Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:6]=[C:5]([NH:16][NH2:17])[N:4]=1)[CH3:2].[C:18](OCC)(OCC)(OCC)[CH2:19][CH3:20]>>[CH2:19]([C:20]1[N:4]2[C:3]([CH2:1][CH3:2])=[N:8][C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)=[CH:6][C:5]2=[N:16][N:17]=1)[CH3:18]
Reactant: CCOC(CC)(OCC)OCC
Reactant: CCc1nc(NN)cc(N2CCN(C)CC2)n1
Product: CCc1nnc2cc(N3CCN(C)CC3)nc(CC)n12
Yield: 37 %

Procedure:
A mixture of 8.3 g (0.045 mole) of 2-ethyl-6-hydrazinyl-4-(4-methyl-1-piperazinyl)pyrimidine and 75 ml of triethyl orthopropionate was heated at reflux for 48 hours. After cooling the mixture was evaporated in vacuo. Diethyl ether was added to the residue and the mixture was cooled. The precipitate was collected by filtration to provide 4.5 g (37%) of 3,5-diethyl-7-(4-methyl-1-piperazinyl)-1,2,4-triazolo[4,3-c]pyrimidine. Recrystallization from ethyl acetate-hexane and then from ethyl acetate-cyclohexane provided a white crystalline product, m.p. 128°-131° C. Analysis for C14H22N6 : Calculated: %C, 61.3; %H, 8.1; %N, 30.6; Found: %C, 59.8; %H, 8.2; %N, 30.1. The structural assignment was confirmed by nuclear magnetic resonance and infrared spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([NH:13][C:14]2[C:15]([CH3:24])=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([O:19]C)=[O:18])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].O.[OH-].[Li+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([NH:13][C:14]2[C:15]([CH3:24])=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([OH:19])=[O:18])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)c1cccc(NC(=O)CNc2ccc(F)c(F)c2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(NC(=O)CNc2ccc(F)c(F)c2)cccc1C(=O)O

Procedure:
A mixture of the product from step (c) (1.33 g) and lithium hydroxide monohydrate (0.84 g) in methanol (120 ml) and water (25 ml) was heated at reflux for 2 hours, cooled and concentrated in vacuo. The residual aqueous solution was acidified with glacial acetic acid and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4) and evaporated to give a cream solid. Yield 1.27 g.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2].[N+:14]([O-])([O-:16])=[O:15].[NH4+]>S(=O)(=O)(O)O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: CC(=O)N1C(=O)Cc2cc([N+](=O)[O-])ccc21

Procedure:
Prepared by reacting 1-acetyl-2-indolinone in concentrated sulphuric acid (5.7 ml/g) at -10° C. with 1.1 equivalents of ammonium nitrate which is added in batches with stirring. After the addition has ended the mixture is stirred for a further 15 minutes, poured onto ice water, the precipitate is filtered off, washed with water and dissolved in ethylacetate. The organic phase is extracted with water, dried, filtered and evaporated down in vacuo. The evaporation residue is stirred with petroleum ether.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)Cl>>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:9][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(Br)c(F)cc1O
Solvent: ClCCl
Product: COc1cc(Br)c(F)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Bromo-5-fluoro-2-methoxyphenol (500 mg, 0.002 mol), phenylboronic acid (0.73 g, 0.0060 mol), TEA (2.0 mL, 0.014 mol), cupric acetate (0.70 g, 0.0038 mol) and DCM (20 mL, 0.4 mol) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=3.83 (s, 3H), 6.73 (d, J=9.09 Hz, 1H), 6.94-7.00 (m, 2H), 7.07-7.15 (m, 2H), 7.34 (dd, J=8.59, 7.58 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([CH2:13][Cl:14])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[Cl:15]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([Cl:15])=[C:4]([NH:9][S:10]([CH2:13][Cl:14])(=[O:11])=[O:12])[CH:3]=1
Reactant: Nc1cc(NS(=O)(=O)CCl)ccc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 50 °C
Yield: 82.1 %

