Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[OH-].[Na+]>[C:11]1([S:17]([O:1][N:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: On1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: O=S(=O)(On1nnc2ccccc21)c1ccccc1
Yield: 85.5 %

Procedure:
In 1 N aqueous sodium hydroxide (49 ml) is dissolved 1-hydroxy-1,2,3-benzotriazole (6.6 g) (pH 6.8). To the solution is added dropwise benzenesulfonyl chloride (8.8 g) with stirring under ice-cooling and the mixture is stirred for 1 hour. The reaction mixture is extracted with ethyl acetate and the extract is washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off. The crystalline residue is cracked well in n-hexane and separated by filtration and dried to give 1-benzenesulfonyloxy-1,2,3-benzotriazole (11.5 g), melting point: 83°-84° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:24]=2[CH2:23][CH2:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:30]([C:28]1[CH:27]=[CH:26][C:25]2[O:21][CH2:22][CH2:23][C:24]=2[CH:29]=1)=[O:31]
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc2c(c1)CCO2
Product: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1NC(=O)c1ccc2c(c1)CCO2

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 2,3-dihydro-benzofuran-5-carboxylic acid. MS: 420.3 (M+H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:22]=[CH:21][CH:20]=[CH:19][C:16]=2[C:17]#[N:18])[CH2:11][CH2:10]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Br:1][C:20]1[CH:21]=[N:22][C:15]([N:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)=[C:16]([CH:19]=1)[C:17]#[N:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1cccnc1N1CCOCC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)cnc1N1CCOCC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 84.7 %

Procedure:
N-bromosuccinimide (141 mg) was added to a DMF (3 ml) solution containing 2-morpholinonicotinonitrile (100 mg), followed by stirring at 80° C. for 5 hours. The reaction solution was adjusted to room temperature. Then, aqueous saturated sodium thiosulfate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1 to 7:3), and a light yellow solid of 5-bromo-2-morpholinonicotinonitrile (120 mg) was thus obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=[CH2:16])[CH2:10][CH2:9]1)=O)(C)(C)C.B1C2CCCC1CCC2.C(=O)([O-])[O-].[K+].[K+].Br[N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[NH:35][O:34]1>C1COCC1.CCOC(C)=O.CN(C=O)C>[NH:33]1[O:34][N:35]([CH2:16][CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]1=2
Reactant: C=CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrN1ONc2ccccc21
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)NON2CCCC1CCNCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 1-t-butoxycarbonyl-4-(prop-2-enyl)piperidine (330 mg, 1.46 mmol, from EXAMPLE 33, Step B) in 0.5 mL dry THF was cooled to 0° C. and a solution of 9-BBN (3.2 mL, 0.5 M in THF, 1.61 mmol) was added. The mixture was warmed to rt and stirred for 5 h. Potassium carbonate (405 mg, 2.93 mmol), 1,2-bis(diphenylphosphino) ferrocenyl palladium dichloride (60 mg, 0.073 mmol) and 3-bromobenzofurazan (292 mg, 1.46 mmol, from EXAMPLE 33, Step C) were added followed by 5 mL of dry DMF. The resulting mixture was heated to 55° C. overnight then diluted with 50 mL EtOAc. The solution was washed with H2O (3×) and sat'd NaCl then dried over Na2SO4 and concentrated. Flash chromatography (15 g silica, 5:1 v/v hexane/EtOAc eluant) afforded the 1-t-butoxycarbonyl derivative of the title compound. Heating in 1% conc. HCl/MeOH at 50° C. for 2h followed by removal of solvent and drying under vacuum afforded 155 mg (38%) of the title compound: 1H NMR (300 MHz, CD3OD) δ 1.31-1.42 (m, 4H), 1.6-1.75 (m, 1H), 1.842.0 (m, 4H), 2.9-3.1 (m, 4H), 3.3-3.4 (m, 2H), 7.25-7.3 (d, 1H), 7.47.5 (dd, 11), 7.7-7.75 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:14]N1C(=O)CCC1=O.ClCCl>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:14][CH2:12][C:10]1[C:9]([F:13])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(F)c(C)cc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(F)c(CBr)cc1F
Temperature: 85 °C
Yield: 104.9 %

