Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[CH2:7](O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CS(O)(=O)=O>>[C:1]([CH2:3][C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:5])#[N:2]
Reactant: N#CCC(=O)O
Reactant: CCCCCCCCCCO
Agent: CS(=O)(=O)O
Product: CCCCCCCCCCOC(=O)CC#N
Temperature: 130 °C

Procedure:
Cyanoacetic acid (85.5 g; 1.0 mol), decyl alcohol (206 g; 1.30 mol) and methanesulfonic acid (0.47 g; 0.005 mol) were introduced into a 500 ml flask under a nitrogen atmosphere. The mixture was warmed slowly to a maximum temperature of 130° C., while gradually reducing the pressure to about 10 mm of Hg. Water was continuously removed from the distillates (bp 60-65° C./50 mm of Hg) and the organic layer of decyl alcohol was returned to the flask until the reaction was complete. After distilling off the unreacted decyl alcohol, the decyl cyanoacetate (bp 143° C./1 mm of Hg) was isolated as a clear liquid. The yield was 219 g (97% of theoretical) with a purity of >99% (GC assay).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH:22]1([NH:25][CH2:26][C:27]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28]2)[CH2:24][CH2:23]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:29]4[CH2:30][CH2:31][C:27]([CH2:26][NH:25][CH:22]5[CH2:23][CH2:24]5)([OH:32])[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: OC1(CNC2CC2)CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(O)(CNC4CC4)C3)c(F)cc2c1=O

Procedure:
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted analogously to Example 6 with 3-cyclopropylaminomethyl-3-hydroxypyrrolidine hydrochloride to give 1-cyclopropyl-7-(3-cyclopropylaminomethyl-3 -hydroxy-1-pyrrolidinyl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 161°-162° (with decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[F:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:28][OH:29]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[F:25])=[N:28][OH:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(C(F)(F)F)ccc2F)CC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(C(=NO)c2cc(C(F)(F)F)ccc2F)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 4-(2-fluoro-5-trifluoromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (59, 0.013M) in pyridine (25 mL) was treated with hydroxylamine hydrochloride (1.11 g, 0.015 M-1.2 eq). The reaction was stirred under N2 at room temperature for 14 hours and then poured onto ice water (250 mL). The mixture was stirred at 0° C. for 1 hour, the product was then filtered off, washed with cold water (3×15 mL) and dried in a vacuum oven at 50° C. A white solid was obtained (5.03 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:13].[CH3:14][CH:15]([CH2:17][CH:18]([NH2:22])[CH2:19][CH2:20][CH3:21])[CH3:16]>>[CH3:1][O:2][C:3]1[C:4]([CH3:13])=[CH:5][C:6]([C:7]([NH:22][CH:18]([CH2:19][CH2:20][CH3:21])[CH2:17][CH:15]([CH3:16])[CH3:14])=[O:9])=[CH:10][C:11]=1[CH3:12]
Reactant: COc1c(C)cc(C(=O)O)cc1C
Reactant: CCCC(N)CC(C)C
Product: CCCC(CC(C)C)NC(=O)c1cc(C)c(OC)c(C)c1

Procedure:
Prepared in a similar manner to example 4 using 4-methoxy-3,5-dimethylbenzoic acid and 2-methylheptan-4-amine (example 2a). MS (M+H, 292.2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]([CH3:20])([CH3:19])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=3)[NH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)C(C)C)(C)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[C:34]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]([CH3:19])([CH3:20])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=3)[NH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(N)cc(Cl)c1)N2
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(Cl)cc(NC(=O)c3ccccc3)c1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
To a solution of methyl 2-(3-amino-5-chlorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (100 mg, 0.29 mmol) and N,N-diisopropylethylamine (75 mg, 0.58 mmol) in dichloro methane (4 mL) was added benzoyl chloride (49 mg, 0.35 mmol) slowly via syringe under nitrogen. The mixture was stirred at room temperature for 1 h. Solid precipitated and was collected by filtration to afford 65 mg of methyl 2-(3-benzamido-5-chlorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid. Yield: 50%; MS (ESI+APCI) M+1-water=431.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH:25]=[CH:26][C:27](=[O:31])[NH:28]5)=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.C(N(CC)CC)C.[CH2:39]([N:41]([CH2:45][CH3:46])[C:42](Cl)=[O:43])[CH3:40].O>ClCCl>[CH2:39]([N:41]([CH2:45][CH3:46])[C:42](=[O:43])[O:31][C:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][N:13]3[CH2:12][CH2:11][N:10]([C:6]4[C:3]5[CH:4]=[CH:5][S:1][C:2]=5[CH:9]=[CH:8][CH:7]=4)[CH2:15][CH2:14]3)=[CH:22][CH:23]=2)[N:28]=1)[CH3:40]
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2[nH]1
Reactant: CCN(CC)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)Oc1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2n1
Yield: 12.2 %

