Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:12][C:11](=O)[CH2:10][CH2:9][N:8]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][CH:3]=1.[N+:23](CS(C1C=CC(C)=CC=1)(=O)=O)#[C-:24].CC(C)([O-])C.[K+].O>COCCOC>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:24]#[N:23])[CH2:10][CH2:9][N:8]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C#N)CC1Cc1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
To a solution of tert-butyl 2-(4-chlorobenzyl)-4-oxopiperidine-1-carboxylate (8.737 g, 26.98 mmol) in DME (200 mL) under nitrogen was added simultaneously 1-(isocyanomethyl-sulfonyl)-4-methylbenzene (7.90 g, 40.47 mmol) in 200 mL DME and potassium tert-butoxide (81 mL, 80.94 mmol) over 1 hour so that the temperature never rose above 0° C. The solution was stirred at −20° C. for 2 h and then let to warm to room temperature overnight. Water (200 mL) was added to the orange reaction mixture and the solution was stirred for 20 min and then extracted with 3× diethyl ether and 3× EtOAc. The organic phases were combined and dried over Na2SO4 and evaporated to give a brown residue. Further purification was done on Biotage (340 g column, 3 runs, heptane/EtOAc, gradient 20-60% EtOAc) to give tert-butyl 2-(4-chlorobenzyl)-4-cyanopiperidine-1-carboxylate (5.54 g, 61%). 1H NMR (400 MHz, cdcl3) δ, 1.21-1.50 (m, 9H), 1.58-2.14 (m, 4H), 2.55-3.27 (m, 4H), 4.06-4.25 (m, 1H), 4.34-4.60 (m, 1H), 7.02-7.34 (m, 4H). MS m/z 235, 237 (M-C5H8O2+H)+
Reaction SMILES: [CH2:1]([CH:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:27]O>C(O)(=O)C>[CH2:1]([C:8]1([OH:27])[C:9](=[O:26])[N:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:12]1=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OO
Reactant: O=C1C(Cc2ccccc2)C(=O)N(c2ccccc2)N1c1ccccc1
Solvent: CC(=O)O
Product: O=C1N(c2ccccc2)N(c2ccccc2)C(=O)C1(O)Cc1ccccc1

Procedure:
Prepared from 4-benzyl-1,2-diphenyl-3,5-pyrazolidinedione (3.3 g; 9.6 mmol), 35% H2O2 (1.4 ml; 16.3 mmol), and acetic acid (50 ml) using the procedure of Example 10 to give 1.0 g (30%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)(Cl)Cl>[CH3:20][O:19][C:17](=[O:18])[C:16]1[CH:21]=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:32](=[O:33])[CH2:31][Cl:30])=[CH:14][CH:15]=1
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1ccc(OCCCCCCCCCCN)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(OCCCCCCCCCCNC(=O)CCl)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
The crude product from (iii) above (5.62 g, 18.84 mmol) and triethylamine (2.6 mL, 18.7 mmol) were dissolved in chloroform (90 mL) and cooled in an ice bath. A solution of chloroacetyl chloride (1.5 mL) in chloroform (40 mL) was added dropwise with stirring. After the completion of the addition, the solution was stirred in the ice bath for 15 minutes and warmed to ambient temperature and stirred for 20 hours. The solution was washed with water (4×80 mL). Drying (MgSO4) and concentration yielded the product (6.71 g, 93%) which was used without further purification. 1H NMR (CDCl3, δ): 7.95 (d), 6.87 (d), 6.54 s, br), 4.01 (d), 3.96 (t), 3.86 (s), 3.28 (q), 1.76 (m), 1.55 (m), 1.45 (m), 1.29 (m). 13C NMR (CDCl3, δ): 130.71, 130.66, 121.52, 113.23, 75.37, 67.33, 50.95, 41.85, 39.04, 28.56, 28.53, 28.47, 28.43, 28.33, 28.25, 25.94, 25.11.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[C:12]1([NH:11][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccccc1)C1CCCCC1
Reaction time: 18 h
Yield: 91.5 %

Procedure:
Cyclohexanecarbonyl chloride (14.66 g, 0.1 mol) was added dropwise to a stirred solution of aniline hydrochloride (12.96 g 0.1 mol) and N, N-diisopropylethylamine (15.20 g, 0.2 mol) in dichloromethane (100 ml). The solution was stirred under an atmosphere of argon for 18 h, washed with 0.1 N-HC1 (3×50 ml) and dilute sodium hydrogen carbonate solution (50 ml), dried (MgSO4), and evaporated in vacuo to give the product (18.6 g) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18](Cl)=[O:19].O.[NH3:24]>O1CCCC1>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([NH2:24])=[O:19]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)Cl)C(C)(C)CCC1
Reactant: N
Solvent: O
Solvent: C1CCOC1
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(N)=O)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
10 g (0.031 mole) of retinoic acid chloride as prepared according to the procedure described in Example 2 was added to the mixture of 300 ml of ammonia water (35%) and 100 ml of tetrahydrofuran and then stirred at room temperature for 20 hours. The reaction solution was distilled under reduced pressure and then concentrated. The residue was extracted with methylene chloride. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, filtered and then distilled under reduced pressure to obtain 9.43 g (Yield 99%) of the desired retinamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[OH:9]O>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-:9]
Reactant: OO
Reactant: Cc1ccc(Cl)nc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(Cl)[n+]([O-])c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 2-chloro-5-methylpyridine (10 mL) in 155 mL of glacial acetic acid was added 19 mL of 30% aqueous hydrogen peroxide. The mixture was stirred at 80° C. for 8 hours. The mixture was diluted with 100 mL of water and then concentrated in a vacuum. The residue was made strongly alkaline with anhydrous sodium carbonate and shaken with 200 mL of chloroform. The solids were removed via filtration, and the filtrate was dried over sodium sulfate, filtered and concentrated to give 10.8 g of the 2-chloro-5-methylpyridine-N-oxide (82%). Mass Spec. M+H=144.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]([CH:20]([CH3:22])[CH3:21])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.ClC1N=C(NCCNC(=O)OC(C)(C)C)C([C:41]#[C:42][CH:43]([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])=CN=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].ClC1N=CC2C=C(C(OCC)OCC)N(CCNC(=O)OC(C)(C)C)C=2N=1>>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[CH:41]=[C:42]([CH:43]([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])[N:9]([CH:10]([CH:20]([CH3:22])[CH3:21])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:3]=2[N:4]=1
Reactant: CC(C)C(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Reactant: CCOC(C#Cc1cnc(Cl)nc1NCCNC(=O)OC(C)(C)C)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCOC(OCC)c1cc2cnc(Cl)nc2n1CCNC(=O)OC(C)(C)C
Agent: [F-]
Product: CCOC(OCC)c1cc2cnc(Cl)nc2n1C(CNC(=O)OC(C)(C)C)C(C)C

Procedure:
tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-3-methyl-butyl]carbamate was synthesized by subjecting tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate to Sonogoshira conditions as described for tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]carbamate followed by subsequent treatment with TBAF as described in the synthesis of tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate. 1H NMR (600 MHz, DMSO-d6) δppm 1.11 (d, J=6.44 Hz, 3H) 1.18 (t, J=7.03 Hz, 6H) 1.21-1.26 (m, 12H) 2.88 (br. s., 1H) 3.43-3.78 (m, 6H) 3.97-4.08 (m, 1H) 5.61 (s, 1H) 6.65 (s, 1H) 6.71-6.78 (m, 1H) 8.87 (s, 1H). LCMS (ESI) 441 (M+H).
