Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[CH2:11](O)[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)=O>[OH:10][C:7]1[CH:6]=[C:4]2[O:5][CH2:1][O:2][C:3]2=[CH:9][C:8]=1[CH:11]=[CH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: OCC=Cc1ccccc1
Solvent: O=CO
Product: Oc1cc2c(cc1C=CCc1ccccc1)OCO2

Procedure:
The compounds of Category II may be prepared in the following manner: A mixture of sesamol and cinnamyl alcohol in aqueous formic acid is refluxed to yield 2-hydroxy-4,5-methylenedioxy-cinnamylbenzene. This intermediate is then etherified in conventional manner by reaction with an appropriate alkyl halide or alkyl sulphate to yield the desired compound. The synthesis is illustrated by the following formulas. ##EQU4##
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Cl.[CH:21]([NH:23][CH2:24][CH:25]1[O:30][CH2:29][CH2:28][NH:27][CH2:26]1)=[O:22].N12CCCN=C1CCCCC2>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:27]3[CH2:28][CH2:29][O:30][CH:25]([CH2:24][NH:23][CH:21]=[O:22])[CH2:26]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: O=CNCC1CNCCO1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CNC=O)C3)c(F)c21
Reaction time: 8 h

Procedure:
A solution of 813 mg of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 650 mg of 2-(formylaminomethyl)morpholine hydrochloride and 1.0 g of 1,8-diazabicyclo[5.4.0]undec-7-ene in 10 ml of acetonitrile is refluxed for 3 hours and allowed to stand at room temperature overnight. The precipitated crystals are collected by filtration and successively washed with acetonitrile, water and acetone to give 1-ethyl-6,8-difluoro-7-[2-(formylaminomethyl)morpholino]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, melting at 234°-236° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:8][CH:7]=1)=[O:5].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C(Cl)Cl>[CH3:24][S:25]([N:14]1[CH2:15][CH2:16][CH:11]([C:9]2[O:8][CH:7]=[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[N:10]=2)[CH2:12][CH2:13]1)(=[O:27])=[O:26]
Reactant: CCOC(=O)c1coc(C2CCNCC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1coc(C2CCN(S(C)(=O)=O)CC2)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Ethyl 2-(4-piperidino)-1,3-oxazole-4-carboxylate (500 mg, 2.230 mmol) and triethylamine (0.466 ml, 3.34 mmol) were dissolved in dry DCM and cooled down to 0° C. Methanesulfonyl chloride (0.190 ml, 2.453 mmol) was added slowly at 0° C. and the reaction mixture was stirred at RT overnight. Small amount of water was added carefully and organic phase was washed with 1M Na2CO3 and water. Organic phase was dried and evaporated to yield the title compound 89%. 1H-NMR (400 MHz; CDCl3): δ 1.38 (t, 3H), 1.97-2.11 (m, 2H), 2.15-2.24 (m, 2H), 2.81 (s, 3H), 2.88-3.07 (m, 3H), 3.72-3.82 (m, 2H), 4.39 (q, 2H), 8.17 (s, 1H).
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[CH:10]=1)=[C:2](C)[CH3:3].[O:14]=[O+][O-].S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>Cl.O.CO>[N:13]1[CH:12]=[CH:11][N:9]2[CH:10]=[C:5]([CH2:1][C:2](=[O:14])[CH3:3])[CH:6]=[CH:7][C:8]=12
Reactant: O=[O+][O-]
Reactant: CC(C)=Cc1ccc2nccn2c1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: O
Solvent: CO
Product: CC(=O)Cc1ccc2nccn2c1
Temperature: -5 °C
Yield: 70.5 %

