Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>N1C=CC=CC=1.[Na+].[Cl-]>[CH2:18]([O:17][C:15]([N:12]=[S:10]([CH3:13])([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:11])=[O:16])[CH3:19]
Reactant: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOC(=O)N=S(C)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
8.50 g (42.5 mmol) of (RS)—S-(4-nitrophenyl)-S-methyl sulfoximide in 400 ml of pyridine is mixed drop by drop at room temperature with 18.8 ml (197.2 mmol) of ethyl chloroformate. The batch is stirred for 4 hours at room temperature and then added in dilute NaCl solution. It is extracted from ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate 1:1). 8.94 g (32.8 mmol, corresponding to 77% of theory) of the product is obtained.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[Br:21][C:22]1[CH:23]=[C:24]([F:31])[C:25]([O:29][CH3:30])=[C:26]([F:28])[CH:27]=1.CN([CH:35]=[O:36])C>C1COCC1>[Br:21][C:22]1[C:27]([CH:35]=[O:36])=[C:26]([F:28])[C:25]([O:29][CH3:30])=[C:24]([F:31])[CH:23]=1
Reactant: CN(C)C=O
Reactant: COc1c(F)cc(Br)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1c(F)cc(Br)c(C=O)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Add n-butyl lithium 1.6N (22 ml, 35.2 mmol) to diisopropylamine (4.8 ml, 34.2 mmol) in anhydrous THF (7 ml) at 0° C. Stir the resulting yellow solution for 30 min at 0° C. Add this LDA solution dropwise via canula to a solution of 5-bromo-1,3-difluoro-2-methoxybenzene (5.83 g, 26.17 mmol) in anhydrous THF (40 ml) at −78° C. over 40 min. Stir the resulting bright yellow solution for 50 min at −78° C. Add anhydrous DMF (2.7 ml, 34.8 mmol) and stir the mixture for 1.5 h at −78° C. Quench the mixture with dilute sulfuric acid and extract the product with EtOAc (×3). Wash the combined organic layers with water (×3), saturated aq. sodium chloride and dry over anhydrous sodium sulfate. Filter and concentrate to yield the crude product. Purification by flash chromatography (Silica gel-hexane/EtOAc) yields the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:20][C@@H:19]([N:21]([CH2:32][CH3:33])[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C@H:18]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:42]1C=CC(OC(=O)N([C@H]2[C@H](C3C=CC(Cl)=CC=3)CN(CC3C=CC=CC=3)C2)C(C)C)=CC=1.C(OC(N1CCC(C(O)=O)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([N:16]2[CH2:20][C@@H:19]([N:21]([C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)=[O:23])[CH:32]([CH3:42])[CH3:33])[C@H:18]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:17]2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)N(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@H]1c1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Product: CC(C)N(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of rac-4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester the title compounds were prepared from rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-isopropyl-carbamic acid 4-fluoro-phenyl ester by cleavage of the benzyl group and subsequent coupling with 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid. The resulting rac-4-{(3S,4R)-3-(4-Chloro-phenyl)-4-[(4-fluoro-phenoxycarbonyl)-isopropyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester was subjected to separation by chiral HPLC on CHIRALPAK AD eluting with i-propanol/heptane. After evaporation of the product containing fractions 4-{(3S,4R)-3-(4-Chloro-phenyl)-4-[(4-fluoro-phenoxycarbonyl)-isopropyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester was obtained as yellow viscous oil. MS m/e: 588.3 [M+H]+. 4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[(4-fluoro-phenoxycarbonyl)-isopropyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester was obtained as yellow viscous oil. MS m/e: 588.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(OCC)(=O)CC(O)=O.[CH2:23]([NH2:25])[CH3:24].BrC1C=CC([C@H](N)C)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:25][CH2:23][CH3:24])=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccc(Br)cc1
Reactant: CCN
Agent: CCOC(=O)CC(=O)O
Agent: C[C@@H](N)c1ccc(Br)cc1
Product: CCNC(=O)C(C)(C)c1ccc(Br)cc1
Yield: 82 %