Procedure:
To a solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (800 mg) synthesized in the same manner as in WO2006/112464 (Example 1) in dichloromethane (20 ml) was added triethylamine (0.65 ml), with stirring under ice-cooling, diethylcarbamoylchloride (0.5 g) was added and the mixture was stirred at room temperature overnight. Water, was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=20:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yl diethylcarbamate (120 mg).
Reaction SMILES: [Na].[C:2]([O:10]CC)(=[O:9])[CH2:3][C:4]([O:6]CC)=[O:5].[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26](OS(C2C=CC=CC=2)(=O)=O)[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Li]>C(O)C.CO.O>[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH:3]([C:4]([OH:6])=[O:5])[C:2]([OH:10])=[O:9])[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(OCc1ccccc1)N1CCC(OS(=O)(=O)c2ccccc2)CC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Li]
Agent: [Na]
Solvent: O
Solvent: CO
Solvent: CCO
Product: O=C(O)C(C(=O)O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
Sodium metal (3.2 g) was dissolved in ethanol (50 ml) under a nitrogen atmosphere at room temperature. A solution of diethyl malonate (56.4 ml) in ethanol (50 ml) was added dropwise, followed by a solution of 4-benzenesulfonyloxy-piperidine-1-carboxylic acid benzyl ester (31.88 g) in ethanol (50 ml), also added dropwise. The mixture was heated to reflux for 16 h then the solvent was removed under reduced pressure. The residue was partitioned between water (100 ml) and diethyl ether (100 ml) and the aqueous washed with further diethyl ether (60 ml). The combined organics were washed with 10% citric acid solution (50 ml), water (50 ml) and brine (50 ml). After drying (Na2SO4) and filtering the solvent was removed under reduced pressure to leave a yellow liquid. Half of this crude diester was taken and dissolved in methanol (150 ml) and water (50 ml). Lithium hydroxidemonohydrate (18.14 g) was added slowly and the reaction left to stir at room temperature for 16 h then the methanol was removed under reduced pressure. The aqueous was washed with diethyl ether (3×40 ml), acidified to pH=3 with citric acid and extracted with ethyl acetate (2×40 ml). The combined organics were washed with water (2×40 ml) and brine (40 ml), dried (Na2SO4), filtered and evaporated under reduced pressure to give the title compound (8.29 g, 56%) as a white crystalline solid.
Reaction SMILES: C(N1CCN([NH:14][C:15](=[O:32])[CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][N:23]=[C:24]([N:27]4[CH:31]=[N:30][CH:29]=[N:28]4)[CH:25]=3)[NH:20][CH:19]=2)CC1)C1C=CC=CC=1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C>[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][N:43]([NH:14][C:15](=[O:32])[CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][N:23]=[C:24]([N:27]4[CH:31]=[N:30][CH:29]=[N:28]4)[CH:25]=3)[NH:20][CH:19]=2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(CCc1c[nH]c2cnc(-n3cncn3)cc12)NN1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(NC(=O)CCc2c[nH]c3cnc(-n4cncn4)cc23)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-(5-(1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl) propionic acid (0.34 g, 1.3 mmol) (prepared as described in Example 53 Step 7) in anhydrous DMF (5 ml) was added 1-tert-butyloxycarbonylpiperazine (0.5 g, 2.7 mmol), 1-hydroxybenzotriazole (225 mg, 1.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.45 g, 2.3 mmol) and triethylamine (0.23 ml, 1.7 mmol). The mixture was stirred at room temperature for 2 days. The solvent was evaporated and the residue partitioned between ethyl acetate (25 ml) and water (20 ml). The organic layer was separated and the aqueous phase extracted with ethyl acetate (3×20 ml). The combined organic layers were dried (Na2 SO4) and evaporated. The residue was chromatographed on silica gel, eluting with CH2Cl2 /MeOH (90:10) to afford the title compound, with some impurities, as a pale yellow foam.
Reaction SMILES: [CH2:1]([Mg][Cl:6])[CH2:2][CH2:3][CH3:4].[CH3:7][N:8]([CH3:21])[C:9]1(C#N)[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:11][CH2:10]1.[Cl-].[NH4+].Cl[Si](C)(C)C>O1CCCC1.O>[ClH:6].[CH2:1]([C:9]1([N:8]([CH3:21])[CH3:7])[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reactant: CCCC[Mg]Cl
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC1(N(C)C)CCC2(CC1)OCCO2
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
