethylsulphoxide using tetramethylsilane as internal standard (δ=0) included the following resonances (δ):-1.6 (multiplet, 4H); 1.8 (singlet, 3H); 3.3 (multiplet, 2H); 4.2 (quartet, 2H); 6.6 (singlet, 1H); 7.5 (singlet, 1H).