Procedure:
A solution of methyl 2,5-difluoro-4-methylbenzoate (Preparation 2, 500 mg, 2.69 mmol), N-bromosuccinimide (526 mg, 2.96 mmol) and dibenzoyl peroxide (20 mg, 0.08 mmol) dissolved in carbon tetrachloride (10 mL) was heated to reflux at 85° C. for 18 hours. The mixture was cooled to room temperature, dichloromethane (20 mL) added and the mixture poured into a separating funnel. The resulting organic layer was separated and washed successively with water (20 mL) and aqueous sodium thiosulphate solution (20 mL). The organic layer was dried over magnesium sulphate and filtered. The solvent was removed under reduced pressure to give an oil (748 mg). The crude product was purified by flash column chromatography (Biotage™ 50 g silica cartridge) eluting with 10% ethyl acetate in heptane to give the title compound (479 mg, 67%) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([CH3:15])=[CH:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].ClC(OCC)=O.[CH3:22][CH:23]([NH2:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>ClCCl.C(N(CC)CC)C>[CH3:22][CH:23]([NH:33][C:12](=[O:14])[CH:11]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:15])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CC(=CC(=O)O)c1cccc([N+](=O)[O-])c1
Reactant: CCCCCCCCCC(C)N
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(C)NC(=O)C=C(C)c1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
To a stirred slurry of 5.2 g. of the 3-(3-nitrophenyl)-2-butenoic acid from Preparation 12 having a melting point of 208°-210° C., in 100 ml. of dichloromethane, was added 2.8 g. of triethylamine in 10 ml. of dichloromethane. This was followed by the addition of a solution of 3.0 g. of ethyl chloroformate in 20 ml. of dichloromethane, during 20 minutes. Stirring was continued for 30 minutes, and then a solution of 1-methyldecylamine in 20 ml. of dichloromethane was added dropwise during 25 minutes. Stirring was continued overnight, and the reaction mixture was washed successively with 1 N potassium carbonate, water and saturated sodium chloride. The resulting solution was dried using sodium sulfate, and then it was evaporated in vacuo leaving an oil which solidified on trituration under petroleum ether. This afforded 4.9 g. of the title compound, m.p. 72.5°-74° C.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=1>O>[Cl:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:7]([C:5]3[O:6][C:2]([Br:1])=[CH:3][CH:4]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)c1ccc(Br)o1
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccc(Br)o1
Yield: 73.6 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 5-bromo-2-furancarboxylic acid (2.9 g), N,N'-carbonyldiimidazole (2.4 g) and 2-amino-7-chloro-1,8-naphthyridine (1.8 g). The product obtained by precipitation in water is purified by recrystallization in a dimethylformamide/methanol (5:5 by volume) mixture (100 cc). N-(7-Chloro-1,8-naphthyridin-2-yl)-5-bromo-2-furancarboxamide (2.6 g), m.p. 285° C., is thereby obtained.
Reaction SMILES: [P:1]([CH2:5][NH:6][CH2:7][C:8]([OH:10])=[O:9])([OH:4])([OH:3])=[O:2].C(N(CP(O)(O)=O)[CH2:14][C:15]([OH:17])=[O:16])=O>>[P:1]([CH2:5][N:6]([CH2:14][C:15]([OH:17])=[O:16])[CH2:7][C:8]([OH:10])=[O:9])([OH:4])([OH:3])=[O:2]
Reactant: O=CN(CC(=O)O)CP(=O)(O)O
Reactant: O=C(O)CNCP(=O)(O)O
Product: O=C(O)CN(CC(=O)O)CP(=O)(O)O

