Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)=[O:26]>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[CH:25]=[O:26])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: O=Cc1ccccc1B(O)O
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=Cc1ccccc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 49.5 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2-formylphenylboronic acid (available from Frontier Scientific, Inc.; 60 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′-formyl-biphenyl-2-carboxylic acid (45 mg, 49%). 1H NMR (400 MHz, DMSO-d6) δ 13.11 (br s, 1H), 9.80 (br s, 1H), 8.54 (s, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 8.27 (d, J=7.8 Hz, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.73 (t, J=7.2 Hz, 1H), 7.61 (t, J=7.3 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.36 (d, J=7.5 Hz, 1H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([NH:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#N)=[CH:30][CH:29]=1)[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][CH3:26].C[OH:37]>C1(C)C=CC=CC=1.ClCCl>[CH2:11]([NH:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:37])=[CH:30][CH:29]=1)[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][CH3:26]
Reactant: CO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C#N)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Di-isobutylaluminum hydride (54-ml., 25% solution in toluene) is added with stirring to a solution of p-hexadecylaminobenzonitrile (11.4 g.) under a nitrogen atmosphere. The temperature rises to 40° C. during the addition which takes 30 minutes and the reaction is then stirred for 1 hour. A solution of methanol in toluene (50 ml., 1:1) is added over 30 minutes and the mixture is poured into vigorously stirred ice-cold aqueous sulfuric acid (500 ml., 5%). After 10 minutes diatomaceous earth (30 g.) is added, the mixture filtered and the organic layer separated. The aqueous solution is extracted twice with toluene (100 ml.) and the combined organic layers are washed with aqueous sodium bicarbonate, dried over magnesium sulfate, decolorized with charcoal, filtered and evaporated in vacuo to give a light yellow crystalline solid. The crude product is dissolved in dichloromethane and filtered through hydrated magnesium silicate (80 g.) to give a white crystalline material on removal of the solvent. The product is recrystallized from dichloromethane/hexanes giving colorless fine needles (6.0 g.), m.p. 84°-85° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7]Cl.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17].C(N(CC)CC)C>C(O)C>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][CH2:7][C:6]1[CH:9]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: COC(CN)OC
Reactant: Cc1ccc([N+](=O)[O-])c(CCl)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(CNCc1cc(C)ccc1[N+](=O)[O-])OC

Procedure:
A solution of 43 g of 5-methyl-2-nitrobenzyl chloride in 200 ml of ethanol is added drop-wise to a solution of 40 g of aminoacetaldehyde dimethylacetal and 40 g of triethylamine in 300 ml of ethanol at reflux temperature, and the solution is heated for 18 hours at reflux. It is then evaporated in a vacuum until dry and the residue is dissolved in ethyl acetate, and extracted several times with water. After the organic phase is dried and evaporated, the heading compound remains as a reddish oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([CH2:10]O)[CH:7]=[C:6]([CH3:12])[C:5]=1[N:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15].C(Br)(Br)(Br)[Br:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([CH2:10][Br:34])[CH:7]=[C:6]([CH3:12])[C:5]=1[N:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: COC(=O)c1cc(CO)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(CBr)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
To a 0° C. solution of 1.08 g (2.37 mmol) of the product of Example 278 and 983 mg (2.96 mmol) of carbon tetrabromide in 24 ml of dichloromethane was added 933 mg (3.55 mmol) of triphenyl phosphine. The resulting mixture was stirred for 15 min and then concentrated in vacu. The residue was chromatographed on silica gel using EtOAc:Hexane (1:6) as eluant to provide 1.1 g (96%) of the desired product as a white crystalline solid. Electrospray Mass Spec 520 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:23])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][C:11]=2[Cl:22])[C:6]=1[CH2:7]Cl.[NH3:24].C(=O)([O-])O.[Na+]>C(#N)C>[NH2:24][CH2:7][C:6]1[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][C:11]=2[Cl:22])[C:4]([CH3:23])=[N:3][C:2]=1[Cl:1]
Reactant: CCCCCOc1ccc(Cn2c(C)nc(Cl)c2CCl)c(Cl)c1
Reactant: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCCCOc1ccc(Cn2c(C)nc(Cl)c2CN)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-chloro-5-chloromethyl-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole (340 mg) in acetonitrile (3 ml) was added gradually to a mixed solvent of 28% aqueous ammonia (6 ml) and acetonitrile (6 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogencarbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with chloroform/methanol=100/1. The objective fraction was concentrated under reduced pressure to give 5-aminomethyl-4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole (82 mg) as a pale-brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]#[C:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH3:1][C:2]1[N:3]=[C:4]([C:8]#[C:9][CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([C:18]3[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:15][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(CC#CC2CCNCC2)n1
Reactant: O=[N+]([O-])c1cccnc1Cl
Product: Cc1cccc(C#CCC2CCN(c3ncccc3[N+](=O)[O-])CC2)n1
Yield: 54.1 %

