Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:3](=[O:10])[CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][CH:7]=1.[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[I:1][C:2]1[C:3]2([CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][CH:7]=1)[O:13][CH2:12][CH2:11][O:10]2
Reactant: CC1(C)CC=C(I)C(=O)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)CC=C(I)C2(C1)OCCO2
Yield: 46.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 67a by using 2-iodo-5,5-dimethylcyclohex-2-en-1-one (J. Org. Chem., 1994, 59, 5393-5396; 6.10 g, 24.4 mmol), ethylene glycol (3.00 g, 48.3 mmol), p-toluenesulfonic acid hydrate (230 mg, 1.22 mmol) and benzene (70 mL), to yield the title compound (3.33 g, 46%) as a brown oil.
Reaction SMILES: [N+:1]([O:4][CH2:5][C:6]1[N:10]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)[CH:9]=[N:8][CH:7]=1)([O-:3])=[O:2]>[O-2].[Mn+4].[O-2].O1CCOCC1>[N+:1]([O-:4])([OH:3])=[O:2].[CH:11]1([N:10]2[C:6]([CH:5]=[O:4])=[CH:7][N:8]=[CH:9]2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])OCc1cncn1C1CCCc2ccccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: O=Cc1cncn1C1CCCc2ccccc21
Product: O=[N+]([O-])O
Yield: 53.6 %

Procedure:
A solution of 8.5 parts of 1-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-imidazole-5-methanol mononitrate and 17 parts of manganese(IV) oxide in 50 parts of 1,4-dioxane was stirred for 10 hours at 90° C. The reaction mixture was filtered and the filtrate was evaporated. The residue was converted into the nitrate salt in 2-propanone and 2,2'-oxybispropane. The salt was filtered off and dried, yielding 5.9 parts (53.6%) of 1-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-imidazole-5-carboxaldehyde mononitrate; mp. 161.6° C. (compound 2.05).
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:16]1([NH:22][S:23](Cl)(=[O:25])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[C:16]1([NH:22][S:23]([N:13]2[CH2:14][CH2:15][CH:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][Br:2])[CH2:11][CH2:12]2)(=[O:25])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCCCCCOC1CCNCC1
Reactant: O=S(=O)(Cl)Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Nc1ccccc1)N1CCC(OCCCCCCBr)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 135.2 %

Procedure:
A solution of 3 g (10 mmol) 4-(6-Bromo-hexyloxy)-piperidine hydrochloride and 3.44 g (18 mmol) of Phenylsulfamoyl chloride in 100 ml dry CH2Cl2 was treated with 6.95 ml (49.9 mmol) of triethylamine. The reaction was stirred for 4 h at RT, diluted with CH2Cl2 and washed with water. The organic phase was dried (MgSO4) and evaporated to yield 5.67 g (quantitative) of 4-(6-Bromo-hexyloxy)-piperidine-1-sulfonic acid phenylamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([O:15][CH3:16])[CH:10]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:24]=[O:25]>[OH-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([O:15][CH3:16])[C:10]=1[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: COc1cc(-c2c(F)cccc2F)n(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1nn(C)c(-c2c(F)cccc2F)c1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-(2,6-difluorophenyl)-3-methoxy-1-methyl-1H-pyrazole (0.5 g, 2.2 mmol) (i.e. the product of Step C) in dimethylformamide (5 mL) at 80° C. was added phosphorus oxychloride (0.31 ml, 3.3 mmol). After 2 h the reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with sodium hydroxide (1 N, about 5 mL) and water. The resulting mixture was extracted with diethyl ether (2×) and the combined organic layers were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel chromatography (0 to 100% gradient of ethyl acetate in dichloromethane as eluant) to provide the title compound (0.5 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:5]([O:11][CH3:12])=[C:6]([CH:8](O)[CH3:9])[CH:7]=1.N1C(Cl)=NC(Cl)=NC=1[Cl:29]>>[Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:5]([O:11][CH3:12])=[C:6]([CH:8]([Cl:29])[CH3:9])[CH:7]=1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
This compound was prepared according to the procedure of Example 13 step 6, using tert-butyl 4-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]piperidine-1-carboxylate (racemic) and cyanuric chloride as the starting materials. 1H NMR (400 MHz, CDCl3): δ 7.44 (s, 1H), 5.46 (m, 1H), 4.23 (bs, 2H), 3.73 (s, 3H), 3.29 (bs, 1H), 2.78 (bs, 2H), 2.40 (s, 3H), 2.27-2.09 (m, 2H), 1.78 (d, 3H), 1.63 (m, 2H), 1.43 (s, 9H) ppm.
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N+:8]([C:11]1C=C(C=C[CH:18]=1)C=O)([O-:10])=[O:9].N1CCCCC1.C(O)(=O)C>C(O)(C)C>[C:3](/[C:2](=[C:11](/[N+:8]([O-:10])=[O:9])\[CH3:18])/[C:1]([NH2:7])=[O:6])(=[O:4])[CH3:5]
Reactant: CC(=O)CC(N)=O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CC(=O)/C(C(N)=O)=C(\C)[N+](=O)[O-]
Yield: 117.5 %