Reaction SMILES: [Br:1][C:2]1(Br)[CH:11]([CH3:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]1=[O:15].N12CCCN=C1CCCCC2>CC#N>[Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]=1[OH:15]
Reactant: COc1ccc2c(c1)CC(C)C(Br)(Br)C2=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1ccc2c(O)c(Br)c(C)cc2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 101 %

Procedure:
This compound was prepared according to procedures described for similar compounds (i.e. 2-bromo-1-naphthols) as reported by G. R. Green et. al. (Tetrahedron, (1998), 54, 9875-9894), with modification. To a stirred solution of 3-methyl-6-(methyloxy)-3,4-dihydro-1(2H)-naphthalenone (12) (4.80 g, 25.2 mmol) in CHCl3 (130 mL) was slowly added dropwise a solution of Br2 (8.12 g, 50.81 mmol, 2.02 eq) in CHCl3 (60 mL) over a period of 4 h at RT under N2. The reaction mixture was stirred overnight. The reaction mixture was concentrated to give 9.82 g of crude 2,2-dibromo-3-methyl-6-(methyloxy)-3,4-dihydro-1(2H)-naphthalenone as a dark brown-orange oil [1H NMR (400 MHz; CDCl3): δ 1.49 (d, J=6.3 Hz, 3H), 2.56 (m, 1H), 2.91 (m, 2H), 3.86 (s, 3H), 6.67 (d, J=2.2 Hz, 1H), 6.90 (dd, J=2.5 Hz, 8.9 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H)]. A solution of 2,2-dibromo-3-methyl-6-(methyloxy)-3,4-dihydro-1(2H)-naphthalenone (9.8 g, 25.2 mmol) in CH3CN (160 mL) was cooled in an ice-water bath to 0-5° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (6 mL, 6.11 g, 39.6 mmol, 1.57 eq) was added slowly dropwise under N2. The ice-water bath was removed and the reaction mixture was allowed to stir at RT under N2 for 40 min. To the reaction mixture was added 1 N HCl (160 mL) and the aqueous mixture was extracted with CH2Cl2 (2×). The organic extracts were combined, washed with H2O (2×), dried over MgSO4, filtered, and the filtrate was concentrated to give 6.8 g (100%) of the title compound 13 as a solid. 1H NMR (400 MHz; d6-DMSO-d6): δ 2.43 (s, 3H), 3.83 (s, 3H), 7.07 (dd, J=2.2 Hz, 9.2 Hz, 1H), 7.16 (d, J=2.2 Hz, 1H), 7.29 (s, 1H), 8.04 (d, J=9.1 Hz, 1H), 9.66 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:8]=2)[CH2:3]1.Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:25][CH:24]=1)=[O:22].[BH4-].[Na+].C(O)C>CN(C)C=O>[OH:22][CH:21]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:27][CH:28]=1)[CH2:20][NH:1][C@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:8]=2)[CH2:3]1
Reactant: O=C(CBr)c1ccc(OC2CCCCO2)cc1
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@@H](N)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(OC3CCCCO3)cc1)CC2
Temperature: 0 °C
Yield: 82.8 %

Procedure:
Ethyl (S)-(2-amino-1,2,3,4-tetrahydronaphthalen-7-yl-oxy)acetate (1.14 g) was dissolved in N,N-dimethylformamide (15 ml), and 2-bromo-4'-((2RS)-2-tetrahydropyranyloxy)-acetophenone (600 mg) was added to the solution under ice-cooling with stirring, followed by reaction at room temperature for an hour. Sodium borohydride (380 mg) and ethanol (10 ml) were added to the reaction mixture under ice-cooling with stirring. After reaction for an hour, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. The resulting residue was dissolved in tetrahydrofuran (20 ml), triethanolamine (2 ml) was added to the solution and the mixture was heated under reflux for 17 hours. After cooling, water was poured into the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: ethyl acetate) gave ethyl 2-[(2S)-2-[[(2RS)-2-hydroxy-2-[4-((2RS)-2-tetrahydropyranyloxy)phenyl]ethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]acetate (780 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[C:17](Cl)=[O:18]>N1C=CC=CC=1>[S:3]1[CH:4]=[N:5][N:6]=[C:2]1[NH:1][C:17]([C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1)=[O:18]
Reactant: Nc1nncs1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: c1ccncc1
Product: O=C(Nc1nncs1)c1ccc2ccccc2c1
Yield: 39.2 %

Procedure:
To a stirred solution of 2-amino-1,3,4-thiadiazol (0.84 g, 8.0 mmol) in pyridine (5 ml) was added 2-naphthoyl chloride (1.9 g, 10 mmol). The resulting mixture was stirred at reflux temperature for 15 min. cooled and quenched with water (100 ml). The precipitate was filtered off, washed with water (2×10 ml) and heptane (2×10 ml) and dried in vacuo affording 0.80 g (38%) of the title compound as a solid.
