Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6](=[O:21])[N:7]([CH:18]([CH3:20])[CH3:19])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(N(CC)CC)C>[C:23]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][N:7]([CH:18]([CH3:19])[CH3:20])[C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:22])=[O:21])=[CH:16][CH:15]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)N(CCOc1ccc(N)cc1)C(=O)NCCN(C)C
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)N(CCOc1ccc(NC(=O)c2ccccc2)cc1)C(=O)NCCN(C)C

Procedure:
The title compound is prepared by reacting the compound of Example 64: N'-[2-(dimethylamino)ethyl]-N-(1-methylethyl)-N-[2-(4-aminophenoxy)ethyl]urea with benzoyl chloride in triethylamine.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.[F:26][C:27]1([F:32])[CH2:31][CH2:30][NH:29][CH2:28]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:29]4[CH2:30][CH2:31][C:27]([F:32])([F:26])[CH2:28]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1
Reactant: FC1(F)CCNC1
Reactant: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Product: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CCC(F)(F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-Dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-cyclo hexyl methyl)-amide, and 3,3-Difluoro-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.68-8.71 (bs, 1H), 7.89 (d, J=9.2 Hz, 1H), 7.55-7.62 (m, 2H), 7.03 (d, J=9.3 Hz, 1H), 4.67 (s, 1H), 3.96-4.03 (m, 2H), 3.76-3.80 (m, 2H), 3.37-3.39 (m, 2H), 2.54-2.61 (m, 2H), 1.88-2.08 (m, 4H), 1.68-1.76 (m, 4H). m/z: 460.2 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:30][CH2:31][CH3:32])[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:9]2[O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[CH:4][C:3]=1[O:33]C.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:30][CH2:31][CH3:32])[C:8]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[C:9]2[O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[CH:4][C:3]=1[OH:33]
Reactant: CCCc1cc2cc(OC)c(F)cc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCc1cc2cc(O)c(F)cc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Yield: 83.6 %

Procedure:
Methyl ether (140) (0.15 g, 0.33 mmol) was treated with BBr3 in CH2Cl2 to give the crude product as a brown viscous oil, which was purified by reverse phase preparation HPLC on Agilent 1100 to afford 122 mg (84%) of the title compound (141) as a light yellow solid. mp 118-120° C. 1H NMR (400 MHz, CH3OH-d4): δ 0.77 (t, J=7.3 Hz, 3H), 1.40-1.55 (m, 2H), 2.52 (t, J=7.6 Hz, 2H), 6.27 (d, J=15.9 Hz, 1H), 6.55 (d, J=8.4 Hz, 2H), 7.08-7.16 (m, 2H), 7.20-7.40 (m, 7H), 7.48-7.56 (m, 2H). LCMS (APCI): m/z 443 (M+H)+, m/z 441 (M−H)−. Anal. Calc for C29H25FO4.0.4H2O: C, 74.79; H, 5.33. Found: C, 74.71; H, 5.21.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([NH:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[Br:14]Br>C(O)(=O)C>[Br:14][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([NH:9][CH3:10])=[O:8])=[O:3]
Reactant: CNC(=O)c1cccc(C(C)=O)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: CNC(=O)c1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To an acetic acid (2.4 mL) solution of 3-acetyl-N-methylbenzamide (0.33 g), at room temperature, an acetic acid (0.30 mL) solution of bromine (95 μL) was added dropwise, and the resultant was stirred at room temperature for 3.5 hours and then stirred at 60° C. for 1 hour. The reaction solution was concentrated under reduced pressure and then dried to obtain the title compound (0.50 g) as a yellow oil.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:14]O>>[C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([O:10][CH3:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(C(=O)O)c1ccccc1
Reactant: CO
Agent: Cl
Product: CCC(C(=O)OC)c1ccccc1
Temperature: 25 °C