2M n-butylmagnesium chloride solution in THF (228 ml, 0.456 mole) was slowly added under argon and while cooling with an ice/salt mixture to a solution of 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (38.3 g, 0.182 mole) in absolute tetrahydrofuran (420 ml). In this connection the reaction temperature should not rise above 10° C. The reaction mixture was then stirred for 16 hours at room temperature, a brownish clear solution being formed. The reaction mixture was worked up by the dropwise addition of saturated ammonium chloride solution (150 ml) while cooling with ice (0°-10° C.). A white solid was thereby formed, which was dissolved by adding water (approximately 250 ml). The reaction mixture was extracted with diethyl ether (4×100 ml). The organic phase was washed with water (100 ml) and saturated NaCl-Solution (100 ml), dried and concentrated by evaporation. A yellow oil (44.5 g) remained, which apart from the desired butyl compound also contained the educt nitrile. The crude product was dissolved in ethyl methyl ketone (275 ml), ClSiMe3 (32 ml, 0.245 mole) was added while cooling with ice, and the mixture was stirred in an open flask at room temperature. The hydrochloride was separated by filtering several times at 2-hourly intervals. After a reaction time of 6 to 8 hours (8-butyl-1,4-dioxa-spiro[4.5]dec-8-yl)-dimethylamine hydrochloride was isolated in a yield of 82% (41.8 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]([OH:21])=O)[NH:16][C:15]2=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:24](C)C=O.C(Cl)(=O)C(Cl)=O>O1CCCC1.O>[C:19]([C:17]1[NH:16][C:15](=[O:22])[N:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:18]=1)(=[O:21])[NH2:24]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)O)[nH]c2=O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C(N)=O)[nH]c2=O)CC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
1-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid (355 mg, 1.140 mmol) was dissolved in a mixture of tetrahydrofuran (20 mL,) and N,N-dimethylformamide (15 μl, 0.194 mmol). Mixture was cooled to −10° C. Oxalyl chloride (150 μL, 1.714 mmol) was added to the mixture drop-wise. Reaction mixture was warmed to room temperature and held with stirring for 1 hour. Another 60 μL of oxalyl chloride was added to the mixture. Reaction stirred at room temperature for 30 minutes. Mixture was cooled to −10° C. Ammonia gas was bubbled through the mixture for 5 minutes. Reaction was held at −10° C. with stirring for 30 minutes. Mixture was warmed to room temperature and then diluted with water. Material was extracted three times with ethyl acetate and the aqueous phase was discarded. Material was washed with brine and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as off-white solid in 79% yield. MS (M−H)−=309.2.
Reaction SMILES: [H-].[Na+].[C:3]([SiH2:7][O:8][C:9]([CH3:19])([CH3:18])[C:10]1[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([NH2:17])[CH:11]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:21]1[S:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=1.Cl>O.C1COCC1>[C:3]([SiH2:7][O:8][C:9]([CH3:19])([CH3:18])[C:10]1[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([NH:17][C:21]2[S:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=2)[CH:11]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: N#Cc1cnc(Cl)s1
Reactant: Cc1cnc(N)cc1C(C)(C)O[SiH2]C(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(Nc2ncc(C#N)s2)cc1C(C)(C)O[SiH2]C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
An oven dried flask under N2 was charged with NaH (60% dispersion, 185 mg, 4.63 mmol). 5 mL of anhydrous THF was added followed by addition of 4-(tert-butyl-dimethyl-silanyloxymethyl)-5-methyl-pyridin-2-ylamine (9-6, 0.487 g, 1.93 mmol) and 2-chloro-5-cyanothiazole (1-2, 0.391 g, 2.70 mmol). The resulting solution was heated to reflux. After 1 hour the reaction was allowed to cool to room temperature and was then diluted with water. The pH was adjusted to 7 with 1 M HCl. The resulting precipitate was filtered and washed with water to afford 9-7.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]2[C:7]3=[N:8][C:9]([C:14]#[N:15])=[C:10]([C:12]#[N:13])[N:11]=[C:6]3[C:5](=O)[C:4]=2[CH:3]=1.Cl.[NH2:21][NH:22][C:23]([NH2:25])=[O:24]>C(#N)C>[NH2:25][C:23]([NH:22][N:21]=[C:5]1[C:6]2[C:7](=[N:8][C:9]([C:14]#[N:15])=[C:10]([C:12]#[N:13])[N:11]=2)[C:16]2[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:24]
Reactant: N#Cc1nc2c(nc1C#N)-c1ccc(Cl)cc1C2=O
Reactant: NNC(N)=O
Agent: Cl
Solvent: CC#N
Product: N#Cc1nc2c(nc1C#N)-c1ccc(Cl)cc1C2=NNC(N)=O