Procedure:
The title compound was prepared as described in Step 1 of Example A(39), where 2-(4-bromophenyl)-2-methyl propionic acid was substituted for ethyl hydrogen malonate and ethyl amine was substituted for (R)-(+)-1-(4-bromophenyl)ethylamine on that example. Yield 82%. 1H NMR (CDCl3) δ: 1.01 (t, J=5.3 Hz, 3H), 1.55 (s, 6H),), 3.2 (q, J=7.0, 5.3, 2H), 5.15 (brs, 1H), 7.22-7.26 (m, 2H), 7.46-7.50 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=1.[OH-:16].[Na+].O>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].CO>[O:13]1[CH2:14][CH2:15][CH:10]([CH2:9][O:8][C:6]2[CH:7]=[C:2]([OH:16])[CH:3]=[N:4][CH:5]=2)[CH2:11][CH2:12]1
Reactant: Brc1cncc(OCC2CCOCC2)c1
Reactant: [OH-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Oc1cncc(OCC2CCOCC2)c1
Temperature: 210 °C
Reaction time: 6 h
Yield: 59.4 %

Procedure:
A mixture of 3-bromo-5-(tetrahydro-2H-pyran-4-ylmethoxy)pyridine (300 mg), copper(II) sulfate pentahydrate (130 mg), bronze (100 mg), sodium hydroxide (700 mg), and water (5 mL) was stirred in an autoclave at 210° C. for 6 hours. The reaction mixture was cooled to room temperature, followed by addition of methanol, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure and extracted with chloroform. The aqueous layer was neutralized by addition of 1M hydrochloric acid (3.5 mL), followed by extraction with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 5-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-ol (137 mg).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]1([C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]O1)=[O:6]>>[OH:2][CH2:1][CH2:3][N:4]1[CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]1=[O:6]
Reactant: O=C1OCc2ccccc21
Reactant: NCCO
Product: O=C1c2ccccc2CN1CCO
Temperature: 150 °C
Yield: 81.7 %

Procedure:
Ethanolamine (4.78 g, 78.3 mmol) and phthalide (10.0 g, 74.6 mmol) were placed in a round-bottom flask equipped with a Dean-stark trap. The reaction mixture was heated at 150° C. for 4 h then 18 h at 205° C. The product was solidified upon cooling. Pure 2-(2-hydroxyethyl)isoindolinone (10.8 g, 82%) was isolated by recrystalization in CHC13/hexanes as a white crystal. 1H NMR (CDCl3, 300 MHz) δ3.02-3.15 (br, 1H), 3.78 (t, 2H, J=5.0 Hz), 3.93 (t, 2H, J=4.4 Hz), 4.52 (s, 2H), 7.42-7.58 (m, 3H), 7.84 (d, 1H, J=7.4 Hz) ppm.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[CH:4]=[N:3][CH:2]=1.[N+:10]([O-])([OH:12])=[O:11].C(=O)(O)[O-].[Na+]>O>[N+:10]([C:9]1[C:5]2[CH:4]=[N:3][CH:2]=[N:1][C:6]=2[NH:7][CH:8]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: c1ncc2cc[nH]c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1c[nH]c2ncncc12
Temperature: 0 °C

Procedure:
5-Nitro-7H-pyrrolo[2,3-d]pyrimidine (8) is prepared by adding 7H-pyrrolo[2,3-d]pyrimidine (6) to fuming nitric acid while cooling (e.g. 0° C.). After stirring for one to several hours, water is carefully added and the mixture neutralized with saturated sodium bicarbonate. The solids are collected by filtration and dried to provide 5-nitro-7H-pyrrolo[2,3-d]pyrimidine 8.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([C:22]([O:24]CC)=[O:23])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(O)C>O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([C:22]([OH:24])=[O:23])[CH:12]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN(C(=O)OCc2ccccc2)C1Cc1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(C(=O)O)CCCN(C(=O)OCc2ccccc2)C1Cc1ccc(OC)cc1