Procedure:
In a solution of 12.3 g of conc. hydrochloric acid, 45 ml of water and 45 ml of methanol was dissolved 20 g of 6-isobutenylimidazo[1,2-a]pyridine. The solution was cooled to -5° C. Ozone was introduced to the solution at -5° to 0° C. for 4 hours. The endpoint of the reaction was confirmed by thin layer chromatography. After completion of the reaction, a solution of 30.6 g of sodium sulfite in 160 ml of water was dropwise added under cooling at such a rate that the temperature did not exceed 20° C. Next, 22 g of sodium bicarbonate and an appropriate amount of salt were added as solids and the mixture was extracted with chloroform. The chloroform extract was washed twice with a saturated saline solution. After drying over magnesium sulfate, chloroform was removed by distillation under reduced pressure. The residue was purified by distillation under reduced pressure to obtain 14.2 g (70.5%) of 1 -(imidazo[1,2-a]pyridin-6-yl)-2-propanone.
Reaction SMILES: [C:1]12([CH2:16][CH2:15][CH2:14][CH2:13]1)[C:9]1[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:3](=[CH:10][C:11]#[N:12])[CH2:2]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[NH2:12][CH2:11][CH:10]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:2]1
Reactant: N#CC=C1CC2(CCCC2)c2ccccc21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: NCC=C1CC2(CCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of spiro(cyclopentane-1,1'-indan)-3'-ylideneacetonitrile (10.5 g; 0.05 moles) in anhydrous ether (100 ml) is added dropwise under agitation to lithium aluminum hydride (2.5 g; 0.066 moles) suspended in ether (200 ml). After boiling for 3 hours the mixture is cooled to room temperature and the excess of hydride is decomposed by dropwise addition of a saturated sodium sulphate solution. The precipitate obtained is filtered off and washed with ether. The ether solutions are shaken with 2 N hydrochloric acid. The acid extracts are concentrated to a small volume in vacuum (bath temperature below 40° C.) and the amine hydrochloride is precipitated by treatment with conc. hydrochloric acid in the cooled. Yield 10.6 g (85%). Recrystallization from 2-propanol yields colourless crystals of mp. 190° C. identical with the product prepared according to example 3g.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C@H:14]([N:18]2[CH2:21][C:20]4([CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH2:19]2)[CH2:13][CH2:12]3)=[N:7][CH:8]=1)[CH3:2].[ClH:34].CO>O1CCOCC1>[ClH:34].[ClH:34].[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C@H:14]([N:18]2[CH2:21][C:20]4([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH2:19]2)[CH2:13][CH2:12]3)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCN(C(=O)OC(C)(C)C)CC3)C2)nc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCc1cnc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)nc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 100 %

Procedure:
To a flask charged with tert-butyl 2-[(1R)-5-(5-ethylpyrimidin-2-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (3-1b, 583 mg, 1.39 mmol) was added 8.0 mL of 4N HCl in dioxane at room temperature. A yellow precipitate formed immediately after the addition. The mixture was stirred at room temperature for 40 minutes. Anhydrous methanol (4 mL) was added to solublize the reaction. The resulting solution was stirred at room temperature for 4 hours. Solvent and excess HCl were removed and dried in vacuo to afford 630 mg (100%) of a light yellow solid (3-1c). The crude product was taken on to the next step without further purification. MS (ES+) 349.4 (M+H)+. 1H NMR (CD3OD) δ 1.40 (t, 3H) 2.21-2.28 (m, 5H) 2.61 (br s, 1H) 2.93 (q, 2H) 3.16-3.34 (m, 4H), 3.38-3.51 (m, 1H), 4.12-4.29 (m, 4H) 4.52-4.56 (m, 1H) 5.08-5.12 (m, 1H) 7.89-7.93 (m, 1H) 8.29-8.33 (m, 2H), 9.15-9.19 (m, 2H).
Reaction SMILES: F[C:2]1[C:3]([C@@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:2]2[C:3]([C@@H:8]3[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:24][CH:23]=1
Reactant: O[C@H]1CCC[C@@H](c2nccnc2F)C1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O[C@H]1CCC[C@@H](c2nccnc2Oc2ccc(Nc3ccccn3)cc2)C1
Temperature: 150 °C