Procedure:
A mixture of N-(3-amino-4-fluorophenyl)-1-chloromethanesulfonamide (4.42 g, 18.5 mmol), N-chlorosuccinimide (2.47 g) in 50 mL of anhydrous dimethylformamide was heated to 50° C. for 1.5 hours. The reaction mixture was diluted with 200 mL of ethyl acetate and washed with water (twice with 50 mL). The organic phase was separated, dried (MgSO4), and concentrated under reduced pressure to yield 4.15 g (82%) of the title compound. Purification by flash chromatography provided a solid melting at 107-108° C.
Reaction SMILES: [I:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([C:10]([OH:12])=[O:11])[N:3]=1.I[CH3:14]>>[CH3:14][O:11][C:10]([C:4]1[N:3]=[C:2]([I:1])[C:7]([O:8][CH3:9])=[CH:6][CH:5]=1)=[O:12]
Reactant: COc1ccc(C(=O)O)nc1I
Reactant: CI
Product: COC(=O)c1ccc(OC)c(I)n1

Procedure:
Under the conditions of example 1 D, 9.8 g of 2-iodo-3-methoxy-pyridine-6-carboxylic acid is reacted with 2.5 ml of iodomethane and worked up. 7.4 g of 2-iodo-3-methoxypyridine-6-carboxylic acid methyl ester of melting point 175°-178° C. is obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[Na+].[I-].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:31])=[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=1>CC(C)=O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:31])=[C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][N:5]3[C:13](=[O:14])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]3=[O:15])[CH2:29][CH2:30]2)[CH:24]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Cc1ccc(Cl)cc1N1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ccc(Cl)cc1N1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.7 %

Procedure:
A mixture of 2-(3-bromopropyl)isoindoline-1,3-dione (2.68 g, 10 mmol) and NaI (20 mmol) in acetone was refluxed for 5 h, then to it was added 1-(5-chloro-2-methylphenyl)piperazine (2.11 g, 10.0 mmol). The reflux was continued for 12 h. Reaction was then cooled to room temperature, filtered through celite and concentrated.. The crude product was recrystalized from acetone to give the title compound as a white solid (3.21 g. 81%).
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[F:20][P-:21]([F:26])([F:25])([F:24])([F:23])[F:22].[K+]>O>[F:20][P-:21]([F:26])([F:25])([F:24])([F:23])[F:22].[C:1]1([S+:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: c1ccsc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: O
Product: c1ccc([S+](c2ccccc2)c2cccs2)cc1
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
There was added 20 ml of the PP/MSA solution to a mixture of 10.1 grams (0.05 mole) of diphenylsulfoxide and 4.2 grams (0.05 mole) of thiophene. The resulting mixture exothermed to 50° C. and became viscous and purple in color. After 0.5 hours, the blue reaction mixture was poured into 200 ml of water. A very dark colored solution was obtained. It was added to the solution, 9.2 grams (0.05 mole) of potassium hexafluorophosphate. A dark colored solid was obtained. The solid was isolated by decantation and washed several times with fresh water and thenfiltered. The solid was dissolved in dichloromethane and passed through a column of neutral alumina. A pale yellow crystalline solid was obtained upon evaporation of the solvent. It was recovered, 10.6 grams for a 51.2% yield of diphenyl (2-thiophenyl) sulfonium hexafluorophosphate having a melting point of 177°-173° C. Elemental analysis showed; Calculated: % carbon 46.30; % hydrogen 3.14; % sulfur 15.46; Found: % carbon 46.80; % hydrogen 3.12; % sulfur 15.75.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.C(N(C(C)C)CC)(C)C.[N+:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26])([O-:21])=[O:20]>C(O)C>[Br:8][C:6]1[N:7]=[C:2]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: NCc1cccc([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1ncc(Br)nc1NCc1cccc([N+](=O)[O-])c1
Temperature: 180 °C
Yield: 30.9 %