Procedure:
2-Phenylbutyric acid (10 g, 61 mmole) was dissolved in methanol (30 ml) treated with concentrated HCl (1 ml) and heated at reflux for 20 hours. The heating was stopped and the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the oily residue was treated with ethyl acetate (100 ml). The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a clear oil. Yield 10.61 g (97%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.81 (t, J=7.35 Hz, 3H) 1.69 (m, 1H) 1.98 (m, 1H) 3.53 (d, J=7.35 Hz, 1H) 3.58 (s, 3H) 7.30 (m, 5H).
Reaction SMILES: C[CH:2]([O:10][C:11]([C:13]1[CH:18]=CC=C(S(O)(=O)=O)[C:14]=1[C:23](O)=O)=[O:12])[CH2:3][O:4][C:5]([C:7]([CH3:9])=[CH2:8])=[O:6].C(OCCO)(=O)C(C)=C.CC1C(C)C(=O)[O:38][S:37]1(=[O:44])=[O:43]>>[CH3:18][CH:13]([CH:14]([S:37]([OH:44])(=[O:43])=[O:38])[CH3:23])[C:11]([O:10][CH2:2][CH2:3][O:4][C:5](=[O:6])[C:7]([CH3:9])=[CH2:8])=[O:12]
Reactant: CC1C(=O)OS(=O)(=O)C1C
Reactant: C=C(C)C(=O)OCC(C)OC(=O)c1cccc(S(=O)(=O)O)c1C(=O)O
Agent: C=C(C)C(=O)OCCO
Product: C=C(C)C(=O)OCCOC(=O)C(C)C(C)S(=O)(=O)O
Yield: 70 %

Procedure:
By procedure (9) (a) above, β-hydroxyethyl methacrylate is reacted with an equimolar amount of 3,4-dimethyl-1,2-oxathiolane-5-one-2,2-dioxide. There is obtained a 70% yield of methacryloxyethyl 2-methyl-3-sulfo-butyrate.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.O.Cl.C(O[CH:18](OCC)[CH2:19][CH:20](OCC)OCC)C>C(O)C>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]([N:9]2[CH:20]=[CH:19][CH:18]=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(CC(OCC)OCC)OCC
Reactant: NNc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1cccc(-n2cccn2)c1
Yield: 80 %

Procedure:
Into a 500 ml., 2-neck flask, fitted with a condenser and a magnetic stirrer, is successively added 35.2 g. (0.2 M.) of m-trifluoromethylphenyl hydrazine, 15 ml. of water, 20 ml. of 100% ethanol, 16.5 ml. of concentrated hydrochloric acid (slowly) and 44.0 g. (0.2 M.) of 1,1,3,3-tetraethoxypropane. The reaction mixture is then heated slowly to between 80° C. and 90° C., and after maintaining the mixture at this temperature range for a period of between 2 and 3 hours, the reaction mixture is cooled, quenched on ice water, extracted with ethylacetate and washed several times with water. After drying the organic solution over sodium sulfate, the solvent is evaporated on a rotary evaporator to obtain a very dark liquid which is then distilled at 70° to 80° C. and a pressure of about 100 microns to yield a light yellow oil (Yield: 80%).
Reaction SMILES: CC1(C)C(C2C=CC=CC=2)O1.[CH3:12][C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH:14]=O.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([S@@:29]([NH2:31])=[O:30])=[CH:25][CH:24]=1>C1C=CC=CC=1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.FC1C(B(C2C(F)=C(F)C(F)=C(F)C=2F)C2C(F)=C(F)C(F)=C(F)C=2F)=C(F)C(F)=C(F)C=1F>[CH3:12][C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH:14]=[N:31][S@:29]([C:26]1[CH:27]=[CH:28][C:23]([CH3:32])=[CH:24][CH:25]=1)=[O:30]
Reactant: Cc1ccc([S@@](N)=O)cc1
Reactant: CC(C)(C=O)c1ccccc1
Agent: [Ti+4]
Agent: CC1(C)OC1c1ccccc1
Agent: CC[O-]
Solvent: c1ccccc1
Product: Cc1ccc([S@](=O)N=CC(C)(C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 81 %