Procedure:
A mixture of (rac)-cis-3-(3-fluoropyrazin-2-yl)cyclohexanol, prepared according to Scheme 35a, (48 mg, 0.245 mmol), 4-(pyridin-2-ylamino)phenol (91 mg, 0.489 mmol), and cesium carbonate (159 mg, 0.489 mmol) in NMP (2 mL) was heated in a Biotage™ microwave reactor at 150° C. for 0.5 h. The mixture was partitioned between H2O (10 ml) and CH2Cl2 (20 ml), the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×20 ml). The combined organic layers were dried (MgSO4), concentrated under reduced pressure, and the resulting brown oil was purified by reversed phase HPLC (Gilson Gemini-NX 10u C18 110A, 100×50.0 mm, 10% to 95% H2O/MeCN, 0.1% TFA). The product containing fractions were combined, neutralized by the addition of solid Na2CO3, and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to deliver (rac)-cis-3-(3-(4-(pyridin-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanol as a light yellow solid. MS (ESI, pos. ion) m/z: 363.0 (M+1). IC50 (uM) 0.02837.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([OH:23])[CH:22]=2)[O:19][C:18]([CH3:25])([CH3:24])[CH2:17][C:16]3([CH3:27])[CH3:26])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:36]([CH3:38])[CH3:37]>CC(C)=O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([O:23][CH:36]([CH3:38])[CH3:37])[CH:22]=2)[O:19][C:18]([CH3:24])([CH3:25])[CH2:17][C:16]3([CH3:27])[CH3:26])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cc1ccc(C#Cc2cc(OC(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Yield: 91 %

Procedure:
A solution of [4-(8-hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-acetic acid methyl ester (Intermediate 20, 0.02 g, 0.076 mmol) in acetone (2 mL) was treated with potassium carbonate (0.026 g, 0.19 mmol) and 2-iodopropane (5 mL, large excess) and the resulting reaction mixture was refluxed for 30 h. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as an oil (0.02 g, 91%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.[O:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:28]1[CH2:29][CH:30]=[C:31]([C:2]2[C:10]3[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=4)=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=2)[CH2:32][CH2:33]1
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cc(C2=CCOCC2)c2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 5-bromo-4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 2.23 mmol) in toluene/EtOH/H2O (4:2:1, 14 mL), was added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.70 g, 3.3 mmol), sodium carbonate (0.70 g, 6.7 mmol) and Pd(PPh3)4 (0.13 g, 0.11 mmol). The resulting solution was stirred for 12 hours at 80° C., cooled, and quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (×3) and the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was then purified by chromatography using silica gel, eluting with 1-50% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford 5-(3,6-dihydro-2H-pyran-4-yl)-4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as a yellow solid. LRMS (ESI) calc'd for C23H29N4O4Si [M+H]+: 453, found 453.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:14][CH2:15][CH2:16][O:17][S:18](=[O:21])(=[O:20])[OH:19].[OH-].[Na+]>O>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:14][CH2:15][CH2:16][O:17][S:18](=[O:20])(=[O:19])[OH:21])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: NCCOS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)NCCOS(=O)(=O)O)c1
Reaction time: 1 h
Yield: 93.5 %

Procedure:
221.5 g of 3-nitro-benzenesulphonyl chloride are introduced in portions into a solution of 150 g of sulphuric acid mono-2-amino-ethyl ester and 0.6 liter of water at 60°-70° C. During this procedure, the pH value is continuously kept between 9.0 and 10.0 by adding 45% strength sodium hydroxide solution dropwise. The mixture is subsequently stirred at 60°-70° C. and pH 9.0 to 10.0 for 1 hour and then allowed to cool and the resulting precipitate is filtered off. The precipitate is washed with water and dried at 80° C. 305 g of sulphuric acid mono-N-(3-nitro-benzenesulphonyl)-2-amino-ethyl ester are obtained. This ester is dissolved in 1.5 liters of dimethylformamide and hydrogenated over Raney nickel. After subsequently filtering off the catalyst and distilling off the solvent in vacuo, about 220 g of sulphuric acid mono-N-(3-aminophenylsulphonyl)-2-aminoethyl ester are obtained. ##STR16##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:25][C:26](=[O:34])OC1C=CC=CC=1.[CH3:35][NH2:36].O>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[NH:25][C:26]([NH:36][CH3:35])=[O:34])[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: CN
Reactant: COC(=O)c1cc2c(Oc3ccc(NC(=O)Oc4ccccc4)c(Cl)c3)ccnc2cc1OC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)OC)cc23)cc1Cl
Yield: 85 %