Procedure:
A well homogenised mixture of Compound 31a (24 mg, 0.11 mmol) and 2-chloro-3-nitropyridine (19.5 mg, 0.12 mmol) was stirred at 120° C. for 40 min. The reaction crude was purified by flash chromatography (EtOAc—Petroleum Ether 3:7) affording the title product (20 mg).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][CH2:6][C:7]1[S:11][C:10]([NH2:12])=[N:9][N:8]=1>C(OCC)(=O)C>[Cl:5][CH2:6][C:7]1[S:11][C:10]([N:12]=[C:1]=[O:2])=[N:9][N:8]=1
Reactant: Nc1nnc(CCl)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1nnc(CCl)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-chloromethyl-2-amino-1,3,4-thiadiazole (10 grams) in ethyl acetate (300 ml) is added to the reaction vessel, and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the desired product 5-chloromethyl-1,3,4-thiadiazol-2-yl isocyanate dimer as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)C>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:6]([N+:19]([O-:21])=[O:20])[CH:7]=1
Reactant: COc1ccc(CCCCCC(=O)O)cc1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc(CCCCCC(=O)O)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)hexanoic acid (2.7 g) in acetic acid (10 ml) was added nitric acid (5.4 ml of a 2 M solution in acetic acid) and the mixture stirred at room temperature for one hour. The mixture was evaporated and the product used as such for the next step. Yield: 3.2 g.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH2:7][OH:8])=[CH:5][N:6]=1.Cl[C:10]1[CH:16]2[CH2:17][CH:13]([CH2:14][CH2:15]2)[C:12](=[O:18])[CH:11]=1.[H-].[Na+]>O1CCCC1>[Br:1][C:2]1[S:3][C:4]([CH2:7][O:8][C:10]2[CH:16]3[CH2:17][CH:13]([CH2:14][CH2:15]3)[C:12](=[O:18])[CH:11]=2)=[CH:5][N:6]=1
Reactant: O=C1C=C(Cl)C2CCC1C2
Reactant: OCc1cnc(Br)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C=C(OCc2cnc(Br)s2)C2CCC1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of (2-bromothiazol-5-yl)methanol (4.85 g, 25 mmol) and 4-chloro-bicyclo[3.2.1]oct-3-en-2-one (3.92 g, 25 mmol) in anhydrous tetrahydrofuran (100 ml) is added, in small portions, sodium hydride (60% dispersion in oil, 1.00 g, 25 mmol) at 0° C. The reaction mixture is stirred overnight and allowed to warm to room temperature. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 4-(2-bromothiazol-5-ylmethoxy)bicyclo[3.2.1]oct-3-en-2-one (6.43 g)
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[NH:4][C:3]=1[C:14]([O:16]C)=O.[NH2:18][C:19]1[S:20][C:21]([CH3:24])=[CH:22][N:23]=1>>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[NH:4][C:3]=1[C:14]([NH:18][C:19]1[S:20][C:21]([CH3:24])=[CH:22][N:23]=1)=[O:16]
Reactant: Cc1cnc(N)s1
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1
Product: Cc1cnc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2)s1
Yield: 31 %

