Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([C@H:9]([C:11](=[O:30])[NH:12][C@H:13]([C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][CH:20]1[CH2:28][OH:29])=[O:18])[CH:14]([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:39](Cl)([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40]>C(Cl)Cl>[C:1]([O:5][C:6]([N:7]([CH3:8])[C@@H:9]([CH3:10])[C:11]([NH:12][C@@H:13]([CH:14]([CH3:16])[CH3:15])[C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C@H:20]1[CH2:28][O:29][S:39]([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40])=[O:18])=[O:30])=[O:31])([CH3:2])([CH3:4])[CH3:3].[C:1]([O:5][C:6]([N:7]([CH3:8])[C@@H:9]([CH3:10])[C:11]([NH:12][C@@H:13]([CH:14]([CH3:16])[CH3:15])[C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C@@H:20]1[CH2:28][O:29][S:39]([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40])=[O:18])=[O:30])=[O:31])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2CC1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2Cc3cccnc3N2C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C)cc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2Cc3cccnc3N2C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 25 °C

Procedure:
To a solution of {(S)-1-[(S)-1-(2-hydroxymethyl-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl)-2-methyl-propylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (4.5 g, 10.36 mmol) in DCM (150 mL), was added triethylamine (4.25 mL, 31.106 mmol) followed by the slow addition of tosyl chloride (3.0 g, 15.55 mmol) at 0° C. The reaction mixture was stirred at rt for 16 hand then the reaction mixture was concentrated in vacuo. Water was added to the residue and the resulting mixture was extracted with EtOAc (300 mL×2). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel, 18% EtOAc in hexanes) to give toluene-4-sulfonic acid (S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyryl}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl ester (2.7 g) and toluene-4-sulfonic acid (R)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyryl}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl ester (1 g), m/z=589 (M+H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]1([NH:15][N:16]=[CH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[Cl:1][N:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[N:16]=[CH:17][C:18]1[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=1
Reactant: C(=NNc1ccccc1)c1ccncc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: ClN(N=Cc1ccncc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.4 %

Procedure:
N-Chlorosuccinimide (2.11 g, 16 mmol) was added portionwise to a solution of compound 1 (2.97 g, 15 mmol) in DMF (15 mL). The reaction mixture was stirred for 10 min at room temperature. The resulting precipitates were collected and washed with petroleum ether to afford 1.82 g (52%) of 2 as a solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH2:13])=[O:12])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[C:16](OCC)(=[O:22])[C:17](OCC)=[O:18].CC(C)([O-])C.[K+].Cl>CN(C)C=O.O>[CH2:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][C:10]2[C:11](=[O:12])[NH:13][C:17](=[O:18])[C:16]=2[OH:22])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)Cc1ccc(OCC(N)=O)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Cc1ccc(OC2=C(O)C(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-acetonylphenoxyacetamide, ethylene ketal (3.2 g) and diethyl oxalate (2.0 g) in dry dimethylformamide at 0° C. was treated with potassium tert-butoxide (3.24 g) in two portions at 15 min. intervals. The solution was then stirred 16 h at ambient temperature, poured into water, and acidified with 6N hydrochloric acid. The aqueous solution was extracted with ethyl acetate, the combined organic extracts dried (magnesium sulphate), filtered and evaporated and the residue crystallised from acetone/ether to give 4-[4-acetonylphenoxy]-3-hydroxy-1H-pyrrole-2,5-dione, (1.5 g).
Reaction SMILES: [O-]Cl=O.[Na+].[CH2:5]([O:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[C:16]([F:22])[CH:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(=O)(=O)([OH:26])N.Cl>O.CC#N>[CH2:5]([O:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:26])=[O:21])=[C:16]([F:22])[CH:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NS(=O)(=O)O
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(C(=O)O)c(F)c1
Reaction time: 1 h

