Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](N(OC)C)=[O:14])=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25](=[O:32])(=[O:31])[N:26]=CN(C)C)=[CH:21][CH:20]=3)[C:9]=2[CH2:33][N:34]([CH3:36])[CH3:35])=[CH:4][CH:3]=1.[CH2:37]1COC[CH2:38]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13](=[O:14])[CH2:37][CH3:38])=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:26])(=[O:32])=[O:31])=[CH:21][CH:20]=3)[C:9]=2[CH2:33][N:34]([CH3:36])[CH3:35])=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1sc(-c2ccc(Cl)cc2)c(CN(C)C)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Reactant: C1CCOC1
Product: CCC(=O)c1sc(-c2ccc(Cl)cc2)c(CN(C)C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 0 °C
Yield: 19.28 %

Procedure:
Grignard reagent (ethyl magnesium bromide, 0.48 g, 3.6 ml 1M solution in THF, 3.64 mmol) was added drop wise to a stirred solution of 5-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-N-methoxy-N-methylthiophene-2-carboxamide (compound 35e, 0.4 g, 0.72 mmol) in anhydrous THF (20 ml) at 25° C. The reaction mixture was then heated at about 70 to about 75° C. for 2 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0° C., the reaction mixture was quenched by addition of a saturated solution of ammonium chloride (15 ml). The mixture so formed was then extracted with ethyl acetate (2×30 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent from the dried organic layer was evaporated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 60% ethyl acetate in hexanes as an eluent to obtain the title compound (0.065 g, 19.28%)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:9]=3[N:8]=2)[CH2:3][CH2:2]1.[Cl:18][C:19]1[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:18][C:19]1[C:24]([N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[NH:11][C:10]4[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:9]=4[N:8]=3)[CH2:5][CH2:6]2)=[N:23][CH:22]=[CH:21][N:20]=1
Reactant: N#Cc1ccc2[nH]c(C3CCNCC3)nc2c1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc2[nH]c(C3CCN(c4nccnc4Cl)CC3)nc2c1
Temperature: 80 °C
Yield: 50.3 %

Procedure:
The mixture of 2-piperidin-4-yl-1H-benzoimidazole-5-carbonitrile (2 g, 8.8 mmol), 2,3-dichloro-pyrazine (1.43 g, 9.7 mmol) and K2CO3 (2.4 g, 17.6 mmol) in CH3CN (20 mL) was heated to 80° C. for 10 h, then it was concentrated and partitioned between DCM and H2O. The organic layer was dried over Na2SO4 and concentrated to give the desired compound (1.5 g, 65%). The crude product was used for next step without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)c1ccccc1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)c3ccccc3)cc2)n1

Procedure:
Following the procedure described in Example 1 with 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and benzoyl chloride provided the title compound. ESMS [M+H]+: 408.2
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[S:9][N:8]=[C:7]([CH3:10])[C:6]=1[Cl:11].C([O:14][C:15](=O)[CH2:16][C:17]1[CH:25]=[CH:24][C:23]2[C:19](=[CH:20][N:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[N:22]=2)[CH:18]=1)C>O1CCCC1>[Cl:11][C:6]1[C:7]([CH3:10])=[N:8][S:9][C:5]=1[NH:4][C:15](=[O:14])[CH2:16][C:17]1[CH:25]=[CH:24][C:23]2[C:19](=[CH:20][N:21]([CH2:26][CH:27]([CH3:28])[CH3:29])[N:22]=2)[CH:18]=1
Reactant: CCOC(=O)Cc1ccc2nn(CC(C)C)cc2c1
Reactant: Cc1nsc(N)c1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nsc(NC(=O)Cc2ccc3nn(CC(C)C)cc3c2)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.3 %