Procedure:
Prepared from methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2-amino-5-methyl-thiazole analogous to Example 1. The crude product (65% of theory) was purified by column chromatography (Merck-silica gel 60, particle size: 0.2-0.5 mm), using chloroform/ethanol (97:3) as eluant. 4-Hydroxy-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide was obtained with a yield of 31% of theory.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[CH:5]=1)=[O:3].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40][CH:41]([C:45](O)=[O:46])[C:42](O)=[O:43])([CH3:33])[CH3:32]>C(Cl)Cl>[Cl:11][C:6]1[CH:5]=[C:4]([C:2]2[O:3][C:42](=[O:43])[C:41]([S:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[CH:31]([CH3:32])[CH3:33])=[C:45]([OH:46])[CH:1]=2)[CH:9]=[C:8]([Cl:10])[CH:7]=1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1cc(Cl)cc(Cl)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2cc(Cl)cc(Cl)c2)oc1=O
Yield: 70 %

Procedure:
The title compound was prepared by Method A using 3,5-dichloroacetophenone (2 g, 10.58 mmol), trimethylsilyl triflate (2.35 g, 10.58 mmol), triethylamine (2.14 g, 21.16 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (1.64 g, 5.29 mmol). Isolated yield: 70% m.p. 168°-169° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, 6H), 3.42 (m, 1H), 6.92 (d, 1H), 7.01 (s, 1H), 7.06 (t, 1H), 7.13 (t, 1H), 7.28 (d, 1H), 7.83 (m, 1H), 7.88 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][C:15]([CH3:20])([NH:17][CH:18]=O)[C:14]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.C(Cl)(Cl)=O>C(Cl)Cl>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][C:15]([CH3:20])([N+:17]#[C-:18])[C:14]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CC1(NC=O)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Agent: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [C-]#[N+]C1(C)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Yield: 17.2 %

Procedure:
To 4.5 g (10 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-methyl-4-(N-formylamino)-4,5-dihydro-1H-pyrazole-1-carboxamide (Example 64) and 3.4 ml (23 mmole) of triethylamine in 25 ml of methylene chloride at reflux was slowly added 5.5 ml of a 2.0M solution of phosgene in methylene chloride. After refluxing for 30 minutes the mixture was twice washed with water, dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and chromatographed on silica gel using diethyl ether and hexanes to yield 0.7 g of the title compound, a yellow solid, mp 171°-173° C.
Reaction SMILES: [OH-:1].[K+].OO.[CH2:5]([NH:9][C:10]([N:12]1[C:16]([CH3:17])=[CH:15][C:14]([O:18][C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=2)=[N:13]1)=S)[CH2:6][CH2:7][CH3:8].Cl>CO>[CH2:5]([NH:9][C:10]([N:12]1[C:16]([CH3:17])=[CH:15][C:14]([O:18][C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=2)=[N:13]1)=[O:1])[CH2:6][CH2:7][CH3:8]
Reactant: [OH-]
Reactant: CCCCNC(=S)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CO
Product: CCCCNC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 18 %