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:9])[CH3:8].[NH2:11][C:12]1[C:25]2[N:24]([CH3:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[C:15]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[C:7]([NH:11][C:12]1[C:25]2[N:24]([CH3:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[C:15]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:14][CH:13]=1)(=[O:9])[CH3:8]
Reactant: Cn1c2ccccc2c(=O)c2c(Oc3ccccc3)ccc(N)c21
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(Oc2ccccc2)c2c(=O)c3ccccc3n(C)c12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.3 ml (16 mmol) of pyridine and 0.28 (4 mmol) of acetyl chloride are added to a solution of 0.7 g (2 mmol) of 4-amino-N-methyl-1-phenoxyacridone in 20 ml of chloroform, and the mixture is stirred at room temperature for 6 hours. The solution is washed with hydrochloric acid (18%), water and saturated aqueous sodium chloride solution, dried using sodium sulphate and evaporated. The residue is washed with diethyl ether nad filtered off. Yield: 0.6 g (83%) melting point: 252°-254° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:14])[CH3:13])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
4-Fluoro-3-nitro-aniline (45.0 g, 288.2 mmol) was added portionwise to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the desired title compound (42.0 g, 70%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:8]([OH:10])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:29]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH:35]=1)[CH:30]([CH3:32])[CH3:31]>C(Cl)Cl.CN(C)C=O>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:8](=[O:10])[C:39]2[CH:38]=[CH:37][C:36]([O:40][CH2:41][CH:42]([CH3:44])[CH3:43])=[CH:35][C:34]=2[O:33][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C(=O)O)ccc1OCC(C)C
Reactant: CC(C)COc1cccc(OCC(C)C)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Oc1cc(C(=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
In 10 ml of methylene chloride is dissolved 1.00 g of 3-(acetyloxy)-4-isobutoxybenzoic acid. After adding 0.41 ml of oxalyl chloride and 20 μl of N,N-dimethylformamide successively at ambient temperature, the mixture thus obtained is stirred at ambient temperature for one hour. Then, 1.06 g of aluminum chloride and 1.15 g of 1,3-diisobutoxybenzene are successively added at 5-10° C., and the mixture is stirred at the same temperature as above for one hour. The reaction mixture is added to a mixture of methylene chloride and ice water, and the organic layer is separated. The organic layer is successively washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography [eluent; n-hexane:ethyl acetate=5:1] to obtain 1.24 g of 5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl acetate as a yellow oily product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8](Br)=[CH:7]2.[I-:15].[Na+].CNCCNC>O1CCOCC1.[Cu](I)I>[NH2:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([I:15])=[CH:7]2
Reactant: COc1cc(N)c2ncc(Br)cc2c1
Reactant: [I-]
Agent: I[Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(N)c2ncc(I)cc2c1

Procedure:
In a similar procedure to Step 2 of Example 1 8-amino-3-bromo-6-methoxyquinoline (preparation described in Journal of Pharmaceutical Sciences (1984), 73(12), 1854-6) (6.0 g) is treated with sodium iodide, copper iodide and N,N′-dimethyl-ethane-1,2-diamine in dioxane in a sealed tube under argon, at 120° C. for 14 h. After work-up the crude is purified by flash chromatography (ethyl acetate: cyclohexane, 1:4) to provide 8-amino-3-iodo-6-methoxyquinoline (4.6 g) as a pure product. 1H NMR (CDCl3) δ ppm: 8.70 (1H, d); 8.30 (1H, d); 6.55 (1H, d); 6.35 (1H, d); 5.00 (2H, br s); 3.85 (3H, s). (M+1)+: 301
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([NH:15][C@@H:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[O:34]>C1COCC1>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[NH:32][C:33](=[O:34])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([NH:15][C@@H:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](NC(=O)c1csc(-c2ccc(N)cc2)n1)C(C)C
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: C1CCOC1
Product: COC(=O)[C@@H](NC(=O)c1csc(-c2ccc(NC(=O)Nc3ccc(F)cc3F)cc2)n1)C(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