Procedure:
Sodium methoxide (0.42 g, 0.0078 mol) was added to a solution of 5-amino-4-chloro-3-methylisothiazole (0.46 g, 0.0031 mol) in tetrahydrofuran (THF) (15 ml) and the mixture was stirred at ambient temperature for 15 minutes. A solution of ethyl[2-(2-methylpropyl)indazol-5-yl]acetate (0.80 g, 0.0031 mol) in THF was added dropwise and, once the addition was complete, the mixture was stirred at ambient temperature for 3 hours. The mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution and then the organic extract was dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was triturated with diethyl ether to give N-(4-chloro-3-methylisothiazol-5-yl)-[2-(2-methylpropyl)indazol-5-yl]acetamide (0.78 g) as a pale-brown solid (m.p. 133–135° C.).
Reaction SMILES: [C:1]([Si:5]([NH:8][C:9]1[N:10]=[C:11]([Cl:18])[C:12]2[CH:17]=[CH:16][NH:15][C:13]=2[N:14]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].CI.[C:21]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Si:5]([NH:8][C:9]1[N:10]=[C:11]([Cl:18])[C:12]2[CH:17]=[CH:16][N:15]([CH3:21])[C:13]=2[N:14]=1)([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Nc1nc(Cl)c2cc[nH]c2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cn1ccc2c(Cl)nc(N[Si](C)(C)C(C)(C)C)nc21
Yield: 101.1 %

Procedure:
2-(t-Butyl-dimethyl silyl)amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (CXXII) (700 mg, 2.5 mmol), 0.18 mL (3.5 mmol) of methyl iodide in DMF (10 mL), and K2CO3 (552 mg, 4 mmol) were reacted at ambient temperature for 15 h. After addition of H2O (10 mL), the reaction was extracted with EtOAc (100 mL), and the organic layer was washed with a brine solution (10 mL), and dried over Na2SO4. The solvents were removed in vacuo, and the residue was purified by flash column chromatography (PE/EtOAc=10/1 to 5/1) to afford 2-(t-butyl-dimethylsilyl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine (CXXIII) (750 mg, 100%) as a light yellow oil. LCMS (ESI) m/z=297 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:25][CH:26]([CH3:28])[CH3:27].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:25]([N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:21])[F:22])[S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:11])=[O:12])[CH:26]([CH3:28])[CH3:27]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccccc2C(F)(F)F)cc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CN(c1ccccc1C(F)(F)F)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 76.5 %

Procedure:
A mixture of 4-nitro-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (1.90 g, 5.49 mmol), 1-bromo-2-methyl propane (1.19 mL, 10.97 mmol) and K2CO3 (1.51 g, 10.97 mmol) in DMF (20 mL) was heated at 100° C. for 18 hours. The cooled mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-30% EtOAc in cyclohexane) gave N-isobutyl-4-nitro-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (1.69 g, 77%). 1H NMR (300 MHz, CDCl3) δ 8.34 (d, J=8.8 Hz, 2H), 7.88 (d, J=8.8 Hz, 2H), 7.78-7.70 (m, 1H), 7.61-7.47 (m, 2H), 7.23-7.16 (m, 1H), 3.48-3.31 (m, 2H), 1.76-1.60 (m, 1H), 0.88 (dd, J=10.1, 6.6 Hz, 6H). LCMS (m/z, Method A) ES+ no mass ion observed.
Reaction SMILES: [C:1]([N:4]1[CH2:11][CH2:10][CH2:9][C@H:5]1[C:6]([OH:8])=O)(=[O:3])[CH3:2].Cl[C:13]([O:15]CC(C)C)=[O:14].CN1CCOCC1.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32](C(O)=O)[C:31]2=[O:41].C(N(CC)CC)C.Cl[Si](C)(C)C>ClCCl>[C:1]([N:4]1[CH2:11][CH2:10][CH2:9][CH:5]1[C:6]([NH:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([C:13]([OH:15])=[O:14])=[CH:32][C:31]2=[O:41])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC[C@H]1C(=O)O
Reactant: Nc1ccc2[nH]cc(C(=O)O)c(=O)c2c1
Reactant: CC(C)COC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(=O)N1CCCC1C(=O)Nc1ccc2[nH]c(C(=O)O)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
A mixture of 7.07 g (45 mmol) of N-acetyl-L-proline, 5.85 ml (45 mmol) isobutyl chloroformate, 4.95 ml 45 mmol) N-methyl morpholine, and 90 ml of dichloromethane is stirred at -10° to -20° for 30 minutes. A mixture of 6.13 g (30 mmol) of 6-amino-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 12.6 ml (90 mmol) triethylamine, 11.4 ml (90 mmol) chlorotrimethylsilane, and 150 ml of dichloromethane is stirred at room temperature for 30 minutes and then is cooled to -20°. The cold mixed anhydride solution is added to the cold silylated quinoline and is stirred with cooling for 4 hours and at room temperature ovenight. The reaction mixture is evaporated to dryness and the residue is treated with 1 N hydrochloric acid and the solid is filtered. The solid is digested with ethanol and filtered to give 6.43 g of 6-[[(1-acetyl- 2-pyrrolidinyl)-carbonyl]amino]-1,4-dihydro-4-oxo-quinolinecarboxylic acid.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH:29]4[CH2:31][CH2:30]4)[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[C:2]1([N:8]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH:29]4[CH2:30][CH2:31]4)[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C1CC1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)O)c4ccccc4)ccc3n2C2CC2)cc1