Procedure:
The percent selectivity to N-phosphonomethylglycine was determined by dividing the moles of N-phosphonomethylglycine and N-formyl-N-phosphonomethylglycine produced by the total moles of N-phosphonomethyliminodiacetic acid consumed and multiplying by 100. The percent conversion of N-phosphonomethyliminodiacetic acid was determined by dividing the moles of N-phosphonomethyliminodiacetic acid that were reacted by the total moles of starting N-phosphonomethyldiacetic acid and multiplying by 100.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=2)[C:4]1=[O:14].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(NC(C)C)(C)C.Cl>ClCCl>[CH3:13][O:12][C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][CH:3]([NH:2][C:16](=[O:17])[O:18][CH2:19][CH3:20])[C:4]2=[O:14])=[CH:9][CH:8]=1
Reactant: CCOC(=O)Cl
Reactant: COc1ccc2c(c1)C(=O)C(N)C2
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCOC(=O)NC1Cc2ccc(OC)cc2C1=O
Temperature: 25 °C

Procedure:
To a suspension of 2-amino-6-methoxy-2,3-dihydro-1H-inden-1-one hydrochloride (15.4 g, 72.1 mmol) in dichloromethane was added ethyl chloroformate (10.38 ml, 108 mmol) followed by dropwise addition of a solution of diisopropylamine (25.2 ml, 144 mmol) in 10 ml dichloromethane. The reaction mixture was stirred at room temperature over night. Added 1N hydrochloric acid, diluted with dichloromethane, separated organic layer and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed subsequently with water, sodium bicarbonate and brine, dried, filtered and evaporated to obtain the product (ethyl 6-methoxy-1-oxo-2,3-dihydro-1H-inden-2-ylcarbamate) as a purple solid. m=16.4 g (95%)
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:11]1[C:19](=[O:20])[N:18]2[C@@H:12]1[CH2:13][C:14](=O)[CH2:15][CH:16]=[C:17]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.F[C:45](F)(F)[S:46](OS(C(F)(F)F)(=O)=O)(=O)=O>C(#N)C>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:19](=[O:20])[N:18]2[C@@H:12]1[CH2:13][C:14]([S:46][CH3:45])=[CH:15][CH:16]=[C:17]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCC(=O)C[C@H]12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CSC1=CC=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2C1
Temperature: -40 °C
Reaction time: 0.08 h
Yield: 48.7 %

Procedure:
To a solution of 4-nitrobenzyl (7R,8S)-8-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-5,9-dioxo-1-azabicyclo[5.2.0]non-2-ene-2-carboxylate (1.5 g, 3.07 mmol) in acetonitrile (15 ml) was added at 0° C. N,N-diisopropylethylamine (1.1 ml, 6.45 mmol). The reaction mixture was cooled at -40° C. and trifluoromethanesulfonic anhydride (0.57 ml; 3.38 mmol) was added. After 5 minutes, further N,N-diisopropylethylamine (1.1 ml, 6.45 mmol) was added to the reaction mixture. Methylmercaptan was then bubbled through the solution at -40° C. during a few seconds. The mixture was allowed to warm to ambient temperature over 1.5 hours. The solvent was evaporated and the residue purified by chromatography on silica gel eluting with ethyl acetate/dichloromethane 3:97 to give 4-nitrobenzyl (7R,8S)-8-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]5-methylthio-9-oxo-1-azabicyclo[5.2.0]non-2,4-diene-2-carboxylate (776 mg, 47%).
Reaction SMILES: CI.[C:3]123[CH2:16][CH2:15][CH2:14][C:8]1([C:9](=O)[NH:10][C:11]2=O)[CH:7]1[CH2:17][CH:4]3[CH:5]=[CH:6]1.N.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[C:8]123[CH2:14][CH2:15][CH2:16][C:3]1([CH2:11][NH:10][CH2:9]2)[CH:4]1[CH2:17][CH:7]3[CH:6]=[CH:5]1
Reactant: O=C1NC(=O)C23CCCC12C1C=CC3C1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: CI
Product: C1=CC2CC1C13CCCC21CNC3