Procedure:
A mixture of 257 g. of diethyl 1-benzyloxycarbonyl-2-(p-methoxybenzyl)-3,3-piperidinedicarboxylate, 35 g. of 86 percent potassium hydroxide, 530 ml. of ethyl alcohol, and 530 ml. of water was stirred and refluxed for seven and one-half hours. The reaction mixture was concentrated under reduced pressure until only water distilled. More water was added to the reaction mixture, which was then extracted twice with diethyl ether. The ether extracts were combined, washed with water, dried, filtered, and the filtrate was concentrated under reduced pressure to recover 108 g. of unhydrolyzed diester starting material. The aqueous layers from the extractions were combined and acidified with concentrated hydrochloric acid, causing separation of an oil. This oil crystallized when shaken with a few ml. of diethyl ether. The mixture was filtered and the solid thus collected was washed with diethyl ether and air-dried. This product was a first crop of 1-benzyloxycarbonyl-2-(p-methoxybenzyl)-3-carbethoxy-3-piperidinecarboxylic acid. By repeating the hydrolysis procedure on the 108 g. of recovered diethyl 1-benzyloxycarbonyl-2-(p-methoxybenzyl)-3,3-piperidinedicarboxylate, using 14.6 g. of 86 percent potassium hydroxide, 225 ml. of ethyl alcohol, and 225 ml. of water, there was obtained a second crop of 1-benzyloxycarbonyl-2-(p-methoxybenzyl)-3-carbethoxy-3-piperidinecarboxylic acid. The two crops were combined and recrystallized from ethyl alcohol to yield 157 g. of this product as a white solid. When recrystallized from ethyl alcohol, this compound melted at 186°-188° C. (dec.); ir (K·Br) 1740 (ester C=O), 1720 (acid C=O), and 1650 cm-1 (urethane C=O).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[C:19]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:18]=[CH:17][C:16]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34]O)[CH:29]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:14][C:15]1[CH:20]=[C:19]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:18]=[CH:17][C:16]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[CH:29]=1
Reactant: Cc1cc(OC2CCCCO2)ccc1-c1cccc(CO)c1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCc2cccc(-c3ccc(OC4CCCCO4)cc3C)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
A solution of methyl 3-(4-hydroxyphenyl)propanoate (1.43 g, 7.94 mmol), [2′-methyl-4′-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-yl]methanol (2.37 g, 7.94 mmol) and tributylphosphine (2.97 mL, 11.9 mmol) in toluene (120 mL) was stirred under ice-cooling and 1,1′-(azodicarbonyl)dipiperidine (3.00 g, 11.9 mmol) was added by small portions. The mixture was warmed to room temperature and stirred for 24 hrs. Hexane (60 mL) was added to the reaction mixture and the precipitated insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-20% ethyl acetate/hexane) to give the title compound as a colorless oil (3.05 g, yield 83%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[O:15][C:14](=S)[NH:13][C:12]1=[O:17].C([OH:20])C.OO>C(Cl)(Cl)Cl.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[O:15][C:14](=[O:20])[NH:13][C:12]1=[O:17]
Reactant: O=C1NC(=S)OC1c1ccc2ccccc2c1
Reactant: CCO
Agent: OO
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1NC(=O)C(c2ccc3ccccc3c2)O1

Procedure:
5-(2-Naphthyl)oxazolidin-4-one-2-thione (2.0 g., 8.2 mmoles) was partially dissolved in 25 ml. of aqueous ethanol at 50° C. Hydrogen peroxide (30%, 7 ml. was added) and the mixture refluxed for 4 hours. The reaction mixture was cooled, diluted with chloroform and water and the organic layer separated. The organic layer was extracted with saturated sodium bicarbonate. The bicarbonate layer was carefully acidified with dilute hydrochloric acid and the precipitated product recovered by filtration. Recrystallization from toluene gave purified 5-(2-naphthyl)oxazolidine-2,4-dione [0.2 g., m.p. 187°-188° C., pnmr/CDCl3 /delta: 6.54 (s, 1H), 7.3-8.1 (m, 7H)].
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]([NH2:8])=[O:7])(=[O:3])[CH3:2].[C:9]1([CH2:15][C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCOCC>S(=O)(=O)(O)O.CCCCCC>[C:9]1([CH2:15][C:16]([NH:8][C:6](=[O:7])[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(=O)SCC(N)=O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(=O)SCC(=O)NC(=O)Cc1ccccc1
Reaction time: 8 h

Procedure:
A reaction mixture comprising 6.65 g. (0.05 mole) of 2-(acetylthio) acetamide, 10 ml. of 2-phenylacetyl chloride, and 1 drop of sulfuric acid was heated in a steam bath for 0.5 hour, and then allowed to stand overnight at room temperature, after which it solidified. There was then added 50 ml. of ether and 20 ml. of hexane, followed by stirring for 10 minutes and then filtering. A yield of 8.5 g. of a tan solid was obtained, which was then chromatographed on 100 g. of silica gel. eluting with 5% ether in dichloromethane, followed by concentration to dryness. The solid was suspended in 60 ml. of ethanol and stirred in an ice bath for 1 hour. The product of white crystals, m.p. 153°-155° C., was obtained in a 5.6 g. yield.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][CH2:2][CH2:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7])[CH3:24])=[CH:19][CH:18]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: C=C(C)CC(O)(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)CC(O)(CCN[C@@H](C)c1ccc(Br)cc1)c1ccccc1
Temperature: 96 °C
Yield: 60.1 %