Procedure:
A solution of 80% NaClO2 (0.19 mol) in H2O (100 mL) is added dropwise to a solution of crude 3-fluoro-4-formyl benzoic acid benzyl ester (6, 0.19 mol) and sulfamic acid (0.19 mol) in H2O (300 mL) and CH3CN (150 mL). After stirring for 1 h, the reaction mixture is poured into 1 N HCl and extracted three times with EtOAc. The combined organic layers are washed with brine, dried over MgSO4, and evaporated in vacuo. Crystals are collected by filtration and washed with ether/hexane (1:1) to give 2-fluoroterephthalic acid 4-benzyl ester (7) as white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=O.[CH:19]([NH:22][CH:23]([CH3:25])[CH3:24])([CH3:21])[CH3:20]>>[CH2:10]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:9][CH2:17][N:22]([CH:23]([CH3:25])[CH3:24])[CH:19]([CH3:21])[CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)NC(C)C
Reactant: C=O
Product: CC(C)N(CON(Cc1ccccc1)Cc1ccccc1)C(C)C

Procedure:
The procedure of Example I is repeated using 21.33 g of dibenzylhydroxylamine, 9.73 g of aqueous formaldehyde (37%) solution and 10.12 g of diisopropylamine, to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)(=O)[CH2:2][CH3:3].[NH:11]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[NH2:12]>CO.C(O)(=O)C>[O:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[NH:11][N:12]=[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3]
Reactant: CCC(=O)c1ccccn1
Reactant: NNc1nc2ccccc2o1
Solvent: CC(=O)O
Solvent: CO
Product: CCC(=NNc1nc2ccccc2o1)c1ccccn1

Procedure:
A mixture of 2-propionyl pyridine (0.60 g, 4.42 mmol) and 2-hydrazinobenzoxazole (0.60 g 4.02 mmol) in 25 ml of methanol is refluxed for 24 hours after the addition of 6 drops of glacial acetic acid. The reaction mixture is stored over night in the refrigerator at approximately 5° C. The precipitate is filtered and recrystallized from diisopropyl ether. Yield: 0.68 g (64% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([NH2:12])[CH2:11][C:5]=2[CH:4]=1.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([O:32][Si](CC)(CC)CC)[CH2:30]I)=[CH:25][C:24]=1[NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C.S([O-])(O)=O.[Na+]>CN(C)C(=O)C>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([OH:32])[CH2:30][NH:12][CH:10]2[CH2:9][CH2:8][CH2:7][C:6]3[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH2:11]2)=[CH:25][C:24]=1[NH:40][S:41]([CH3:44])(=[O:42])=[O:43])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc2c(c1)CC(N)CCC2
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CC(NC[C@H](O)c1ccc(OCc3ccccc3)c(NS(C)(=O)=O)c1)CCC2
Yield: 20 %

Procedure:
Under nitrogen, a solution of 3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamine (720 mg), N-[2-benzyloxy-5-[(1R)-2-iodo-1-(triethylsilyloxy)ethyl]phenyl]-methanesulfonamide (2.1 g) and N,N-diisopropylethylamine (2.6 ml) in N,N-dimethylacetamide (10 ml) was stirred at 110° C. for 96 hours. The resulting mixture was poured into aqueous 10% sodium hydrogensulfite and extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=40:1 to 20:1) to give N-[2-benzyloxy-5-[(1R)-1-hydroxy-2-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamino)ethyl]phenyl]methanesulfonamide (381 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1.C([Sn](CCCC)(CCCC)[C:29]1[O:30][CH:31]=[CH:32][N:33]=1)CCC>O1CCOCC1.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>[O:30]1[CH:31]=[CH:32][N:33]=[C:29]1[C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: CCCC(CCC)N1CCc2c(C(=O)OC)cc(Br)cc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCCC(CCC)N1CCc2c(C(=O)OC)cc(-c3ncco3)cc2C1=O
Temperature: 145 °C