Procedure:
A mixture of 600 mg (2.25 mmol) 17g and 329 mg (2.92 mmol) semicarbazide hydrochloride in 20 ml acetonitrile was heated 14 h under reflux. After that time, TLC indicated complete conversion of the starting product. After evaporation of the solvent, the crude product was recrystallised from aqueous ethanol, and compound 43 was obtained in slightly greenish crystals (90%). 1H-NMR (d6-DMSO, 400 MHz): δ (ppm)=7.40 (sl, 1H); 7.70 (sl, 1H); 7.71 (d, J=8 Hz, 1H); 8.17 (d, J=8 Hz, 1H); 8.89 (s, 1H); 10.95 (s, 1H). ESI+MS: calcd for C14H6ClN7O: 323.70; found: 324 (MH+).
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](OC)=[O:19].[CH2:22]([C:25]1[S:29][C:28]([NH2:30])=[N:27][CH:26]=1)[CH2:23][CH3:24]>>[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]([NH:30][C:28]1[S:29][C:25]([CH2:22][CH2:23][CH3:24])=[CH:26][N:27]=1)=[O:19]
Reactant: CCCc1cnc(N)s1
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Product: CCCc1cnc(NC(=O)C2=C(O)c3sc4ccccc4c3S(=O)(=O)N2C)s1
Yield: 37 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 5-propyl-2-thiazolamine with a yield of 37% of theory.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:4]([O:20][CH3:21])[CH:3]=1.[CH3:22][N:23]([CH3:40])[S:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](O)=[O:31])(=[O:26])=[O:25]>C(Cl)Cl.CCOC(C)=O>[CH3:22][N:23]([CH3:40])[S:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:38])([F:37])[F:39])[CH:35]=1)[C:30]([N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[O:20][CH3:21])[CH2:15][C:16]([F:18])([F:17])[F:19])=[O:31])(=[O:25])=[O:26]
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COc1cc(F)ccc1-c1ccncc1NCC(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(F)ccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N(C)C)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine and 3-dimethylsulfamoyl-5-trifluoromethyl-benzoic acid (Buttpark Ltd.) and using a gradient of CH2Cl2: EtOAc (100:0 to 90:10) for the chromatographic purification. Light yellow foam (42%). MS (ESI): m/z=580.112 [M+H]+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:23])[C:11]([OH:22])([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[CH2:2]2.[O:24]([CH2:31][CH2:32][CH2:33][Br:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Br-:34].[OH:22][C:11]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:10]([O:9][C@@H:3]1[CH:4]2[CH2:7][CH2:8][N+:1]([CH2:33][CH2:32][CH2:31][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([CH2:6][CH2:5]2)[CH2:2]1)=[O:23]
Reactant: BrCCCOc1ccccc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1cccs1)c1cccs1
Product: O=C(O[C@H]1C[N+]2(CCCOc3ccccc3)CCC1CC2)C(O)(c1cccs1)c1cccs1
Product: [Br-]
Reaction time: 6 h