Procedure:
1-chloro-5-methyl-3-phenylhex-5-en-3-ol (1.28 g, 5.7 mmol), (S)-1-(4-bromophenyl)ethanamine (1.37 g, 1.2 equiv), KI (995 mg, 1.05 equiv), K2CO3 (1.57 g, 2 equiv) were mixed with acetonitrile (15 mL) and heated to reflux (oil bath 96° C.) for overnight. After being cooled to rt, the mixture was filtered, concentrated, and purified by chromatography on a 40-g silica gel column, eluted with 0-8% MeOH in CH2Cl2, to afford 1-((S)-1-(4-bromophenyl)ethylamino)-5-methyl-3-phenylhex-5-en-3-ol (1.33 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[N:11]1([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:26][S:23]([C:20]2[CH:19]=[CH:18][C:17]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:22][CH:21]=2)(=[O:24])=[O:25])=[O:10])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(N2CCOCC2)cc1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chlorophenylisocyanate (2.61 g, 17 moles) was dissolved in 16 ml of acetone and was then added dropwise to the sulfonamide solution. The mixture was then stirred overnight at room temperature, resulting in the formation of a white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][CH2:12][C:13](Cl)=[O:14])(=[O:10])[CH3:9].[F:16][C:17]([F:22])([F:21])[CH2:18][NH:19][CH3:20]>C1(C)C=CC=CC=1>[F:16][C:17]([F:22])([F:21])[CH2:18][N:19]([CH3:20])[C:13](=[O:14])[CH2:12][O:11][C:8](=[O:10])[CH3:9]
Reactant: CNCC(F)(F)F
Reactant: CC(=O)OCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)N(C)CC(F)(F)F
Temperature: 20 °C
Reaction time: 15 h
Yield: 79.8 %

Procedure:
10 g (0.1 mol) of triethylamine and 13.6 g (0.1 mol) of acetoxyacetyl chloride were added to a solution of 9.9 g (0.1 mol) of N-(2,2,2-trifluoroethyl)-N-methylamine in 150 ml of toluene and the mixture was stirred at 20° C. for 15 hours. It was then filtered and the filtrate was distilled. 17 g (79.8% of theory) of N-(2,2,2-trifluoroethyl)-N-methyl-acetoxyacetamide of boiling point 110° C./3 mbar were obtained. ##STR11## was obtained analogously; ND20 :1.4333. ##STR12##
Reaction SMILES: C[CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][CH2:4][N:3]1[C:9]#[N:10].[CH3:11][O-:12].[Na+]>CO>[CH3:8][CH:6]1[CH2:5][CH2:4][N:3]([C:9](=[NH:10])[O:12][CH3:11])[CH2:2][CH2:7]1
Reactant: CC1CCN(C#N)C(C)C1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)N1CCC(C)CC1

Procedure:
In the manner given in Example 2, methyl 4-methyl-1-piperidinecarbonitrile is treated with sodium methoxide in methanol to give methyl 4-methyl-1-piperidinecarboximidate.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>>[CH3:10][S:11]([O:8][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)(=[O:13])=[O:12]
Reactant: CC1(C)OCC(CO)O1
Reactant: CS(=O)(=O)Cl
Product: CC1(C)OCC(COS(C)(=O)=O)O1

Procedure:
reacting an optically active isomer of 2,2-dimethyl-1,3-dioxolane-4-methanol with methanesulphonyl chloride, to obtain a corresponding (2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulphonate;
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[C:9]([O:10][C:11]2[C:16]([S:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[CH:24]=[CH:25][S:26][C:19]=34)=[CH:15][N:14]=[C:13]([NH:27][C:28]3[S:29][CH:30]=[C:31]([CH:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)[N:32]=3)[CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.C(N(CC)CC)C.[C:46](OC(=O)C)(=[O:48])[CH3:47].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:3][C:4]1[C:9]([O:10][C:11]2[C:16]([S:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[CH:24]=[CH:25][S:26][C:19]=34)=[CH:15][N:14]=[C:13]([NH:27][C:28]3[S:29][CH:30]=[C:31]([CH:33]4[CH2:38][CH2:37][N:36]([C:46](=[O:48])[CH3:47])[CH2:35][CH2:34]4)[N:32]=3)[CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncccc1Oc1cc(Nc2nc(C3CCNCC3)cs2)ncc1Sc1ccnc2ccsc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2csc(Nc3cc(Oc4cccnc4C)c(Sc4ccnc5ccsc45)cn3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.9 %