Procedure:
Prepared analogously to Example 26 from 1-cyclopropyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:25]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:25])[C:3](=[O:2])[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[CH3:12])=[O:8]
Reactant: COC(=O)C=CC(C(=O)OC)=C(C)NCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n(Cc2ccccc2)c1C
Temperature: 25 °C
Yield: 66.2 %

Procedure:
MeOH (28 mL) was added to a flask containing 4-(1-benzylamino-ethylidene)-pent-2-enedioic acid dimethyl ester (1.0 g, 3.46 mmol). NaOMe solution (7 mL, 3.46 mmol, 0.5M in MeOH) and N-bromosuccinimide (0.74 g, 4.15 mmol) were added. The resulting mixture was refluxed for 1 h. After cooling to r.t., the solvent was evaporated in vacuo. The residue was partitioned between saturated NH4Cl (50 mL) and CH2Cl2 (50 mL). The aqueous layer was extracted with additional CH2Cl2 and the organic layers were combined, dried over MgSO4, and concentrated. The crude product was chromatographed (0-40% EtOAc/hexanes) to give 0.77 g of the title compound. MS: (+) m/z 357.95, 359.92 (M+Na, 79/81Br).
Reaction SMILES: FS([O-])(=O)=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][NH+:14]=[C:15]2SC)=[CH:10][CH:9]=1.[NH3:20]>C(O)C>[NH2:20][C:15]1[C:16]2[C:11](=[CH:10][CH:9]=[C:8]([O:7][CH3:6])[CH:17]=2)[CH2:12][CH2:13][N:14]=1
Reactant: COc1ccc2c(c1)C(SC)=[NH+]CC2
Reactant: N
Agent: O=S(=O)([O-])F
Solvent: CCO
Product: COc1ccc2c(c1)C(N)=NCC2
Yield: 72 %

Procedure:
3,4-Dihydro-7-methoxy-1-methylthioisoquinolinium fluorosulfonate (10.0 g., 0.0362 mole) was added to ethanol (100 ml.) which was saturated with ammonia in a steel bomb. The stirred mixture was heated on a steam bath for 2 hours. The mixture was combined with material from four similar runs andd flash evaporated to dryness. The residue was partitioned between 5N NaOH (300 ml.) and methylene chloride. The organic layer was washed with water (2×) and dried with sodium sulfate. The solid obtained after removal of the methylene chloride was recrystallized from benzene to give 23 g. (72% yield) of 1-amino-3,4-dihydro-7-methoxyisoquinoline, m.p. 114°-117.5°. Recrystallization from ethyl acetate afforded the analytical sample, m.p. 117.5°-119.5°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:17]=3[N:18]=2)[C@H:10]([CH2:27][OH:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29]I.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[CH:19][C:17]=3[N:18]=2)[C@H:10]([CH2:27][O:28][CH3:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ccc(C(F)(F)F)cc3s2)[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nc2ccc(C(F)(F)F)cc2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
To a solution of (S)-3-hydroxymethyl-4-(6-trifluoromethyl benzothiazole-2-yl) piperazine-1-carboxylic acid t-butyl ester (209 mg) in dimethylformamide (2 mL) were sequentially added methyl iodide (0.5 mL) and sodium hydride (62.4 mg). The mixture was stirred at room temperature for 24 hours. To the reaction solution was added ice water and extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (167 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].C1(C)C=CC=CC=1.[SH:17][CH2:18][C:19](O)=O.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:19][CH2:18][SH:17])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)CS
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: SCCNc1ccc(Cl)c(Cl)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 125.3 %