Procedure:
Potassium hydroxide (0.42 g, 7.5 mmol) and 30% hydrogen peroxide (2.7 ml) were added to a solution of N-butyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carbothioamide (0.98 g, 2.5 mmol) in methanol (10 ml), and the mixture was stirred at room temperature for 3 hours. Concentrated hydrochloric acid was added to the reaction mixture up to a pH of 1, and the mixture was further stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (15 ml×3), and the organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10→1/1), to give a colorless viscous substance of N-butyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (0.17 g, yield: 18.1%). 1H-NMR (CDCl3, TMS, ppm): δ 0.94 (t, J=7.3 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 2.65 (s, 3H), 3.35 (dt, J=6.3 and 6.3 Hz, 2H), 6.04 (s, 1H), 6.90-7.20 (m, 1H), 8.02 (d, J=2.0 Hz, 1H), 8.35 (m, 1H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].OS(O)(=O)=O.[CH3:10][O:11][C:12]1[C:13]([F:23])=[C:14]([CH:18]=[C:19]([F:22])[C:20]=1[F:21])[C:15]([OH:17])=[O:16]>>[CH3:10][O:11][C:12]1[C:13]([F:23])=[C:14]([C:18]([N+:1]([O-:4])=[O:2])=[C:19]([F:22])[C:20]=1[F:21])[C:15]([OH:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: COc1c(F)c(F)cc(C(=O)O)c1F
Agent: O=S(=O)(O)O
Product: COc1c(F)c(F)c([N+](=O)[O-])c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
5.0 mL of conc. HNO3 at 0° C. was slowly treated with 10.0 mL of conc. H2SO4, then 4.12 g (20 mmol) of 3-methoxy-2,4,5-trifluoro-benzoic acid. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was poured in to a beaker containing ice. The resulting solid was collected by filtration, washed with cold water and dried to produce 4.0 g (16 mmol, 80%) of 3-methoxy-6-nitro-2,4,5-trifluoro-benzoic acid. LCMS: 252 (M+1)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:4]([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH2:14][CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][C@H:17]4[CH3:21])=[CH:11][C:10]=3[CH:22]=2)=[O:5])=[CH:27][CH:26]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Product: C[C@@H]1CCCN1CCc1cc2cc(C(=O)c3ccc(Cl)cc3)ccc2o1

Procedure:
The product from Example 71E and 4-chlorophenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.18 (d, 3H, J=6.1 Hz), 1.46 (m, 1H), 1.78 (m, 2H), 2.01-2.36 (m, 2H), 2.50 (m, 2H), 3.03 (m, 2H), 3.23 (m, 2H), 6.67 (s, 1H), 7.57 (m, 3H), 7.78 (m, 3H), 7.97 (s, 1H); MS (ESI) m/z 368.1 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:18]Br)=[C:8]2[C:13]([Cl:14])=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].O.C([O-])(O)=[O:22].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:18][OH:22])=[C:8]2[C:13]([Cl:14])=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1CBr
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1CO
Temperature: 50 °C
Reaction time: 72 h
Yield: 100.1 %

Procedure:
To a solution of compound 16A (102 mg, 0.30 mmol) in THF (12 mL) was added water (3 mL) dropwise. The reaction was kept at room temperature for 3 days and then heated to 50° C. for 3 hours. Upon cooling to room temperature, NaHCO3 (70 mg) was added to the reaction mixture. The reaction was concentrated to dryness, redissolved in CH2Cl2 and filtered. The filtrate was concentrated to give compound 16B as a yellow solid (84 mg, 100%). This compound was used in the following steps without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH3:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:23][C:24]2[CH:25]=[C:26]([CH3:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=2)[C:9]2[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(C(C)C)cc1C(O)c1ccc(Cl)cc1
Reactant: Cc1cc(N)cn(C)c1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(C(C)C)cc1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-isopropyl-1H-pyrazole-3-carboxylate (Step 41.3) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.40 min (HPLC 1); tR: 1.02 min (LC-MS 2); ESI-MS: 443 [M+H]+ (LC-MS 2); Rf=0.06 (EtOAc).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C1COCC1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:21]=1>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:29]1[CH2:30][CH2:31][N:26]([C:22]2[N:21]=[C:20]([O:19][CH3:18])[CH:25]=[CH:24][N:23]=2)[CH2:27][CH2:28]1)=[O:12]
Reactant: COc1ccnc(N2CCNCC2)n1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccnc(N2CCN(C(=O)c3cc4ccccc4[nH]3)CC2)n1
Reaction time: 8 h