Procedure:
4-(2-Methylpyridin-3-yloxy)-N-(4-(piperidin-4-yl)thiazol-2-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine dihydrochloride (0.051 g, 0.08 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (0.10 mL, 0.74 mmol) and acetic anhydride (0.017 mL, 0.19 mmol) were added and the reaction was stirred at ambient temperature overnight. Saturated sodium bicarbonate solution was added, and the reaction was extracted with ethyl acetate. The organic layer was dried and concentrated to give the title compound (0.051 g, 70% yield) as yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.50 (d, 1H), 8.41 (dd, 1H), 7.73 (d, 1H), 7.56 (d, 1H), 7.19 (m, 1H), 7.17 (m, 1H), 6.92 (d, 1H), 6.40 (d, 1H), 6.36 (s, 1H), 4.67 (m, 1H), 3.86 (m, 1H), 3.13 (m, 1H), 2.69 (m, 2H), 2.16 (s, 3H), 1.94 (m, 2H), 1.60 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=1)=[O:9].B(Br)(Br)Br>C(Cl)(Cl)Cl.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)=[O:9]
Reactant: COc1ccc(C(=O)c2ccccc2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1C(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
4-Methoxyphenyl 2-methylphenyl ketone (1.660 g) obtained in Example 125 was dissolved in chloroform (10 ml), a solution of 1.0 M boron tribromide in dichloromethane (29 ml) was added while cooled in ice, and the admixture was stirred at room temperature overnight. A solution of 1.0 M boron tribromide in dichloromethane (15 ml) was further added, and the admixture was stirred at room temperature for 2 days. The reaction mixture was then treated in the same manner as described in Example 121 to obtain 1.501 g of the title compound (yield: 96%).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][O:9][C:10]([C:12]1[N:13]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:14]2[C:19]([C:20](=[O:45])[C:21]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[CH:18][CH:17]=[C:16]([Cl:46])[CH:15]=2)=[O:11]>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[CH3:8][O:9][C:10]([C:12]1[N:13]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:14]2[C:19]([C:20](=[O:45])[C:21]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)(=[O:31])=[O:30])=[CH:27][CH:28]=1)=[CH:18][CH:17]=[C:16]([Cl:46])[CH:15]=2)=[O:11]
Reactant: COC(=O)c1c(Cc2ccc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(Cc2ccc(S(=O)(=O)N3CCNCC3)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of TFA and DCM (1:4, 5 mL) was added to 3-[4-(4-t-butoxycarbonylpiperazine-1-sulfonyl)-benzyl]-7-chloro-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxylic acid methyl ester (48 mg, 0.07 mmol) and the resulting mixture stirred at RT for 2 h. The reaction mixture was evaporated under reduced pressure, and the oily solid residue was purified by flash chromatography (DCM/MeOH, 100:0 to 90:10) to afford 7-chloro-4-oxo-1-phenyl-3-[4-(piperazine-1-sulfonyl)-benzyl]-1,4-dihydro-quinoline-2-carboxylic acid methyl ester trifluoroacetate as an off-white powder. MS=552 [M+H]+; MP=203.0-205.0° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][NH:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1.CCN(CC)CC>C(Cl)Cl>[NH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([CH2:8][N:7]([CH3:6])[C:1](=[O:4])[CH:2]=[CH2:3])=[CH:10]1
Reactant: C=CC(=O)Cl
Reactant: CNCc1c[nH]c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
Acryloyl chloride (0.33 mL, 4.10 mmole) was added to a solution of 3-(methylaminomethyl)-1H-indole (0.60 g, 3.70 mmole) and Et3N (1.03 mL, 7.40 mmole) in CH2Cl2 (30 mL) at 0° C. The reaction was held at 0° C. for ten minutes, then was stirred overnight at RT. The solution was concentrated in vacuo and the residue was diluted with water. The solution was extracted with ethyl acetate, and the combined organic extracts were washed with brine and dried over Na2SO4. The title compound (0.64 g, 80%) was obtained as a light yellow solid: MS (ES) m/e 215 (M+H)+.