Procedure:
Added to a solution of 0.8 g of methyl 7-bromo-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate in 8 cm3 of dioxane, under an argon atmosphere at a temperature close to 20° C. are 308 mg of tetrakis(triphenylphosphine)palladium and 3.2 g of 2-(tri-n-butylstannyl)oxazole. The reaction medium is heated at 145° C. in a microwave oven for 15 minutes, then left to return to a temperature close to 20° C. The reaction medium is concentrated to dryness under reduced pressure (5 kPa). The residue is taken up by 5 cm3 of dichloromethane and purified by flash chromatography over silica (column: 110 g; spherical silica of BP-SUP type particle size: 20-40 μm; eluent: 90% heptane/10% ethyl acetate then 100% ethyl acetate). After concentrating the fractions under reduced pressure, 320 mg of methyl 7-(2-oxazolyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:11]=3[NH:12][CH2:13][CH2:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>N1C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:11]=3[N:12]([C:23](=[O:24])[N:22]([CH3:26])[CH3:21])[CH2:13][CH2:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)C(=O)Cl
Reactant: CCc1cc2c(s1)NCCN=C2c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Product: CCc1cc2c(s1)N(C(=O)N(C)C)CCN=C2c1ccc(Cl)c(Cl)c1
Product: Cl
Temperature: 60 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
To a suspension of 2.8 g of 5-(3,4-dichlorophenyl)-7-ethyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine in 50 ml of pyridine is added 1.3 g of dimethylcarbamoyl chloride, and stirred for 24 hours at 60° C. Then pyridine is evaporated under reduced pressure. To the residue is added acetone to crystallize. The crude crystals obtained are recrystallized from ethanol to give 1.3 g of 5-(3,4-dichlorophenyl)-7-ethyl-1-dimethylcarbamoyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine hydrochloride as pale yellow crystals, melting at 219°-221° C with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N:11]1([CH2:17][CH2:18][CH2:19][OH:20])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[H-].[Na+]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([O:20][CH2:19][CH2:18][CH2:17][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: OCCCN1CCCCC1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(OCCCN2CCCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-Chloro-4-fluorobenzonitrile (5.0 g) and 3-(1-piperidinyl)-1-propanol (3.4 g) were stirred in DMSO (70 ml) at rt under argon. Sodium hydride (60% wt in mineral oil, 1.976 g) was then added and the reaction stirred at rt for 5 h. The reaction mixture was diluted with ethyl acetate (200 ml), washed with saturated sodium hydrogen carbonate (100 ml), water (3×100 ml), brine (100 ml), dried (MgSO4) and evaporated. The crude product was then purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM)] and fractions containing pure product were combined and evaporated to give the title compound (D26) as a white solid (6.29 g). MS electrospray (+ion) 279/281 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[NH2:11].[Cu][C:14]#[N:15]>CN1CCCC1=O.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([C:14]#[N:15])[CH:7]=[CH:6][C:5]=1[NH2:11]
Reactant: N#C[Cu]
Reactant: COC(=O)c1cc(Br)ccc1N
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(C#N)ccc1N
Temperature: 25 °C
Yield: 28.4 %

Procedure:
2-Amino-5-bromobenzoic acid methyl ester (4.6 g, 20 mmol) and copper (I) cyanide (3.6 g, 40 mmol) were heated at 200° C. in N-methylpyrrolidinone (20 ml) for 4 h. After cooling to room temperature, the solution was diluted with water, extracted with ethyl acetate, the aqueous extract acidified with 2N hydrochloric acid and filtered. The organic layer was separated, dried over magnesium sulphate and evaporated. The residue was purified by flash column chromatography on silica eluting with 50% ethyl acetate in hexane to yield the title compound as a colourless oil (1.0 g). MS (+EI) m /z 176 [M+ ].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:11][C@H:10]2N)=[CH:5][CH:4]=1.[N:13]12CCCN=C1CCCCC2.[CH:24]([S:27](Cl)(=[O:29])=[O:28])([CH3:26])[CH3:25]>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][CH:10]2[CH2:25][CH:24]([S:27]([NH2:13])(=[O:29])=[O:28])[CH3:26])=[CH:5][CH:4]=1
Reactant: N[C@@H]1C[C@H]1c1ccc(Cl)cc1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: C1CCC2=NCCCN2CC1
Agent: Cl
Solvent: ClCCl
Product: CC(CC1CC1c1ccc(Cl)cc1)S(N)(=O)=O
Temperature: 0 °C
Yield: 67.6 %