Procedure:
Template A is synthesized by quaternization of 8-aza-8-ethyltetracyclo[4.3.3.12,5.01,6]tridec-3-ene with methyl iodide. Templates C-E are all made using the methodology described above. The parent imide, 8-aza-tetracyclo[4.3.3.12,5.01,6]tridec-3-ene-7,9-dione, is synthesized by reacting the tetracyclic anhydride with ammonia, which upon LiAlH4-reduction yields the unsubstituted secondary cyclic amine, 8-aza-tetracyclo[4.3.3.12,5.01,6]tridec-3-ene. Quaternization of this amine with the appropriate dihalide in the presence of KHCO3 yields the desired template (Template C from 1,4-diiodobutane, Template D from 1,5-diiodobutane, and Template E from 2-methyl-1,4-diiodobutane). It is to be anticipated that other derivatives can be prepared by the choice of the imide forming reagent coupled with choices for the alkylation step.
Reaction SMILES: [Cl:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1.C(O)C.O.[BH4-].[Na+]>O1CCCC1>[Cl:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2Cl
Temperature: -55 °C
Reaction time: 7 h
Yield: 34 %

Procedure:
A solution of 380 mg of 11β-chloro-7α-methyl-estr-4-ene-3,17-dione (F′) in 7.6 ml of tetrahydrofuran, 4.4 ml of ethanol and 1.15 ml of water was mixed at −55° C. in portions with 596 mg of sodium borohydride and stirred for 7 hours at −55° C. Then, the mixture was added to ice water, extracted three times with ethyl acetate, washed neutral, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 130 mg of pure 11β-chloro-17β-hydroxy-7α-methyl-estr-4-en-3-one (I) was obtained ([α]D20=+136.9° (in chloroform), FD183.2° C.).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.O[NH:38][C:39](=[NH:48])[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][OH:47])=[CH:42][CH:41]=1>CN(C=O)C.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:13]1[O:15][N:48]=[C:39]([C:40]2[CH:45]=[CH:44][C:43]([CH2:46][OH:47])=[CH:42][CH:41]=2)[N:38]=1
Reactant: Nc1c(C(=O)O)cnn1-c1ccccc1
Reactant: N=C(NO)c1ccc(CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(-c2nc(-c3ccc(CO)cc3)no2)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
5-Amino-1-phenyl-1H-pyrazole-4-carboxylic acid (1.8 g, 8.86 mmol), HOBt (1.357 g, 8.86 mmol) and EDCI (1.698 g, 8.86 mmol) were dissolved in DMF (12 mL) under nitrogen at room temperature. The resulting clear, pale yellow solution was stirred for 30 minutes then N-hydroxy-4-(hydroxymethyl)benzimidamide (1.472 g, 8.86 mmol) was added in several portions. The reaction was placed in an oil bath set to 130° C. After 4 hours, the solution was cooled to RT and then added to rapidly stirring water (50 mL). The initial precipitate was stirred and sonicated to give a yellow solid which was collected by filtration, washed with water, air dried and then dried under vacuum to afford (4-(5-(5-amino-1-phenyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)methanol (1.5 g 4.05 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S(=O)(=O)(O)O.[CH3:27]O>>[CH3:27][O:14][C:13]([C:6]1[NH:7][C:8](=[O:12])[C:9]2[C:4]([C:5]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)=[O:15]
Reactant: CO
Reactant: O=C(O)c1[nH]c(=O)c2ccc(Br)cc2c1-c1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1[nH]c(=O)c2ccc(Br)cc2c1-c1ccccc1