Procedure:
To a stirred solution of 2.5 g of 2,2-dimethyl-3-phenyloxirane (16 mmol) in 85 mL of anhydrous benzene is added 0.415 g (0.362 mmol, 5 mol %) of tris(pentafluorophenyl) borane. The light yellow solution is stirred at 25° C. for 19 hours. The reaction mixture containing the 2-methyl-2-phenylpropanal is then treated with (S)-p-toluenesulfinamide (2.3 g, 15 mmol) followed by a solution of 16 mL (73 mmol) titanium ethoxide in 155 mL of benzene. The yellow solution is stirred at 25° C. for 24 hours then cooled to 5–10° C. and quenched with 245 mL of water. The mixture is filtered through diatomaceous earth, and the filter cake washed with methylene chloride (4×50 mL). The aqueous layer is washed with methylene chloride (1×25 mL). The combined organic layers are dried (MgSO4) and concentrated under reduced pressure to give 3.74 g (81%) of the desired product as a white solid. The product is used without further purification in the next step.
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([N:15]1[C:19](=[O:20])[C:18](Cl)=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:16]1(=[O:29])=[O:28])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([N:15]1[C:19](=[O:20])[C:18]([NH:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:16]1(=[O:28])=[O:29])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCOc1ccccc1
Product: CC(C)(C)N1C(=O)C(NCCOc2ccccc2)=C(c2ccccc2)S1(=O)=O
Yield: 13 %

Procedure:
The title compound was prepared as described for Example 24 from (2-phenoxyethyl)amine and 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide. The residue was purified by silica gel column chromatography (Horizons Biotage) using 15-20% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.026 g, 13%). 1H NMR (500 MHz CDCl3): δ 7.60-7.51 (m, 2H), 4.72-7.42 (m, 2H), 7.29 (t, 2H), 6.99 (t, 1H), 6.84 (d, 2H), 5.67 (t, 1H), 3.89 (t, 2H), 3.25 (q, 2H), 1.75 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.7, 158.3, 135.2, 131.7, 129.5, 129.8, 129.0, 125.2, 121.7, 114.7, 108.1, 65.9, 61.8, 43.5, 27.8; Mass Spectrum M+H+ 401.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.C[Li].C([Li])(C)(C)C.[C:20](=[O:22])=[O:21].Cl>CCOCC>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:20]([OH:22])=[O:21])[CH:11]=[CH:10]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: O=C=O
Agent: Cl
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: O=C(O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 653.2 %

Procedure:
To a slurry of 5.00 g (2.4 mmol, Aldrich) of 6-bromo-2-naphthol in 150 ml of dry ether at -78° was added dropwise, 16 ml (1.4M in ether, 22 mmol, Aldrich) of methyllithium solution over 10 minutes. The reaction mixture was stirred for 10 minutes, then 28 ml (1.8M in pentane, 50 mmol, Aldrich) of t-butyllithium solution was added dropwise over 15 minutes. The resulting slurry was stirred at -78° for 30 minutes then at 0° for 15 minutes. The reaction mixture was re-cooled to -78° , added into 100 g of crushed dry ice via cannula, and allowed to warm to room temperature over about ~2 hours, then added to 200 ml of 1M aqueous HCl solution and extracted with 100 ml of ethyl acetate. The organic extract was separated, washed with an additional 200 ml of H2O and concentrated in vacuo to give a pale yellow solid. The crude material was dissolved in 125 ml of warm, saturated aqueous NaHCO3 solution and extracted with two 50 ml portions of ethyl acetate. The aqueous phase was acidified to pH 1 with concentrated HCl. The solid which precipitated was collected on a Buchner funnel then dried under vacuum at 110° to afford 2.95 g (70%) of title compound as an off-white powder, m.p. 237°-241°.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:6][C@H:7]([NH:22][C:23](=[O:25])[CH3:24])[C@H:8]([OH:21])[C@H:9]1[CH2:14][CH2:13][C@@H:12]([O:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[CH2:11][NH:10]1.[H][H]>[Pd].CO>[ClH:1].[F:29][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([F:2])[CH:28]=1)[CH2:6][C@H:7]([NH:22][C:23](=[O:25])[CH3:24])[C@H:8]([OH:21])[C@H:9]1[CH2:14][CH2:13][C@@H:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:11][NH:10]1
Reactant: C=CCCCO[C@@H]1CC[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(C)=O)NC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCCO[C@@H]1CC[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(C)=O)NC1
Yield: 86.2 %