Procedure:
A mixture of 10 g of acetoacetamide and 15 g of 3-nitrobenzaldehyde in 100 ml of isopropanol is stirred at 35° C. for 4 hours in the presence of 0.3 ml of piperidine and 0.5 ml of acetic acid. The precipitated yellow crystals are collected by filtration to give 20 g of α-acetyl-3-nitrocrotonamide, melting at 159°-161° C.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)=O.[Na].[CH:13]1([NH:19][OH:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([N+:19]([O-:20])=[CH:1][C:3]2[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=Cc1ccc(S(=O)(=O)O)o1
Reactant: ONC1CCCCC1
Agent: [Na]
Product: O=S(=O)(O)c1ccc(C=[N+]([O-])C2CCCCC2)o1
Yield: 84.3 %

Procedure:
Following the procedure of Example 1 above and using 5-formylfuran-2-sulfonic acid, sodium salt hydrate and N-cyclohexylhydroxylamine, the title compound was prepared in 84.3% yield as the sodium salt, m.p. 236.1° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([O:13][CH3:14])=[C:5]([CH3:12])[C:6]=1[C:7]([O:9]CC)=O.ClC(Cl)(O[C:19](=[O:25])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:34]1([CH2:40][CH2:41][NH2:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:14][O:13][C:4]1[S:3][C:2]2[NH:1][C:19](=[O:25])[N:42]([CH2:41][CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:7](=[O:9])[C:6]=2[C:5]=1[CH3:12]
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)c1c(N)sc(OC)c1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1sc2[nH]c(=O)n(CCc3ccccc3)c(=O)c2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a solution (30 mL) of ethyl 2-amino-5-methoxy-4-methylthiophene-3-carboxylate (1.0 g) in methylene chloride were added triphosgene (1.8 g) and triethylamine (3.0 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 2-phenylethanamine (1.69 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (15 mL), sodium methoxide (1.0 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (1.2 g, 82%).
Reaction SMILES: N1C=CN=CC=1C1C=CN=[C:9]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=O)=[CH:17][CH:16]=2)N=1.[NH:24]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)[C:25]([NH2:27])=N.CN(/C=C/C(C1C=NC=CN=1)=O)C.CN(C)/C=C/C(C1C=NC=CC=1)=O>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:17]([C:18]2[CH:22]=[CH:23][N:27]=[C:25]([NH:24][C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=3)[CH:19]=2)[CH:9]=1
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: O=C(O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Agent: CN(C)/C=C/C(=O)c1cccnc1
Agent: CN(C)/C=C/C(=O)c1cnccn1
Product: O=C(O)c1ccc(Nc2cc(-c3cccnc3)ccn2)cc1