Procedure:
Trans-2-(4-chlorophenyl)cyclopropanamine hydrochloride (see Bioorganic and Medical Chemistry 12(9), 2021-2034, 2004) (628 mg, 3.08 mmol) was suspended in dry dichloromethane (15 ml) and cooled to 0° C. with stirring under argon. 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.40 g, 9.225 mmol) was added, followed by the dropwise addition of isopropylsulfonyl chloride (877 mg, 6.15 mmol) with stirring under an atmosphere of argon. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was then washed with 1 N HCl (2×50 ml). The organic layer was dried over sodium sulphate and evaporated in vacuo to give a yellow oil. The crude product was chromatographed on a 5 g isolute silica Sep-Pak® column eluting from 0-50% ethyl acetate in petroleum ether to give the title compound (570 mg, 68%); mass spectrum (API−): Found 272 (MH−);
Reaction SMILES: [Br:1][CH2:2][C:3]1[O:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[C:22]1([P:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[Br-:1].[CH3:11][O:10][C:8]([C:7]1[CH:6]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[O:4][C:3]=1[CH2:2][P+:28]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:9]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1CBr
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
Methyl 2-bromomethyl-5-[4-(trifluoromethyl)phenyl]-3-furoate (intermediate 44, 0.20 g) was dissolved in toluene (3 ml) treated with triphenylphosphine (0.159 g) and heated to reflux for 1 hour. The reaction was allowed to cool and the white precipitate was collected by filtration, washed with fresh toluene to give the title compound as a white powder.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3][NH:2]1.[CH:13]([C:15]([CH3:17])=[O:16])=[CH2:14]>C(O)C>[O:16]=[C:15]([CH3:17])[CH2:13][CH2:14][N:3]1[NH:2][C:1](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:11]
Reactant: C=CC(C)=O
Reactant: O=c1[nH][nH]c(=O)c2ccccc12
Solvent: CCO
Product: CC(=O)CCn1[nH]c(=O)c2ccccc2c1=O

Procedure:
2,3-Dihydrophthalazine-1,4-dione (16.2 g; 0.1 mol) was suspended in 95 percent ethanol (200 ml). The suspension was heated to reflux and methyl vinyl ketone (8.4 g; 0.12 mol) was added to the refluxing suspension. With the ketone in the reaction mixture, the mixture was refluxed for 41 hours. The solid remaining after refluxing was filtered. The filtrate was concentrated to obtain the product which was crystallized from ethanol. The yield was determined to be 80 percent. The product had a melting point of 152°-153° C.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6](=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1.C(O)(=O)C>Cl>[CH3:15][O:14][C:11]1[C:10]([O:16][CH3:17])=[CH:9][C:8]2[CH2:7][C:6](=[O:18])[NH:5][CH:4]=[CH:3][C:13]=2[CH:12]=1
Reactant: COc1ccc(CC(=O)NCC(OC)OC)cc1OC
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)CC(=O)NC=C2
Reaction time: 17 h

Procedure:
A solution of 600.6 gm of N-(2,2-dimethoxyethyl)-3,4-dimethoxyphenyl-acetamide in 3 liters of concentrated hydrochloric acid was mixed with 3 liters of glacial acetic acid. After standing for 17 hours at room temperature, the mixture was poured over ice. The crystals precipitated thereby were suction-filtered off, washed with water until neutral and dried.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([OH:17])=[C:12]([Cl:18])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:9][C:10]1[CH:11]=[C:12]([Cl:18])[C:13]([O:17][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[Cl:19])=[C:14]([Cl:16])[CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1cc(Cl)c(O)c(Cl)c1)c1ccccc1
Reactant: ClCc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Oc1cc(Cl)c(OCc2ccccc2Cl)c(Cl)c1)c1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 87.9 %

Procedure:
A mixture of 2.27 g of 4-benzoyloxy-2,6-dichlorophenol, 1.29 g of 2-chlorobenzyl chloride, 1.21 g of potassium carbonate and 50 ml of N,N-dimethylformamide was stirred at 80° C. for 6 hours. The reaction mixture was cooled to room temperature, poured in ice water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, and dried with anhydrous magnesium sulfate, followed by removal of the solvent by distillation under reduced pressure. The residue was subjected to silica gel chromatography, which afforded 2.87 g of 1-benzoyloxy-4-(2-chlorobenzyloxy)-3,5-dichlorobenzene (88% yield).
Reaction SMILES: [CH:1]([C@H:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1)=[C:2]=[CH2:3].Cl.[OH2:11]>>[NH2:8][C@H:4]([CH:1]=[C:2]=[CH2:3])[CH2:5][CH2:6][C:7]([OH:9])=[O:11]
Reactant: O
Reactant: C=C=C[C@@H]1CCC(=O)N1
Agent: Cl
Product: C=C=C[C@@H](N)CCC(=O)O
Yield: 80 %