Procedure:
Stir N-(1S,2R)-{1-(3,5-Difluoro-benzyl)-2-hydroxy-2-[(5R,2R)-5-pent-4-enyloxy-piperdin-2-yl]-ethyl}-acetamide hydrochloride (0.02 g, 0.04 mmol) and 10% Palladium on carbon (0.004 g, 0.004 mmol) in 2 mL methanol under a balloon of hydrogen at room temperature until all starting material is consumed. Filter the suspension through a pad of filtering agent and wash with methanol. Concentrate under reduced pressure to give the desired compound (0.015 g, 88%).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[C:15]([CH3:16])=[C:14]([OH:17])[C:13]([CH3:18])=[CH:12][C:10]=1[OH:11].C(O[CH:23]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(=O)C>CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C(O)C>[CH3:18][C:13]1[C:14](=[O:17])[C:15]([CH3:16])=[C:9]([CH3:8])[C:10](=[O:11])[C:12]=1[CH:23]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: CCOC(=O)CCCCC(OC(C)=O)c1cccs1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCC(C1=C(C)C(=O)C(C)=C(C)C1=O)c1cccs1
Temperature: 60 °C
Yield: 74.8 %

Procedure:
D-Camphor-10-sulfonic acid (0.1 g) was added to a toluene solution (50 ml) of 2,3,5-trimethylhydroquinone (3.1 g, 0.02 mole) and ethyl 6-acetoxy-6-(2-thienyl)hexanoate (5.6 g, 0.02 mole), and the mixture was heated at 60° C. for 6.5 hours, with stirring. After cooling, ethanol (100 ml) and a 10% aqueous solution (20 ml) of ferric chloride were added to the reaction solution, followed by stirring for 10 minutes. The reaction product was extracted with isopropyl ether, and the organic layer was washed with water, dried (over magnesium sulfate) and concentrated under reduced pressure. The residue was chromatographed on a silica gel column, and elution was performed with isopropyl ether-hexane (1:1) to give ethyl 6-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-6-(2-thienyl)hexanoate (5.6 g, 76%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound Nos. 2 to 8 were prepared.
Reaction SMILES: [C:1]([C:9]1[C:10]([OH:21])=[CH:11][C:12]([O:19][CH3:20])=[C:13]([S:15](O)(=[O:17])=[O:16])[CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.CCCCC.S(Cl)([Cl:35])=O>O1CCCC1.C(Cl)(Cl)Cl>[C:1]([C:9]1[C:10]([OH:21])=[CH:11][C:12]([O:19][CH3:20])=[C:13]([S:15]([Cl:35])(=[O:17])=[O:16])[CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(O)c(C(=O)c2ccccc2)cc1S(=O)(=O)O
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(O)c(C(=O)c2ccccc2)cc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-benzoyl-4-hydroxy-2-methoxybenzenesulfonic acid (Uvinul MS-40, a product of BASF Wyandotte Corporation) (20.0g, 0.065 mole) and 250 ml of warm tetrahydrofuran was cooled to room temperature. A solution of 8.0g (0.10 mole) of pyridine in 25 ml tetrahydrofuran was added accompanied by an exotherm. The resulting mixture was stirred at room temperature for 30 minutes, then poured into 200 ml pentane and stirred briefly before the sulfonic acid salt (23.5g) was collected by filtration. This salt was added slowly over 15 minutes to 29.0g (0.244 mole) of thionyl chloride at 50° C. under a nitrogen atmosphere. The resulting mixture was stirred at 55° C. for 1 hour 45 minutes. The reaction mixture was poured into 600 ml of ice water to precipitate the product. The product was isolated by filtration and transferred to a separatory funnel with 200 ml chloroform. The mixture was extracted with 125 ml of 2.5 % HCl, 100 ml of 2.5% HCl and 100 ml water. The organic phase was dried with anhydrous magnesium sulfate and stripped of solvent using aspirator and high vacuum systems. The product weighed 16.5g and melted at 165°-172° C.
Reaction SMILES: [N:1](OCCC(C)C)=O.[CH2:9]([O:11][C:12](=[O:35])[C@@H:13]([CH2:20][C:21]1[CH:26]=[C:25]([Br:27])[C:24]([NH2:28])=[C:23]([CH3:29])[C:22]=1[CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10].C([O-])(=O)C.[K+]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:9]([O:11][C:12](=[O:35])[C@@H:13]([CH2:20][C:21]1[C:22]([CH2:30][O:31][C:32](=[O:34])[CH3:33])=[C:23]2[C:24](=[C:25]([Br:27])[CH:26]=1)[NH:28][N:1]=[CH:29]2)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10]
Reactant: CCOC(=O)C[C@H](Cc1cc(Br)c(N)c(C)c1COC(C)=O)C(=O)OCC
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1COC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 77 %