Procedure:
Title compound was prepared according to the procedure described for the synthesis of compound 25a (scheme 6, step 3) replacing the guanindine 24 by 4-guanidinobenzoic acid (344) (Zlatoidsky P., Maliar T. Eur. J. Med. Chem Chim. Ther.; 1996, 31, 895-900) and (E)-3-(dimethylamino)-1-(pyrazin-2-yl)-prop-2-en-1-one (23a) by (E)-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one (345) (Zimmermann J., Buchdunger E., et al. Bioorg. Med. Chem. Lett., 1996, 6, 1221-1226). Yield of the product 28%. MS (m/z): 292.29 (calc) 293.1 (MH+) (found).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)[CH3:10])[CH:5]=[N:4][CH:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]([NH2:27])[CH:24]=[N:25][CH:26]=1.Cl.CN(C)CCCN=C=NCC.N1(C2C=CN=CC=2)CCCC1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:27][C:23]2[CH:24]=[N:25][CH:26]=[C:21]([CH3:20])[CH:22]=2)=[O:16])[CH3:10])[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncc(N)c1
Reactant: CC(Nc1cncc(Cl)n1)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cncc(NC(=O)c2cccc(C(C)Nc3cncc(Cl)n3)c2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 61.2 %

Procedure:
A mixture of 3-{1-[(6-chloropyrazin-2-yl)amino]ethyl}benzoic acid (11 mg, 0.04 mmol), 5-methylpyridin-3-amine (5 mg, 0.048 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (11 mg, 0.059 mmol), 4-pyrrolidinopyridine (1.2 mg, 0.008 mmol) and triethylamine (0.013 mL, 0.095 mmol) in dichloromethane (1 mL) was stirred at room temperature for 17 hours. After this time the mixture was diluted with dichloromethane (20 mL), washed successively with saturated aqueous sodium hydrogen carbonate (2×15 mL) and brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure to give a dark yellow oil which was purified by flash chromatography (silica, ethyl acetate/methanol) to give 3-{1-[(6-chloropyrazin-2-yl)amino]ethyl}-N-(5-methylpyridin-3-yl)benzamide (9 mg, 61%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:14]([Br:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH:7]1[CH2:10][CH2:9][CH2:8]1)=[O:5].Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.O>C(Cl)Cl>[Br:15][C:14]1[CH:13]=[CH:12][CH:11]=[C:3]2[C:2]=1[NH:1][C:17](=[O:19])[N:6]([CH:7]1[CH2:8][CH2:9][CH2:10]1)[C:4]2=[O:5]
Reactant: Nc1c(Br)cccc1C(=O)NC1CCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]c2c(Br)cccc2c(=O)n1C1CCC1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 326.4 %

Procedure:
A mixture of 2-amino-3-bromo-N-cyclobutylbenzamide (2.127 g, 7.90 mmol) and triphosgene (0.797 g, 2.69 mmol) in DCM (80 mL) was heated at reflux (using a water-cooled reflux condenser) for 17 h. The reaction mixture was then concentrated in vacuo, and the residue was taken up in toluene (80 mL) and heated at 110° C. for 1.5 h. Additional triphosgene (0.040 g, 014 mmol) was added, and the resulting solution was stirred at 110° C. for 45 min. The reaction mixture was then cooled to RT and concentrated in vacuo to give crude 8-bromo-3-cyclobutylquinazoline-2,4(1H,3H)-dione (2.59 g, 8.78 mmol) as a light-yellow solid. m/z (ESI, +ve) 295.0/297.0 (M+H)+. This material was used directly in the subsequent transformation.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH3:32][C:33]1[CH:34]=[C:35]([S:39]([NH2:42])(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([CH3:32])[CH:34]=3)(=[O:41])=[O:40])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1cccc(S(N)(=O)=O)c1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1cccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4ccccc4)c3C)cc2)c1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 3-methylbenzenesulfonamide: 1H-NMR (CDCl3) δ 7.72-7.66 (2H, m), 7.46-7.22 (11H, m), 6.45 (1H, br.s), 3.48-3.45 (2H, m), 2.86-2.81 (2H, m), 2.39 (3H, s), 2.32 (3H, s), 2.25 (3H, s).
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].C(=O)([O-])[O-].[K+].[K+]>O.C1COCC1.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>[N+:22]([C:16]1[CH:17]=[C:18]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:19]=[CH:20][C:15]=1[C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: OB(O)c1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(-c2cccc3ccccc23)ccc1-c1cccc2ccccc12