Procedure:
To a solution of 0.83 g (5.15 mmol) of indol-2-carboxylic acid in 15 mL of dry THF 0.83 g (5.15 mmol) of N,N′-carbonyldiimidazol is added. After 30 minutes 1.0 g (5.15 mmol) of 4 methoxy-2-(1-piperazinyl) pyrimidine is added to the solution and it is left overnight with continuous stirring. The solvent is eliminated under reduced pressure and H2O added. This produces a precipitate which is filtered and dried, to give 1.7 g (5.04 mmol) of 2-[4-(2-indolylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine. m.p.=202-203° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4](CC#N)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:15][C:16]([OH:18])=[O:17]>O.OS(O)(=O)=O>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH2:15][C:16]([OH:18])=[O:17])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CC(=O)O
Reactant: COc1cc(Br)c(OC)c(CC#N)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc(Br)c(OC)c(CC(=O)O)c1
Yield: 55 %

Procedure:
A solution of (3-Bromo-2,5-dimethoxy-phenyl)-acetonitrile 54 (5.2 g, 20.4 mmol) in water (10 ml), conc H2SO4 (10 ml), and AcOH (30 ml) was heated to 100° C. After 3 hr the reaction was cooled; and poured into water. The aqueous layer was extracted with EtOAc which was then dried over MgSO4, filtered and concentrated. The product was purified by column chromatography on silica gel (50% EtOAc/Hex) to give a solid (2.8 g, 55%): Mp=62–65° C.; 1H NMR (DMSO-d6) δ 12.45 (br s, 1 H), 7.09 (d, 1 H, J=2.9 Hz), 6.87 (d, 1 H, J=3.0 Hz), 3.72 (s, 3 H), 3.66 (s, 3 H), 3.59 (s, 2 H); MS 273/27 (M−H)−.
Reaction SMILES: C[C:2]1([CH2:10][CH2:11][CH3:12])[NH:6][S:5](=[O:8])(=[O:7])[NH:4][C:3]1=[O:9].[C:13]1([CH2:19]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:13]1([CH2:19][N:4]2[C:3](=[O:9])[CH:2]([CH2:10][CH2:11][CH3:12])[NH:6][S:5]2(=[O:7])=[O:8])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: CCCC1(C)NS(=O)(=O)NC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Product: CCCC1NS(=O)(=O)N(Cc2ccccc2)C1=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a mixture of 4-methyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (8.25 g, 42.92 mmol) in 80 ml of dry DMF was added phenylmethyl bromide (8.08 g, 47.21 mmol) and tetrabutylammonium bromide (2.08 g, 6.64 mmol) in one portion. The resulting mixture was heated at 120° C. for 8 hours and then stirred at room temperature overnight. The mixture was cooled, poured over ice-water (400 ml), and the mixture was extracted with ethyl acetate (2×250 ml). The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The brown residual oil was purified by flash chromatography (silica gel; 25% ethyl acetate in hexane) to afford 9.34 g (77.1%) of 2-phenylmethyl-4-methyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula IX: R1 =propyl; R2 =CH3) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([N+:21]([O-])=O)=[C:16]([CH3:24])[N:15]=2)=[N:6]1.[H][H]>N1C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[C:16]([CH3:24])[N:15]=2)=[N:6]1
Reactant: Cc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccncc1
Product: Cc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1N

Procedure:
592 mg (1.56 mmol) of the compound from example 53A were initially charged in pyridine (25 ml) and then 133 mg (0.125 mmol) of palladium (10% on charcoal) were added. The mixture was stirred at standard hydrogen pressure overnight. The suspension was then filtered through Celite and the filtercake was washed with methanol. The filtrate was concentrated, methanol was added and the mixture was filtered and concentrated again. The residue was dried under high vacuum. This gave 396 mg of the title compound (80% purity, 45% of theory), which were converted without further purification.