Procedure:
To the obtained 6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid were added methanol (400 ml) solution and sulfuric acid (40 ml) and the mixture was refluxed for 20 hrs. The reaction mixture was concentrated, and the residue was neutralized with aqueous potassium carbonate solution and extracted with chloroform. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to give the title compound (6.51 g) as colorless crystals.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[CH:10]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1(C2C=C(OC)C=C(OC)C=2)[S:27][CH2:26][CH2:25][S:24]1)CCC>CCCCCC.C(OCC)(=O)C>[CH:1]1([C:7]2([C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[CH:10]=3)[S:27][CH2:26][CH2:25][S:24]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(OC)cc(C(=O)C2CCCCC2)c1
Reactant: CCCCC1(c2cc(OC)cc(OC)c2)SCCS1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(OC)cc(C2(C3CCCCC3)SCCS2)c1

Procedure:
Compound 11 was prepared from Compound 7 using the same procedure as described above for Compound 9. Yield 16.8 g (89.6%) as an oil. Rf=0.43 (hexane:ethyl acetate 92:8); IR (neat) 2930, 1198, 1062, 698 cm−1; 1H NMR δ 6.94 (d, J=2.4 Hz, 2H), 6.33 (t, J=2.25 Hz, 1H), 3.80 (s, 6H), 3.33–3.09 (m, 4H), 2.17–2.09 (m, 1H), 1.92–1.88 (m, 2H), 1.73–1.58 (m, 3H), 1.27–0.97 (m, 5H). 13C NMR δ 160.20, 148.17, 107.00, 98.59, 80.97, 55.60, 50.71, 39.07, 31.18, 26.91, 26.35; MS: (ESI, Pos.) m/z 347 ([M+23]+).
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[CH:15][O:14][N:13]=2)=[CH:8][CH:7]=1)([O-])=O>O.C1COCC1.[Zn]>[O:14]1[CH:15]=[N:16][C:12]([C:9]2[CH:10]=[CH:11][C:6]([NH2:3])=[CH:7][CH:8]=2)=[N:13]1
Reactant: O=[N+]([O-])c1ccc(-c2ncon2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(-c2ncon2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
Ammonium chloride (214 mg, 4 mmol) in water (5 mL) was added to a stirred solution of 3-(4-nitro-phenyl)-[1,2,4]oxadiazole (200 mg, 1 mmol) in THF (15 mL). Zinc powder (262 mg, 4 mmol) was then added portion wise. The reaction was stirred at room temperature for 1 hour and then refluxed at 65° C. for 5 hours. The mixture was filtered over celite, the filtrate was evaporated and the residue was extracted with ethyl acetate. The ethyl acetate was washed with brine solution, dried over Na2SO4 and evaporated to afford 155 mg (92%) of 4-[1,2,4]oxadiazol-3-yl-phenylamine. 1H NMR: (DMSO-d6): δ 9.5 (s, 1H), 7.7 (d, 2H), 6.7 (d, 2H), 5.8 (s, 2H).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH3:9][N:10]([CH:12](OC)OC)[CH3:11]>CC#N>[CH3:9][N:10]([CH:12]=[C:2]1[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]1=[O:8])[CH3:11]
Reactant: COC(OC)N(C)C
Reactant: O=C1CCCC(=O)C1
Solvent: CC#N
Product: CN(C)C=C1C(=O)CCCC1=O