(S)-methyl 2-(2-(4-aminophenyl)thiazole-4-carboxamido)-3-methylbutanoate (150 mg, 0.450 mmol) was taken in 3 mL THF, to this 2,4-difluoro-1-isocyanatobenzene (76.8 mg, 0.495 mol) was added and stirred at RT for 3-4 hr. After completion of reaction solvent was removed under reduced pressure and the residue purified by column chromatography. Yield: 200 mg (91%). MS (ESI) m/z: 487(M−H)−; 1HNMR (DMSO-d6, 300 MHz): δ 9.369 (s, 1H), 8.594 (d, 1H), 8.316 (s, 1H), 8.291 (s, 1H), 8.126 (m, 1H), 8.023 (d, 2H), 7.640 (d, 2H), 7.372 (m, 1H), 7.106 (m, 1H), 4.431 (dd, 1H), 3.696 (s, 3H), 2.300 (m, 1H), 0.981 (dd, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH:3]=1
Reactant: CC(C)=CCBr
Reactant: Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCSc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
25.00 g (132.0 mmol) of 3-bromothiophenol, 200 ml of DMF and 18.23 g (138.0 mmol) of potassium carbonate are introduced into a three-necked flask. 18.0 ml (157.0 mmol) of 1-bromo-3-methyl-2-butene are added dropwise and the mixture is stirred at room temperature for five hours. The reaction medium is poured into water and extracted with ethyl acetate, and the organic phase is separated out after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. 33.00 g (97%) of the expected compound are collected in the form of a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].CC1(C)[O:18][C:17](=O)[C:14]2([CH2:16][CH2:15]2)[C:13](=[O:20])[O:12]1>C(O)C>[CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([N:7]2[CH2:16][CH2:15][CH:14]([C:13]([OH:20])=[O:12])[C:17]2=[O:18])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(N)cc1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: CCc1ccc(N2CCC(C(=O)O)C2=O)cc1
Yield: 66.1 %

Procedure:
A mixture of 4-ethylaniline (1.1 mL; 8.73 mmol) and 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.5 g; 2.94 mmol) in ethanol (3 mL) was irradiated in a microwave oven for 3 minutes at 100° C. and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane with 5% acetic acid) to afford 1-(4-ethylphenyl)-2-oxopyrrolidine-3-carboxylic acid 0.453 g (67%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:26]=[O:27])[C:10]3[N:14]=[C:13]([O:15]CC)[N:12](C(OC(C)(C)C)=O)[C:11]=3[CH:25]=2)=[C:5]([CH3:28])[O:4][N:3]=1.[F:29][C:30]([F:36])([F:35])[C:31]([F:34])([F:33])I.CN(C=O)C.CN(C(N(C)C)=C(N(C)C)N(C)C)C>C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:26]([OH:27])[C:31]([F:34])([F:33])[C:30]([F:36])([F:35])[F:29])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:25]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: FC(F)(F)C(F)(F)I
Reactant: CCOc1nc2c(C=O)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Agent: CN(C)C(=C(N(C)C)N(C)C)N(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1cc(C(O)C(F)(F)C(F)(F)F)c2[nH]c(=O)[nH]c2c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-formyl-1H-benzo[d]imidazole-1-carboxylate (100 mg, 0.26 mmol), pentafluoroiodoethane (350 mg, 1.42 mmol) and DMF was cooled to −15° C. under nitrogen. Tetra(dimethlamino)ethylene was added (0.33 mL, 1.42 mmol) and the reaction mixture was irradiated with a sun lamp. A thick precipitate formed, and after 30 minutes, the reaction mixture was diluted with ethyl acetate filtered. The filtrate was washed with water and the organic layer was concentrated and dissolved in ethanol (3 mL) and 4M HCl in dioxane (1 mL) and heated to 70° C. for 1 h. The reaction mixture was concentrated and purified by reverse-phase HPLC to give the desired product as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]Cl)[CH:17]=3)[N:12]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:32][S-:33].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][S:33][CH3:32])[CH:17]=3)[N:12]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: COCCOCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)ccc21
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CSC)ccc21
Reaction time: 18 h
Yield: 77.5 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-6-(chloromethyl)-1-[2-(2-methoxyethoxy)ethyl]-4-oxo-1,4-dihydro-3-quinolinecarboxamide (175 mg) prepared as described in Example No. 84, in DMF (1.5 11) is added sodium thiomethoxide (40 mg). The mixture is stirred for 18 h, then added to 25 ml of rapidly stirred water. The solid is filtered, washed well with water, dried in vacuo, and recrystallized from acetonitrile to afford 139 mg of the title compound as pale yellow crystals.