Procedure:
A 3-necked 2 L round bottomed flask equipped with an overhead stirrer, temperature probe and reflux condenser with Dean-Stark trap was charged with 100.0 grams (0.617 mol) of 3,4-dichloroaniline and 500 mL of toluene. The resulting solution was then treated with 64.4 mL (0.927 mol, 1.5 equivalents) of mercaptoacetic acid. The solution was heated to reflux (130° C.), while collecting water in the Dean-Stark trap for 20 hours, then cooled to room temperature. Ethyl acetate (250 mL) was then added followed by 123 mL of 1N hydrochloric acid. The layers were separated and the organic layer washed with 250 mL of water then 500 mL of saturated aqueous sodium bicarbonate and concentrated under vacuum to a volume of approximately 200 mL. After addition of 200 mL of toluene, the solution was again concentrated to approximately 200 mL, diluted with 1 L of tetrahydrofuran and filtered. This filtrate was added dropwise to a nitrogen-purged 3-necked 5 L round bottomed flask containing 1.73 L (1.73 mol, 2.80 equivalents) of 1N borane-tetrahydrofuran complex while maintaining a temperature of 10-15° C. Some gassing was observed. The reaction mixture was warmed to room temperature and stirred overnight then cooled to 10° C. A solution of 252 grams (6.91 mol, 11.2 equivalents) of anhydrous hydrogen chloride in 840 mL of ethanol was added at 10-15° C. during which time significant gas evolution was observed and solids precipitated. After stirring for 1 hour at 5-10° C. the solids were collected by filtration, washed with tetrahydrofuran, and dried under vacuum to yield 100.0 grams (62.6% yield) of the title compound as a white solid, mp 185-188° C. 1H NMR (DMF-d7) δ7.20 (d, J=8.7 Hz, 1H), 7.01 (d, J=2.7 Hz, 1H), 6.78 (dd, J=2.7, 8.7 Hz, 1H), 3.18 (dd, J=6.4, 7.7 Hz, 2H) 2.61 (br s, 2H), 2.37 (br s, 1H). 13C NMR (DMF-d7) δ146.02, 132.94, 134.90, 122.70, 118.09, 117.19, 50.05, 23.07. HRMS (FAB) calcd for C8H9Cl2NS: 221.9911; found: 221.9893.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Cl:11])=[N:4][CH:3]=1.[CH3:12][NH2:13].[CH:14]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:32]=[CH:31][C:28]([CH:29]=O)=[C:27]([O:33][CH3:34])[CH:26]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15]1>>[Cl:11][C:5]1[N:4]=[CH:3][C:2]2[N:1]=[C:29]([C:28]3[CH:31]=[CH:32][C:25]([O:24][CH:21]4[CH2:22][CH2:23][N:18]([CH:14]5[CH2:17][CH2:16][CH2:15]5)[CH2:19][CH2:20]4)=[CH:26][C:27]=3[O:33][CH3:34])[N:13]([CH3:12])[C:8](=[O:10])[C:7]=2[CH:6]=1
Reactant: CN
Reactant: COc1cc(OC2CCN(C3CCC3)CC2)ccc1C=O
Reactant: Nc1cnc(Cl)cc1C(=O)O
Product: COc1cc(OC2CCN(C3CCC3)CC2)ccc1-c1nc2cnc(Cl)cc2c(=O)n1C

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 5-amino-2-chloroisonicotinic acid, methylamine and 4-[(1-cyclobutylpiperidin-4-yl)oxy]-2-methoxybenzaldehyde.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([C@@H:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]([OH:27])[CH2:21]1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(=[O:9])=[O:8])[CH3:2].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([C@@H:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]([O:27][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:21]1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(=[O:8])=[O:9])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CN([C@@H]1CCCCC(O)C1)S(=O)(=O)c1ccc2ccccc2c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN([C@@H]1CCCCC(OS(C)(=O)=O)C1)S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of (R)—N-naphthalene-2-sulfonyl (3-hydroxy-cyclohepty)glycine ethyl ester (0.90 g, 2.22 mmol) in dichloromethane (30 mL) at 0° C. is added triethylamine (0.463 mL, 3.3 mmol), methane sulfonyl chloride (0.269 g, 2.35 mmol), 4-dimethylaminopyridine (0.015 g, 0.12 mmol), and the reaction is allowed to warm to ambient temperature and stirred for 2 hours. The reaction is diluted with dichloromethane, washed with water and brine, and dried over magnesium sulfate. The solvents are removed in vacuo, and the residue is purified by column chromatography (35% hexanes-ethyl acetate) to afford the title compound as a colorless oil (0.95 g, 88% yield). LCMS (m/z): 484.17 (M+1), 482.16 (M−1).
Reaction SMILES: Cl.C(OC1C=CC=CC=1N1C=CN=C1)C=C.C(OC(=O)C)(=O)C.[N+]([O-])(O)=O.C[O:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=1[N:39]1[CH:43]=[CH:42][N:41]=[CH:40]1>>[N:39]1([C:31]2[CH:32]=[C:33]([N+:36]([O-:38])=[O:37])[CH:34]=[CH:35][C:30]=2[OH:29])[CH:43]=[CH:42][N:41]=[CH:40]1
Reactant: COc1ccc([N+](=O)[O-])cc1-n1ccnc1
Agent: C=CCOc1ccccc1-n1ccnc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc(O)c(-n2ccnc2)c1