Procedure:
Phenyl N-(2-chloro-4-(7-methoxy-6-methoxycarbonyl-4-quinolyl)oxyphenyl)carbamate (1.92 g, 4.00 mmol) and 40% methylamine (methanol solution) (2 ml) were stirred in dimethylformamide (8 ml) at room temperature for 30 minutes. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and the drying agent was filtered out and the filtrate distilled off under reduced pressure. The obtained crude product was suspended in ethyl acetate, the suspension was diluted with hexane, and the crystals were filtered out, washed with hexane and blow-dried to obtain the title compound (1.41 g, 3.39 mmol, 85%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.C(=O)=O>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][C@@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:19][CH:20]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1Oc1ccc(Br)cc1
Agent: O=C=O
Solvent: CO
Product: CC(C)S(=O)(=O)N[C@H]1CCC[C@H]1Oc1ccc(Br)cc1

Procedure:
Separation of the enantiomers comprising cis-N-[2-(4-bromophenoxy)cyclopentyl]propane-2-sulfonamide (1.586 g, 4.38 mmol) was carried out by chiral chromatography. Column: Chiralpak® AD-H, 2.1×25 cm, 5 μm; Mobile phase: 75:25 carbon dioxide:methanol; Flow rate: 65 g/min. The first-eluting compound was enantiomer N-[(1R,2S)-2-(4-bromophenoxy)cyclopentyl]propane-2-sulfonamide (767 mg, 2.12 mmol, 48%) and the second-eluting peak provided desired product N-[(1S,2R)-2-(4-bromophenoxy)cyclopentyl]propane-2-sulfonamide upon removal of solvent in vacuo. Yield: 758 mg, 2.09 mmol, 48%. The absolute stereochemistry of these enantiomers was assigned by analogy to their higher homologues (see Example 7). The title compound, synthesized in the following step, proved significantly more potent than its enantiomer (prepared in the same way from N-[(1R,2S)-2-(4-bromophenoxy)cyclopentyl]propane-2-sulfonamide. On this basis, the (1S,2R) configuration was assigned to N-[(1S,2R)-2-(4-bromophenoxy)cyclopentyl]propane-2-sulfonamide. MS (APCI) m/z 364.2 (M+1). 1H NMR (500 MHz, CDCl3) δ 1.35 (d, J=6.8 Hz, 3H), 1.38 (d, J=6.8 Hz, 3H), 1.64 (m, 1H), 1.79-1.98 (m, 4H), 2.12 (m, 1H), 3.13 (septet, J=6.8 Hz, 1H), 3.86 (m, 1H), 4.59 (m, 1H), 4.63 (d, J=9.5 Hz, 1H), 6.78 (d, J=9.0 Hz, 2H), 7.39 (d, J=9.1 Hz, 2H). Data for N-[(1R,2S)-2-(4-bromophenoxy)cyclopentyl]propane-2-sulfonamide: MS (APCI) m/z 362.2, 364.2 (M+1). 1H NMR (500 MHz, CDCl3) δ 1.35 (d, J=6.8 Hz, 3H), 1.38 (d, J=6.8 Hz, 3H), 1.58-1.68 (m, 1H), 1.78-1.97 (m, 4H), 2.12 (m, 1H), 3.13 (septet, J=6.8 Hz, 1H), 3.86 (m, 1H), 4.59 (m, 1H), 4.64 (d, J=9.5 Hz, 1H), 6.78 (d, J=9.1 Hz, 2H), 7.39 (d, J=9.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH:26][CH2:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])(=[O:25])=[O:24])=[CH:21][CH:22]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(S(=O)(=O)NCCC(=O)OC(C)(C)C)cc3)n2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(S(=O)(=O)NCCC(=O)O)cc3)n2)cc1Cl
Yield: 70.5 %

Procedure:
To a solution of tert-butyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylsulfonamido)propanoate (0.28 g, 0.536 mmol) in dichloromethane (6.0 ml) was added TFA (2.0 ml, 26.0 mmol). After about 3 h the reaction mixture was concentrated in vacuo and the resulting solid was triturated with ether, filtered and dried to provide 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylsulfonamido)propanoic acid (0.176 g, 70%) as a colorless solid. LCMS (Table 1, Method c) Rt=2.54 min, m/z 466 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[C:9](SC)[S:8][CH2:7][C:6]=2[CH:13]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[C:9]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:15]([Cl:14])[CH:16]=3)[S:8][CH2:7][C:6]=2[CH:13]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CSC1=Nc2ccc(Cl)cc2CS1
Solvent: CCCCO
Product: Clc1cccc(NC2=Nc3ccc(Cl)cc3CS2)c1
Yield: 51.7 %