Procedure:
Isoamyl nitrite (2.3 mL, 17 mmol), was added drop-wise to an ice cold solution of 2-(S)-(2-Acetoxymethyl-4-amino-5-bromo-3-methyl-benzyl)-succinic acid diethyl ester (7.14 g, 16 mmol) in 5% acetic acid in toluene (280 mL). Mixture stirred at 0° C. for 40 minutes. Potassium acetate (4.00 g, 41 mmol) was added to the mixture. Mixture was slowly warmed to room temperature. Reaction was stirred at room temperature for 14 hours. Mixture was washed twice with water and once with brine. Organic was dried (magnesium sulfate) filtered and concentrated. Silica gel chromatography (ethyl acetate-hexanes) afforded the desired product in 77% yield as an amber oil. MS m/e (M+H)+=455.0, 457.0.
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([O:20]CC)=O.[NH2:23][C:24]1[S:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1>>[S:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[NH:23][C:18]([C:3]1[N:4]([CH3:17])[S:5](=[O:15])(=[O:16])[C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][C:7]=2[C:2]=1[OH:1])=[O:20]
Reactant: CCOC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1nc2ccccc2s1
Product: CN1C(C(=O)Nc2nc3ccccc3s2)=C(O)c2sc3ccccc3c2S1(=O)=O
Yield: 70 %

Procedure:
Prepared analogous to Example 1 from ethyl 4-hydroxy-2-methyl-2H-[1]-benzothieno[2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-benzothiazole with a yield of 70% of theory.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[CH2:21][NH:20][CH2:19]5)[C:12]=3[O:14][CH3:15])[C:7](=[O:25])[C:6]([C:26]([OH:28])=[O:27])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:29]=O>C(O)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[CH2:21][N:20]([CH3:29])[CH2:19]5)[C:12]=3[O:14][CH3:15])[C:7](=[O:25])[C:6]([C:26]([OH:28])=[O:27])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1c(-c2ccc3c(c2)CNC3)ccc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C=O
Solvent: O=CO
Product: COc1c(-c2ccc3c(c2)CN(C)C3)ccc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 73.3 %