Procedure:
2.4 g (2.1 mmol) of Pd(PPh3)4 are added to a well-stirred, degassed suspension of 67.8 g (190 mmol) of 1-naphthylboronic acid, 53.3 g (190 mmol) of 2,5-dibromonitrobenzene and 137.9 g (648.5 mmol) of potassium carbonate in a mixture of 250 ml of water and 250 ml of THF, and the mixture is heated under reflux for 20 h. After cooling, the organic phase is separated off, washed three times with 200 ml of water and once with 200 ml of saturated, aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo in a rotary evaporator. The grey residue is recrystallised from hexane. The deposited crystals are filtered off with suction, washed with a little MeOH and subsequently dried in vacuo; yield: 86.1 g, 71% of theory; purity: 98.4% according to HPLC.
Reaction SMILES: [CH3:1][C:2]([NH2:11])([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:3].S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18].O>C(Cl)(Cl)Cl>[CH3:3][C:2]([NH2:11])([CH3:1])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([N+:17]([O-:19])=[O:18])=[CH:9][CH:10]=1
Reactant: CC(C)(N)Cc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(N)Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
A solution of phentermine (1.0 g) in chloroform (20 ml) was added dropwise to sulfuric acid (3.57 ml) at 0° C.; then fuming nitric acid (specific gravity=1.52; 2.8 ml) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 2 h, made alkaline with water and a 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=9:1) to give 367 mg of the titled compound (yield, 28%).
Reaction SMILES: Br[CH2:2][C:3]1[S:18][C:6]2[N:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=2[C:4]=1[C:19]([O:21][CH3:22])=[O:20].[C:23]1([NH:29][NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Zn]>[CH3:2][C:3]1[C:4]([CH2:2][C:3]2[S:18][C:6]3[N:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=3[C:4]=2[C:19]([O:21][CH3:22])=[O:20])=[C:5]([CH3:6])[N:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:30]=1
Reactant: NNc1ccccc1
Reactant: COC(=O)c1c(CBr)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: CC(=O)/C=C(/C)O
Agent: [Zn]
Product: COC(=O)c1c(Cc2c(C)nn(-c3ccccc3)c2C)sc2c1c(=O)n(C)c(=O)n2CC(C)C

Procedure:
Prepared from methyl 6-(bromomethyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate (500 mg), zinc acetylacetonate hydrate and phenyl hydrazine following the procedure of example 26, part a). Crude product was purified by column chromatography over silica, eluting with ethyl acetate/iso-hexane (2:3) to give the sub-title compound (555 mg) as a solid. MS(ESI) 481 [M+H]+. δ 1HDMSO 0.95 (6H, d), 2.24 (3H, s), 2.27 (3H, s), 2.20-2.30 (1H, m), 3.39 (3H, s), 3.71 (2H, d), 3.95 (3H, s), 3.96 (2H, s), 7.36-7.50 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][NH2:12])=O.[CH2:13]([O:15][C:16](=[O:21])[C:17](Cl)=[N:18][CH3:19])[CH3:14].Cl>ClCCl>[CH2:13]([O:15][C:16]([C:17]1[N:18]([CH3:19])[C:9]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:11][N:12]=1)=[O:21])[CH3:14]
Reactant: CCOC(=O)C(Cl)=NC
Reactant: NNC(=O)Cc1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1nnc(Cc2ccccc2Cl)n1C
Reaction time: 2 h