Procedure:
A mixture of 6-chloro-2-methylthio-4H-3,1-benzothiazine (69 g, 0.30 mole) and 3-chloroaniline (38.2 g, 0.30 mole) in n-butanol (250 ml) was refluxed overnight. After cooling in ice, the solid was collected by filtration and recrystallized from ethanol-water mixture to give 48 g (52%) of title product, m.p. 174°-175°.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[Cl:17])=[C:6]([CH3:18])[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[K].[CH:26]([C:29]1[CH:30]=[CH:31][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[N:33][CH:34]=1)([CH3:28])[CH3:27]>CS(C)=O>[Cl:17][C:10]1[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=1[O:8][C:7]1[C:2]([NH:38][S:35]([C:32]2[CH:31]=[CH:30][C:29]([CH:26]([CH3:28])[CH3:27])=[CH:34][N:33]=2)(=[O:37])=[O:36])=[N:3][C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:5][C:6]=1[CH3:18]
Reactant: CC(C)c1ccc(S(N)(=O)=O)nc1
Reactant: COc1ccc(Cl)c(Oc2c(C)nc(N3CCOCC3)nc2Cl)c1
Agent: [K]
Solvent: CS(C)=O
Product: COc1ccc(Cl)c(Oc2c(C)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)C)cn2)c1
Yield: 77.6 %

Procedure:
9.2 g of 4-[4-chloro-5-(2-chloro-5-methoxy-phenoxy )-6-methyl-pyrimidin-2-yl]-morpholine and 17.8 g of 5-isopropyl-pyridine-2-sulphonamide potassium in 130 ml of dry dimethyl sulphoxide were heated to 120° C. under argon for 16 hours. Thereafter, the dimethyl sulphoxide was distilled off, the residue was partitioned between ethyl acetate and 1 N hydrochloric acid and the organic phase was washed neutral. The organic phase was dried, the solvent was evaporated and the residue was recrystallized from ethanol. 10.3 g of 5-isopropyl-pyridine-2-sulphonic acid 5-(2-chloro-5-methoxy-phenoxy )-6-methyl-2-morpholin-4-yl-pyrimidin-4-ylamide, MS: M =534, were obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:35]=[CH:34][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[C:18](=[O:33])[NH:19][C:20](=[O:32])[C:21]=3[C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:31])[CH:23]=3)=[CH:9]2)=[CH:5][C:4]=1[O:36]COCC[Si](C)(C)C.O.FC(F)(F)C(O)=O.C(OCC)(=O)C.C(O)C.[OH-].[NH4+]>C(Cl)Cl.C(OCC)(=O)C>[NH2:1][CH2:2][C:3]1[CH:35]=[CH:34][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[C:18](=[O:33])[NH:19][C:20](=[O:32])[C:21]=3[C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:31])[CH:23]=3)=[CH:9]2)=[CH:5][C:4]=1[OH:36]
Reactant: Cn1cc(C2=C(c3cn(Cc4ccc(CN)c(OCOCC[Si](C)(C)C)c4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cn1cc(C2=C(c3cn(Cc4ccc(CN)c(O)c4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
The product of Example 10 (0.068 g, 0.11 mmol) was dissolved in methylene chloride (0.5 ml). Water (0.1 mL) was added and the solution cooled on ice. Trifluoroacetic acid (1 mL) was added and the reaction allowed to proceed for 30 minutes. Extractive workup with ethyl acetate followed by chromatography (ethyl acetate/ethanol/ammonium hydroxide:90/10/2) yields 3-[1-(4-aminomethyl-3-hydroxybenzyl)-indol-3-yl]-4-[1-methyl-indol-3-yl]-pyrrole-2,5-dione (0.012 g,) as a red solid. Treatment with hydrochloric acid yields the title compound.