Procedure:
To 100 mg of 1-cyclopropyl-7-(isoindolin-5-yl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid were added 1 ml of formic acid and 65 mg of formalin, and the resulting mixture was heated under reflux for 1 hour, after which the solvent was distilled under reduced pressure to remove the solvent. To the resulting residue was added 5 ml of water, and the resulting mixture was adjusted to pH 7 with a saturated aqueous sodium hydrogencarbonate solution and extracted with five 5-ml portions of chloroform. The chloroform layer obtained was dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent. To the resulting residue were added ethanol and diethyl ether, and the crystals were collected by filtration. To the crystals collected were added 1 ml of ethanol, 1 ml of a 1N aqueous sodium hydroxide solution and 1 ml of water to dissolve the crystals, after which carbon dioxide was bubbled into the resulting solution and the crystals were collected by filtration to obtain 76 mg of light-yellow 1-cyclopropyl-8-methoxy-7-(2-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([NH:34][CH2:35][CH3:36])=[O:33])=[CH:28][CH:27]=3)[C:11]=2[CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)=[O:6])[CH2:3][CH2:2]1.O.NN>C(O)C>[NH2:15][CH2:14][CH2:13][CH2:12][C:11]1[N:10]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([NH:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:31]=2)[N:9]=[N:8][C:7]=1[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:6]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCN)cc1
Yield: 97.1 %

Procedure:
A solution of N-cyclopropyl-5-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (1.27 g, 2.6 mmol) obtained in Example 1201 and hydrazine hydrate (261 mg, 5.2 mmol) in ethanol (20 ml) was boiled under reflux for 3 hr, and the precipitated insoluble material was filtered off. The filtrate was concentrated to dryness to give the title compound as a white powder (0.9 g, 97%).
Reaction SMILES: [N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:27][C:28]1[N:32]=[C:31](Cl)[S:30][N:29]=1>C1COCC1>[C:16]([O:15][C:13]([N:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:31]3[S:30][N:29]=[C:28]([Cl:27])[N:32]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: Clc1nsc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3nc(Cl)ns3)CC2)CC1

Procedure:
A solution of tert-butyl 4,4′-bipiperidine-1-carboxylate (537 mg; 2.00 mmol) in dry THF (10 mL) was treated with triethylamine (307 μL; 2.20 mmol). A solution of 3,5-dichloro-1,2,4-thiadiazole (341 mg; 2.20 mmol) in THF (5 mL) was added dropwise at ambient temperature. An immediate precipitate was accompanied by a mild exotherm. The mixture was stirred until it returned to ambient temperature. The mixture was filtered and the filtrate evaporated to afford the title compound. LRMS calc: 386.2 obs: 387.2 (M+H), 287.1 (M-BOC+H).
Reaction SMILES: ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O.C([O-])(=O)C.[Na+].[CH2:18]([OH:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(Cl)Cl.CC1(C)N([O])C(C)(C)CCC1>[CH:18](=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCO
Agent: CC(=O)[O-]
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: CCCCCCCC=O
Reaction time: 1.33 h
Yield: 91.4 %

Procedure:
3.5 g (15.1 mmol) of trichloroisocyanuric acid, 3.7 g (45.1 mmol) of sodium acetate and 10 mg (0.06 mmol) of TEMPO were suspended in 40 ml of methylene chloride in a 100 ml sulphonation flask and the suspension was cooled to (-7)-(-9)° C. while stirring. A solution of 5 g (38.4 mmol) of 1-octanol in 20 ml of methylene chloride was dosed in within 20 minutes, whereupon the mixture was held at (-7)-(-9)° C. for 80 minutes. Thereafter, the reaction had finished. For the working up, the white precipitate was filtered off and the filtrate was washed with sodium bicarbonate solution and with sodium chloride solution. Distillation of the crude product gave 4.5 g (91%) of octanal, GC content: (98.2%) (area percent).