Procedure:
To a solution of 3,5-dibromopyrazin-2-ylamine (253 mg, 1.0 mmol), diisopropylethyl-amine (0.2 mL, 1.5 mmol) and anhydrous ethanol (2 mL) in a microwave tube (Smith process vial, 2-5 mL) was added m-nitrobenzylamine (192 mg, 1.2 mmol). The tube was sealed and heated at 180° C. in a microwave reactor (Smith Synthesizer) for 1.5 h. The reaction mixture was then concentration under reduced pressure and the resultant residue was purified by flash chromatography [silica gel, hexanes/ethyl acetate (2:1)] to afford 5-bromo-N3-(3-nitrobenzyl)pyrazine-2,3-diamine as a brown solid (100 mg, 31%).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH:8]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][N:3]=1.[CH3:17][CH2:18][CH2:19][CH2:20][CH:21]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH2:24][CH3:25].[NH2-].[Na+]>>[CH3:12][CH2:11][CH2:10][CH2:9][CH:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:28]2[CH:27]=[C:26]([CH:21]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH2:19][CH2:18][CH3:17])[CH:31]=[CH:30][N:29]=2)[CH:7]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(CCCC)c1ccnc(N)c1
Reactant: CCCCC(CCCC)c1ccncc1
Agent: [NH2-]
Agent: [Na+]
Product: CCCCC(CCCC)c1ccnc(-c2cc(C(CCCC)CCCC)ccn2)c1

Procedure:
A mixture of 50.7 g (1.3 moles) of sodamide preformed in situ as in Example 1, 350 cc of xylene containing 0.1 cc of oleic acid, and 205 g (1 mole) of 4-(5-nonyl)pyridine was placed in a Magne Drive such as the one described in Example 2. The autoclave was closed and purged of air with nitrogen, pressurized to 10 psig with ammonia and 200 psig with nitrogen. The pressure relief valve was set at 350 psig. The mixture was heated to 173° C. at which temperature amination began. The temperature was reduced and the reaction was run at 158°-163° C. for 8.7 hours. Hydrogen was evolved during this time. The autoclave was cooled to room temperature, vented to atmospheric pressure and hydrolyzed with 150 cc of water. The xylene phase was separated and the bottom aqueous caustic phase was re-extracted with 25 cc of xylene. Both xylene extracts were combined and distilled to give 2-amino-4-(5 -nonyl)pyridine boiling at 197°-225° C. at 22 mm Hg. The yield was 67.3%. This result substantially increases the yield of 2-amino-4-(5-nonyl)pyridine over that reported previously by one of the applicants, McGill, U.S. Pat. No. 4,177,349 (1979) and McGill, U.S. Pat. No. 4,267,335 (1981). In this prior work, 4-(5-nonyl)pyridine was shown to prefer to couple in the presence of sodamide, giving high yields of 4,4'-di-(5-nonyl)-2,2'-bipyridyl but only low yields of 2-amino-4-(5-nonyl)pyridine. This increased yield of 2-amino-4-(5-nonyl)pyridine is of importance because the compound has valuable biocidal properties.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:3]=1[CH3:19].[H-].[Na+].[CH3:22]I>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH3:22])[C:10]2[C:11]([CH3:18])=[CH:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[C:3]=1[CH3:19]
Reactant: CI
Reactant: Cc1cc(C)c(Nc2nc(C)nc(Cl)c2C)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(N(C)c2nc(C)nc(Cl)c2C)c(C)c1
Reaction time: 0.03 h