Procedure:
The moles of 2-hydroxy-2,2-dithien-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R)yl ester indicated in column B were suspended in the amount (column E) of the solvent indicated in column D. Then, the amount of 3-phenoxypropyl bromide resulting from multiplying column B by column C was added to the resulting suspension and the mixture was stirred for 6 h at reflux in an inert atmosphere. The solvents were subsequently evaporated to yield 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide. The product was isolated by filtration at room temperature and both the yield and the level of 3-phenoxypropyl bromide were determined and indicated in columns F and G, respectively.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5](I)[S:4][C:3]=1[CH:9]1[O:13]CCO1.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:20]=1[O:21]C.C[O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[F:14][C:15]1[CH:16]=[C:17]([C:5]2[S:4][C:3]([CH:9]=[O:13])=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([OH:27])=[CH:29][CH:30]=3)[C:6]=2[CH3:7])[CH:18]=[CH:19][C:20]=1[OH:21]
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1ccc(B(O)O)cc1F
Reactant: Cc1c(I)sc(C2OCCO2)c1Br
Product: Cc1c(-c2ccc(O)c(F)c2)sc(C=O)c1-c1ccc(O)cc1
Yield: 86 %

Procedure:
Starting from 2-(3-bromo-5-iodo-4-methylthien-2-yl)-1,3-dioxolane (2.3 g, 6.1 mmol) and 3-fluoro-4-methoxyphenylboronic acid (1.6 g, 9.4 mmol) in place of 4-methoxyphenylboronic acid (Step 1), and substituting 4-methoxyphenylboronic acid in place of 3-methoxyphenylboronic acid (Step 2), the title compound (0.42 g, 86%, m.p. 227-29° C.) was synthesized in essentially the same manner as described in Example 1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[C:10]1[C:15]([F:16])=[C:14]([F:17])[C:13](F)=[C:12]([F:19])[C:11]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29]([O:33][C:34](=[O:41])[NH:35][C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1)([CH3:32])([CH3:31])[CH3:30]>C(#N)C>[CH2:1]([O:8][C:9](=[O:21])[C:10]1[C:11]([F:20])=[C:12]([F:19])[C:13]([N:38]2[CH2:39][CH2:40][C@H:36]([NH:35][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:41])[CH2:37]2)=[C:14]([F:17])[C:15]=1[F:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1c(F)c(F)c(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(F)c(F)c(C(=O)OCc3ccccc3)c(F)c2F)C1
Yield: 63.6 %

Procedure:
A solution of 2,3,4,5,6-pentafluorobenzoic acid benzyl ester (Example 1d, 8.05 g, 26.6 mmol), triethylamine (26 mL, 186 mmol), and (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (5.6 g, 30 mmol) in acetonitrile (150 mL) is stirred at room temperature for 24 hours. The solvent is removed under vacuum and the residue dissolved in chloroform, washed with NaHCO3 and then brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a solid. The solid is then purified by column chromatography (1:1:6 ethyl acetate/chloroform/hexanes) to yield the title compound as a solid (7.92 g). 1H NMR (CDCl3): δ 7.48-7.30 (m, 5H, 5.35 (s, 2H), 4.77-4.50 (m, 1H), 4.37-4.19 (m, 1H), 4.01-3.63 (m, 3H), 3.59-3.46 (m, 1H), 2.29-2.09 (m, 1H), 2.01-1.82 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][C:17]#N)=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][N:30]([CH3:34])[CH2:31]CCl>>[CH:1]1([CH2:6][C@H:7]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][CH2:29][N:30]([CH3:34])[CH3:31])=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCCl
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(SC#N)s2)cc1
Product: CN(C)CCSc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1

Procedure:
The title compound was prepared from (R)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-thiocyanato-thiazol-2-yl)-propionamide and 2-(dimethylamino)ethyl chloride as described in Example 10. 1H-NMR (CD3OD): δ 7.92 (d, 2H), 7.67 (d, 2H), 7.55 (s, 1H), 3.96 (t, 1H), 3.29 (m, 2H), 3.10 (s, 3H), 3.06 (m, 2H), 2.87 (s, 6H), 2.26-2.19 (m, 1H), 1.89-1.48 (m, 8H), 1.18 (m, 2H); HPLC-MS: m/z: 482 (M+1).