Procedure:
2.15 g. of 1-(2-methoxyphenyl)-imidazole (literature citation in Example 56) is nitrated in a mixture of 60 ml. of acetic anhydride and 20 ml. of 65% nitric acid for 2 hours at 10°. By ether splitting (literature citation in Example 56) of the thus-formed 1-(2-methoxy-5-nitrophenyl)-imidazole (1.8 g.; m.p. 139°-140° from methylene chloride/ether), 420 mg. of 2-(1-imidazolyl)-4-nitrophenol is obtained according to the literature citation in Example 56. This product is etherified analogously to Example 56 with the use of 400 mg. of 2,4 -dichlorobenzyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=[O:5].CC1(C)OC(=O)[CH:23]([CH:27]([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22](=O)O1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>N1C=CC=CC=1>[C:28]1([CH:27]([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][CH:35]=2)[CH2:23][C:22]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=3)[C:4](=[O:5])[C:3]3[C:2](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:1]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC1(C)OC(=O)C(C(c2ccccc2)c2c[nH]c3ccccc23)C(=O)O1
Reactant: COc1cccc(NC(=O)c2ccccc2N)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: COc1cccc(-n2c(CC(c3ccccc3)c3c[nH]c4ccccc34)nc3ccccc3c2=O)c1
Yield: 25.8 %

Procedure:
2-Amino-N-(3-methoxyphenyl)benzamide (2.77 g, 11.5 mmol), 3-[α-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)benzyl]indole (4.00 g, 11.5 mmol), and PPTS (1.44 g, 5.7 mmol) in 20 ml of pyridine was refluxed for seven days. The reaction mixture was concentrated in vacuo to an oil and partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed (1N hydrochloric acid, saturated sodium bicarbonate, and brine), dried over anhydrous sodium sulfate, and concentrated in vacuo to dryness. The reaction was incomplete. The product was therefore mixed with PPTS (3 g) and 10 ml of 2,4,6-collidine and refluxed for five hours. The product was worked up as above to provide an oil which, upon standing for about one month, began to crystallize. Trituration with ethyl acetate and filtration provided 1.4 g of the title product: mp 160°-164° C.
Reaction SMILES: [NH:1]([CH2:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[O:12][CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:28](Cl)(=[O:38])[O:29][C@@H:30]1[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1>CC#N.CCOC(C)=O>[N:32]12[CH2:37][CH2:36][CH:35]([CH2:34][CH2:33]1)[C@@H:30]([O:29][C:28]([N:1]([CH2:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:38])[CH2:31]2
Reactant: COC(=O)c1ccc(COc2cccc(CNc3ccccc3)c2)cc1
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COc2cccc(CN(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1
Temperature: 25 °C
Yield: 76 %

Procedure:
A suspension of methyl 4-[[3-(anilinomethyl)phenoxy]methyl]benzoate (380 mg, 1.1 mmol) and (R)-quinuclidin-3-yl carbonochloridate hydrochloride (described in the co-pending International Patent Application No. PCT/EP2013/075529 (published as WO 2014/086855) as Intermediate 16) (300 mg, 1.33 mmol) in anhydrous CH3CN (5 mL) was heated to 100° C. for 15 min under microwave irradiation. After cooling to room temperature, the mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (20 mL) The layers were separated and the organic phase was dried over Na2SO4, filtered and the solvent was removed in vacuo to yield the title compound (419 mg, 76% yield) which was used directly in the next step without any further purification.