Procedure:
A solution of (6-chloro-2,5-dimethylpyrimidin-4-yl)-(2,4,6-trimethylphenyl)-amine (276 mg, 1 mmol) in dry THF (2 ml) was treated with sodium hydride (60% in oil, 60 mg, 1.5 mmol) at room temperature. After stirring for 2 minutes, an excess of methyl iodide (0.5 ml) was added and the resulting mixture was stirred at room temperature for 20 minutes. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a pale yellow solid (255 mg). 1H NMR (CDCl3) δ 6.85 (s, 2H), 3.26 (s, 3H), 2.50 (s, 3H), 2.27 (s, 3H), 2.03 (s, 6H), 1.39 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([N:9]=[CH:10][N:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[CH:26])=[CH:21][CH:20]=1>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([C:26]#[C:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[CH:6][N:5]=[C:4]([N:9]=[CH:10][N:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[N:3]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: CC(C)N(C=Nc1ncc(I)c(Cl)n1)C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CC(C)N(C=Nc1ncc(C#Cc2ccc(Cl)cc2)c(Cl)n1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
A mixture of 0.722 g 4-chloro-2-diisopropylaminomethyleneamino-5-iodopyrimidine, 3.5 mL triethylamine, 0.025 g copper iodide, 0.037 g dichlorobis(triphenyl)phosphine palladium II and 0.289 g 1-chloro-4-ethynylbenzene was stirred under nitrogen at room temperature for 18 hours. The dark brown mixture was evaporated in vacuo at a bath temperature of 30–35° C. The beige residue was partitioned between dichloromethane and water. The organic phase was washed twice with water, dried over sodium sulfate, filtered and evaporated to yield 1.0 g of a caramel colored film. The residue was dissolved in 1:1 dichloromethane/hexanes and purified by column chromatography on silica gel, eluting successively with 1:1 dichloromethane/hexanes, dichloromethane and ethyl acetate. The product was recovered from the latter two eluates by evaporation to yield 0.7 g of 4-chloro-5-(4-chlorophenylethynyl)-2-diisopropylaminomethyleneaminopyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28](=[O:32])[CH2:29][CH2:30][CH3:31]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([O:15][CH2:27][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCCC(=O)CBr
Reactant: O=c1ccn2c3ccc(Br)cc3c3cc(O)cc1c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCC(=O)COc1cc2c(=O)ccn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
10-bromo-2-hydroxy-4H-pyrido[3,2,1-jk]carbazole-4-one (250 mg) obtained in Example 59 was suspended in dimethyl sulfoxide (10 ml), and potassium carbonate (210 mg) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and 1-bromo-2-pentanone (170 mg) was added to the mixture. The mixture was stirred at room temperature for 3 hours, and the reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride containing 2% methanol) to obtain the title compound (130 mg, 41%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:14]#[N:15])[S:12][CH:13]=2)[C:4]1=[O:16].[C:17]([NH:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([S:38](Cl)(=[O:40])=[O:39])[CH:32]=[CH:31]2)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>>[C:14]([C:11]1[S:12][CH:13]=[C:9]([CH2:8][N:5]2[CH2:6][CH2:7][C@H:3]([NH:2][S:38]([C:33]3[CH:32]=[CH:31][C:30]4[C:35](=[CH:36][CH:37]=[C:28]([NH:27][C:17]([O:19][CH2:20][C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)=[O:18])[CH:29]=4)[CH:34]=3)(=[O:40])=[O:39])[C:4]2=[O:16])[CH:10]=1)#[N:15]
Reactant: O=C(Nc1ccc2cc(S(=O)(=O)Cl)ccc2c1)OCc1ccccc1
Reactant: N#Cc1cc(CN2CC[C@H](N)C2=O)cs1
Agent: Cl
Product: N#Cc1cc(CN2CC[C@H](NS(=O)(=O)c3ccc4cc(NC(=O)OCc5ccccc5)ccc4c3)C2=O)cs1

Procedure:
The title compound is prepared from 4-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)thiophene-2-carbonitrile hydrochloride as described in EXAMPLE 125, Part C using N-Cbz-6-aminonaphthalene-2-sulfonyl chloride in place of 7-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc/CH2Cl2 to 25% EtOAc/CH2Cl2 to provide the title compound as a solid.
Reaction SMILES: [BH4-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]#[N:10].BrC[CH2:13][CH2:14][O:15][Si](C(C)(C)C)(C)C>CN(C=O)C>[C:9]([CH:8]([C:4]1[S:3][CH:7]=[CH:6][CH:5]=1)[CH2:13][CH2:14][OH:15])#[N:10]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: N#CCc1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(CCO)c1cccs1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.9 %