Procedure:
A MeCN solution of cyclohexane-1,3-dione 2.24 g (0.02 mol) i and DMF-DMA 11.9 g (0.1 mol) was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the product was used for the next step with no purification.
Reaction SMILES: C([Li])(CC)C.[C:6]([OH:16])(=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.CN(CCN(C)C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[C:29](OCC)=[O:30]>>[F:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[C:29]([C:8]1[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=1[C:6]([OH:16])=[O:15])=[O:30]
Reactant: CCOC(=O)c1cccc(F)c1
Reactant: COc1ccc(C(=O)O)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Product: COc1ccc(C(=O)O)c(C(=O)c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
s-Butyllithium (52 mL, 1.4 M in pentane, 72 mmol) was added at −78° C. over 90 min. to a solution of p-anisic acid (5 g, 33 mmol) and TMEDA (11 ml, 72 mmol) in THE (80 mL). After stirring for 15 min., ethyl 3-fluorobenzoate (5 mL, 40 mmol) was added in one portion. The reaction mixture was stirred for 15 min. then it was quenched with water (20 mL). The reaction mixture was then warmed to room temperature and poured into water (1.5 L) 1N NaOH (30 ml) was added and the reaction mixture was then extracted with EtOAc. The extracts were discarded. The aqueous phase was then acidified with conc. HCl to pH 1 and extracted with EtOAc. Drying (Na2SO4) and concentration gave a residue which was recrystallized from hexanes/EtOAc to give the title compound 59 as a white solid.
Reaction SMILES: [CH3:1][C@@:2]([S:27]([CH3:30])(=[O:29])=[O:28])([CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH3:26])=[N:16]1)[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CCO>[OH:6][NH:5][C:3](=[O:4])[C@:2]([CH3:1])([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH3:26])=[N:16]1
Reactant: Cc1nn(CC[C@](C)(C(=O)NOC2CCCCO2)S(C)(=O)=O)cc1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: Cc1nn(CC[C@](C)(C(=O)NO)S(C)(=O)=O)cc1-c1ccccc1
Yield: 36 %

Procedure:
To a solution of (2R)-2-methyl-4-(3-methyl-4-phenyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (110 mg, 0.253 mmol) in EtOH (5 mL) was added PPTS (20 mg, 0.080 mmol) and the mixture was heated at reflux for 3 h. The solution was concentrated to afford a crude white solid which was purified via flash chromatography using an Analogix SF10-8 g silica column eluting with ethyl acetate in heptane (50-80%) to give (2R)—N-hydroxy-2-methyl-4-(3-methyl-4-phenyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)butanamide (32 mg, 36% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.54-7.25 (m, 1H), 4.39-4.21 (m, 2H), 3.04 (s, 3H), 2.91-2.77 (m, 1H), 2.59-2.46 (m, 1H), 2.43 (s, 3H), 1.71 (s, 3H). LC-MS M+H+352.1.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][C:12](=[O:17])[N:13]([CH3:16])[C:14](=[O:15])[C:9]2=[N:8][C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](OC3C=CC=CC=3)[CH:19]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4].C(=O)C1C=CC=CC=1>>[CH2:1]([N:5]1[C:10]2=[N:11][C:12](=[O:17])[N:13]([CH3:16])[C:14](=[O:15])[C:9]2=[N:8][C:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(-c2cccc(Oc3ccccc3)c2)nc2c(=O)n(C)c(=O)nc1-2
Solvent: O=Cc1ccccc1
Product: CCCCn1nc(-c2ccccc2)nc2c(=O)n(C)c(=O)nc1-2

Procedure:
Compound 22 is prepared, as described in 4, by reacting the hydrazine 20 (176 mg, 0.54 mmol) with benzaldehyde (55 μl, 0.54 mmol).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][N:6]([C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[CH3:7])C.[OH-].[Na+]>CCO>[N:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][C:8]([N:6]([CH2:5][C:4]([OH:19])=[O:3])[CH3:7])=[O:18])=[CH:17][CH:16]=1
Reactant: CCOC(=O)CN(C)C(=O)CCCc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(CC(=O)O)C(=O)CCCc1ccncc1
Reaction time: 8 h

Procedure:
Ester 6-1 (324 mg, 1.22 mmol) was dissolved in 6 mL EtOH, then 1 N NaOH (2.4 mL, 2.4 mmol) was added. After stirring overnight the mixture was concentrated, rediluted with EtOAc, extracted into 10% KHSO4, then concentrated, providing acid 6-2, along with inorganic salts.