Procedure:
14.8 g (80 mmol) of o-chlorophenylacetic acid hydrazide are suspended in 230 ml of dichloromethane. At 5°, 12 g (80 mmol) of 2-chloro-2-(N-methylimino)acetic acid ethyl ester [Tetrahedron Lett. 30, 2827 (1979)] are added dropwise thereto. The whole is then stirred for 2 hours while cooling with ice and then overnight at room temperature. The reaction mixture is then poured onto ice, 50 ml of 2N hydrochloric acid are added thereto and the whole is extracted twice with dichloromethane. The combined dichloromethane phases are washed twice with water. All the acidic aqueous phases are combined, rendered alkaline with solid sodium carbonate and extracted three times by shaking with dichloromethane. These three organic phases are combined, washed in succession with water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The residue is taken up in 150 ml of xylene and stirred under reflux for 44 hours. The reaction mixture is then concentrated and chromatographed over silica gel using ethyl acetate as eluant. The eluate is concentrated by evaporation and recrystallised from ether. 5-(o-chlorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxylic acid ethyl ester of m.p. 87°-88° is obtained in a yield of 12.4 g (55% of the theoretical yield).
Reaction SMILES: O1C2C=CC=CC=2N=C1.[CH2:10]([N:28]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[C:29](=[O:51])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([S:36](=[O:50])(=[O:49])[NH:37][C:38]2[CH:47]=[C:46]([OH:48])[C:41]3[N:42]=C(C)[O:44][C:40]=3[CH:39]=2)[CH:31]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[ClH:70]>CO>[ClH:70].[NH2:42][C:41]1[C:46]([OH:48])=[CH:47][C:38]([NH:37][S:36]([C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([C:29](=[O:51])[N:28]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:31]=2)(=[O:50])=[O:49])=[CH:39][C:40]=1[OH:44]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cccc(S(=O)(=O)Nc2cc(O)c3nc(C)oc3c2)c1
Agent: Cl
Agent: c1ccc2ocnc2c1
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cccc(S(=O)(=O)Nc2cc(O)c(N)c(O)c2)c1
Reaction time: 8 h

Procedure:
To a suspension of N,N-dioctadecyl-m-(2-methyl-4-hydroxy-6-benzoxazolylsulfamoyl)benzamide benzoxazole (17.3 g, 0.02 mole) in methanol (170 ml) was added hydrogen chloride gas. The mixture warmed, and complete solution resulted. Hydrogen chloride addition was continued until saturation had been achieved. The mixture was then refluxed for four hours, then allowed to stand at ambient temperature overnight. The resulting white precipitate was collected and dried to yield 15.3 g (88.4 percent). TLC showed the product to be pure.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.F[C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][C:42]=1[CH3:43])[C:38]#[N:39]>>[CH3:43][C:42]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][C:35]=1[N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Reactant: Cc1ccc(C#N)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)cc1-n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 120 °C

Procedure:
To a mixture of 4-(1H-pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]-pyridine (0.050 g, 0.00016 mol) (see, Example 231, Step 1) and cesium carbonate (0.10 g, 0.00032 mol) in dry DMF (1.0 mL, 0.013 mol) was added 3-fluoro-4-methylbenzonitrile (0.043 g, 0.00032 mol). The reaction mixture was heated in sealed tube to 120° C. for 5.5 hours. The reaction was allowed to cool and partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated to give 4-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile as a crude product, LC/MS (M+H)+: 430.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3([CH3:15])[C:11](=[CH:12][CH2:13][C:4]=2[CH:3]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3.[H-].[Na+].[CH3:20]I.O>C(COC)OC>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3([CH3:15])[C:11](=[CH:12][CH2:13][C:4]=2[CH:3]=1)[N:10]([CH3:20])[C:9](=[O:14])[CH2:8][CH2:7]3
Reactant: CI
Reactant: CC12CCC(=O)NC1=CCc1cc(F)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1C(=O)CCC2(C)C1=CCc1cc(F)ccc12
Temperature: 25 °C
Yield: 56 %

Procedure:
8-fluoro-10b-methyl-1,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one (1.38 g; 6mmol) was added to a suspension of NaH (475 mg; 20 mmol) in glyme (15 ml). The mixture was refluxed for 1.5 hours and cooled quickly to room temperature. Methyl iodide (15 ml) was added and the mixture refluxed for 4 hours, then allowed to cool to room temperature. After addition of water, the mixture was concentrated to near dryness. The residue was partitioned between ethyl acetate and water. The organic layer was washed three times with water, dried over MgSO4 and concentrated under vacuum. Recrystallization from hexane afforded 737 mg (56% yield) of the subtitle compound. Melting point 110°-111° C.