Procedure:
Under a nitrogen atmosphere, sodium borohydride (650 mg) was added in an ice bath to a DMF solution (25 ml) of thiophene-2-acetonitrile (1 g) and (3-bromopropoxy)-tert-butyldimethylsilane (2.06 g). After 20 minutes, the organic layer was separated by adding an aqueous saturated ammonium chloride and ethyl acetate were added thereto. The resulting organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the mixture was evaporated. The resulting residue was dissolved in acetonitrile (20 mL), a 1 M tetrabutylammonium fluoride/tetrahydrofuran solution (9.7 ml) was added thereto, and the mixture was stirred at a room temperature. After 18 hours, the organic layer was separated by adding water and ethyl acetate. The resulting organic layer was rinsed with water and brine, and dried over magnesium sulfate. After filtering off the drying agent, the mixture was evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate system), to give the title compound as a red oil (637 mg, 43%). 1H-NMR (400 MHz, CDCl3) δ 2.08-2.16 (m, 1H), 3.08 (t, J=7.0 Hz, 2H), 3.75 (t, J=7.0 Hz, 2H), 4.15-4.20 (m, 1H), 7.14 (dd, J=3.8 Hz, 4.8 Hz, 1H), 7.65 (dd, J=0.8 Hz, 4.8 Hz, 1H), 7.75 (dd, J=0.8 Hz, 3.8 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([O:16]C)=[O:15])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1
Reactant: COCc1ccc(C(=O)OC)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCc1ccc(C(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a solution of methyl 4-((methyloxy)methyl)-1-naphthalenecarboxylate (780 mg, 3.38 mmol) in methanol (10 ml) was added 1N aqueous sodium hydroxide solution (6.76 ml, 6.76 mmol), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to the reaction solution (10 ml) and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 4-((methyloxy)methyl)-1-naphthalenecarboxylic acid (615 mg, 84%).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:13][CH:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(CN2CCC(O)CC2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(CN2CCC(OC(=O)c3ccccc3)CC2)cc1
Yield: 63.6 %

Procedure:
0.31 g (0.0015 mol) of 1-(4-methyl-benzyl)-piperidin-4-ol and 0.52 ml (0.00375 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.25 ml (0.00215 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:4). 0.295 g (64%) of 1-(4-methyl-benzyl)-piperidin-4-yl benzoate was obtained as a yellow oil.
Reaction SMILES: [Li][CH2:2]CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:18](=O)[CH3:19])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][O:16][CH3:17]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCCCCC>[C:18]([C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][O:16][CH3:17])=[C:8]([O:7][CH3:6])[CH:9]=1)([CH3:19])=[CH2:2]
Reactant: [Li]CCCC
Reactant: COCOc1ccc(C(C)=O)cc1OC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(C)c1ccc(OCOC)c(OC)c1
Temperature: -80 °C
Reaction time: 12 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (1.1 g, 3.09 mmol, 1.3 eq.) in 5 mL dry THF cooled to −80° C. was slowly treated with BuLi (1.94 mL of a 1.6 m solution in hexane, 1.3 eq.). To this yellow suspension a solution of 1-(3-methoxy-4-methoxymethoxy-phenyl)-ethanone (500 mg, 2.38 mmol, 1 eq.) in 5 mL dry THF was added and the reaction mixture was allowed to warm to r.t. where stirring was continued for 12 h. The suspension was filtered and the solvent was evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc 6:1) to yield the desired product as a color-less oil.
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[Cl:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][N:30]2[CH2:34][CH2:33][N:32]([C:35]3[S:36][C:37]([C:41](O)=[O:42])=[C:38]([CH3:40])[N:39]=3)[C:31]2=[O:44])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][N:30]2[CH2:34][CH2:33][N:32]([C:35]3[S:36][C:37]([C:41]([NH2:7])=[O:42])=[C:38]([CH3:40])[N:39]=3)[C:31]2=[O:44])=[CH:27][CH:26]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(Cl)cc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(Cl)cc3)C2=O)sc1C(N)=O

Procedure:
Following the procedure as described in EXAMPLE 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with 2-(3-(4-chlorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp>200° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.46-7.37 (m, 6H), 4.47 (s, 2H), 4.03 (br s, 2H), 3.49-3.37 (m, 2H), 2.50 (s, 3H); MS (ES+) m/z 350.8 (M+1).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[CH3:14])[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.S(=O)(=O)(O)O.C(O)(=O)C>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[CH3:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 0 °C
Yield: 88.3 %

Procedure:
A mixture of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylate (1.97 g), concentrated sulfuric acid (1.6 ml) and acetic acid (12.8 ml) in water (9.6 ml) was refluxed for 1.5 hours. The reacting mixture was poured into ice-water (100 ml), the resulting precipitate was collected by filtration, washed with water and dried to give the title compound (1.58 g) as white powder, mp 243°-245° C.