Procedure:
A solution of (5S)-5-(1,2-propadienyl)pyrrolidin-2-one (37) (1.1 g, 9.0 mmol), 5N HCl (10 mL) and H2O (4 mL) was heated to 80° C. for 18 hours. the solution was cooled, concentrated and neutralized to pH 6 with 1N NaOH. This solution was put on a Dowex 1×2-100 ion exchange column (OH) form. The column was rinsed with distilled H2O (800 mL) and the compound was removed with 0.5N acetic acid. Lyophilization gave (4S)-4-amino-5,6-heptadienoic acid as an off-white foamy solid (1.01 g, 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[NH2:15][C:16]1[CH:17]=[C:18](C=C[CH:33]=1)[CH2:19][CH2:20][CH2:21][NH:22][C:23]1[C:24]([C:28]([NH2:30])=[O:29])=[N:25][NH:26][CH:27]=1.[N+]([C:37]1C=C(C=C[CH:54]=1)CCCNC1C(C(N)=O)=NNC=1)([O-])=O>>[CH2:37]([N:22]([CH2:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:15][C:13]([NH:12][C:3]2[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=2[F:1])=[O:14])[CH:33]=1)[C:23]1[C:24]([C:28]([NH2:30])=[O:29])=[N:25][NH:26][CH:27]=1)[CH3:54]
Reactant: NC(=O)c1n[nH]cc1NCCCc1cccc(N)c1
Reactant: NC(=O)c1n[nH]cc1NCCCc1cccc([N+](=O)[O-])c1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: CCN(Cc1cccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c1)c1c[nH]nc1C(N)=O

Procedure:
4-(Ethyl-{3-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]benzyl}amino)-1H-pyrazole-3-carboxamide is prepared by condensing 1-fluoro-2-isocyanato-4-trifluoromethylbenzene with 4-[(3-aminobenzyl)ethylamino]-1H-pyrazole-3-carboxamide according to the procedure described in Example 34, the latter derivative itself being prepared from 4-[(3-nitrobenzyl)ethylamino]-1H-pyrazole-3-carboxamide according to the procedure also described in Example 34.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[C:4]([CH:27]=[O:28])[CH:3]=1.[C:29](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:29])=[O:16])=[C:4]([CH:27]=[O:28])[CH:3]=1
Reactant: COc1ccc(CN(CCCCCCC(=O)O)c2ccc(Br)cc2C=O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCCN(Cc1ccc(OC)cc1)c1ccc(Br)cc1C=O
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of 7-((4-bromo-2-formylphenyl)(4-methoxybenzyl)amino)heptanoic acid (41.0 g) and potassium carbonate (15.2 g) in DMF (400 ml) was added dropwise a DMF (100 ml) solution of iodomethane (18.2 g) under nitrogen atmosphere at 0° C. After returning to room temperature, the reaction mixture was stirred for 2 hours, water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with water five times and with saturated brine once, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure to give methyl 7-((4-bromo-2-formylphenyl)(4-methoxybenzyl)amino)heptanoate (40.8 g) as a brown oily material.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:12])[CH2:5][CH2:6][S:7]2.[CH2:13]=[O:14].[C:15](=[O:18])([O-])[O-].[K+].[K+]>CO.O>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:12])[C:5]([CH2:15][OH:18])([CH2:13][OH:14])[CH2:6][S:7]2
Reactant: Cc1cccc2c1C(=O)CCS2
Reactant: O=C([O-])[O-]
Reactant: C=O
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cccc2c1C(=O)C(CO)(CO)CS2
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of 5-methylthiochroman-4-one (1.00 g) in MeOH (20 ml) and water (4 ml) was admixed with 35% eq. formalin solution (4 ml) and potassium carbonate (100 mg). The reaction mixture was stirred at 40° C. for 2 h and then at RT for 2 h, the solvent was removed under reduced pressure and the residue was admixed with water. The aqueous solution was extracted repeatedly with EtOAc (3×50 ml), the combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. After column chromatography purification of the residue (silica gel, 1:1 cyclohexane/EtOAc), the desired product was obtained as a white solid (697 mg, 52% of theory, m.p. 138-142° C.).