Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C(=O)[S:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[NH2:18].[OH-].[K+].O>C(O)CO>[NH2:18][C:6]1[CH:7]=[C:8]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][C:5]=1[S:4][S:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][C:6]=1[NH2:18]
Reactant: CN(C)C(=O)Sc1ccc(Cc2ccccc2)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Nc1cc(Cc2ccccc2)ccc1SSc1ccc(Cc2ccccc2)cc1N
Temperature: 60 °C

Procedure:
To a slurry of S-2-amino-4-benzylphenyl dimethylcarbamothioate (1.43 g, 4.99 mmol) in 15 mL ethylene glycol was added potassium hydroxide (0.840 g, 15.0 mmol) (solid, finely crushed). The reaction was heated to 60° C. under nitrogen. 10 mL 2-BuOH was added as cosolvent and the resulting solution was heated for 2 h. The reaction was fitted with a water-cooled reflux condensor and heated to 90° C. for 3 h. The reaction was cooled, and concentrated in vacuo. The material was partitioned between Et2O and water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give an oil, which was purified by silica gel chromatography, ISCO, 0-30% EtOAc/hexanes to give 2-(2-(2-amino-4-benzylphenyl)disulfanyl)-5-benzylbenzenamine as a brown oil. MS (ESI) m/z: Calculated: 428.1; Observed: 429.0 (M++1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:3]1[CH3:18].[CH2:19]([O:21][C:22](=[O:27])[C:23](Br)([CH3:25])[CH3:24])[CH3:20]>>[CH2:19]([O:21][C:22](=[O:27])[C:23]([CH3:25])([O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]([CH3:18])=[C:4]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:24])[CH3:20]
Reactant: Cc1c(-c2ccccn2)c2cc(O)ccc2n1C
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccccn1)c(C)n2C

Procedure:
The above compound was prepared from 1,2-dimethyl-3-(2-pyridyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1>COC(Cl)Cl>[C:3]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][Br:1])=[CH:4][CH:5]=1)([CH3:11])([CH3:4])[CH3:2]
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: COC(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 979.1 %

Procedure:
p-Bromomethyl benzoic acid (8.1 g) was refluxed with α,α dichloromethyl methyl ether (50 mL) for 1 h. The reaction mixture was evaporated to dryness, co-distilled with toluene twice and pumped under high vacuum. To the acid chloride redissolved in THF (100 mL) at −78° C. was added potassium tert-butoxide 1M in THF (30 mL) dropwise. Then temperature was raised to −20° C. and stirred for 1 h. The reaction mixture was quenched with NH4OAc and extracted with EtOAc. The organic phase was dried over Na2SO4 and evaporated to yield 50 g of tert-butyl-4-(bromomethyl)benzoate.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:26])[CH2:25][CH2:24][CH:23]=[CH:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:26])[CH2:25][CH2:24][CH:23]=[CH:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1
Reactant: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CC=CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CC=CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 5-cyclopropyl-2-fluoro-4-((1-methylcyclohex-3-en-1-yl)methoxy)benzoate (0.041 g, 0.11 mmol) in dichloromethane (2 mL), was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuo to afford 5-cyclopropyl-2-fluoro-4-((1-methylcyclohex-3-en-1-yl)methoxy)benzoic acid (0.033 g, 0.11 mmol) which was used directly in the next step. This compound was dissolved in tetrahydrofuran (2 mL) under an atmosphere of nitrogen and carbonyldiimidazole (0.024 g, 0.15 mmol) was added to the solution and the reaction mixture was stirred at 70° C. for 1 hour. The mixture was cooled to ambient temperature and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.04 mg, 0.17 mmol) was added, followed by cyclopropanesulfonamide (0.021 mg, 0.170 mmol) and stirring continued at ambient temperature for 18 hours. 5% aqueous hydrochloric acid solution (0.15 mL) was added and the mixture was concentrated and purified by column chromatography (0 to 30% ethyl acetate in hexanes) to afford the title compound (0.012 g, 24%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 9.18-8.28 (br, 1H), 7.60 (s, 1H), 6.56 (d, J=14.4 Hz, 1H), 5.75-5.57 (m, 2H), 3.76 (d, J=8.5 Hz, 1H), 3.69 (d, J=8.6 Hz, 1H), 3.17-3.00 (m, 1H), 2.18-1.95 (m, 4H), 1.95-1.81 (m, 1H), 1.78-1.63 (m, 1H), 1.57-1.36 (m, 3H), 1.23 (s, 3H), 1.18-1.05 (m, 2H), 0.96-0.85 (m, 2H), 0.68-0.59 (m, 2H); MS (ES+) m/z 408.2 (M+1); MS (ES−) m/z 406.2 (M−1).
Reaction SMILES: [ClH:1].C(OC([N:9]([CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)=[CH:38][CH:37]=1)[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]1=2)=O)(C)(C)C>O1CCOCC1>[ClH:1].[ClH:1].[F:33][C:31]1[CH:30]=[CH:29][C:28]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][C:44]3[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=3)=[CH:38][CH:37]=2)=[C:27]([CH2:26][CH2:25][NH:9][CH:10]2[CH2:19][CH2:18][CH2:17][C:16]3[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]2=3)[CH:32]=1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1cc(F)ccc1OCc1ccc(CCc2ccc(F)cc2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1cc(F)ccc1OCc1ccc(CCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
23 ml of a 4 N solution of hydrogen chloride in dioxane were added to 6080 mg (9.06 mmol) of ethyl 5-[(tert-butoxycarbonyl){2-[5-fluoro-2-({4-[2-(4-fluorophenyl)ethyl]benzyl}oxy)phenyl]-ethyl}amino]-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 140A), and the mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated to dryness. This gave 6240 mg of the target product which was reacted further without further analytical characterization.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[S:6][CH:7]=1.CO>[O-2].[Mn+4].[O-2].C(Cl)(Cl)Cl>[CH:2]([C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:13])[CH:10]([CH3:11])[CH3:12])[S:6][CH:7]=1)=[O:1]
Reactant: CC(C)C(=O)Nc1nc(CO)cs1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)C(=O)Nc1nc(C=O)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
A mixture of N-[4-(hydroxymethyl)-1,3-thiazol-2-yl]-2-methylpropanamide (520 mg), manganese (IV) oxide (2.26 g), methanol (0.5 ml) and chloroform (5 ml) was stirred at ambient temperature for 18 hours. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo. The crystalline residue was collected and washed with diisopropyl ether to give N-(4-formyl-1,3-thiazol-2-yl)-2-methylpropanamide (365 mg).
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[CH3:23]/[C:24](=[CH:27]\[CH3:28])/[CH2:25]O>>[CH:10]([N:8]1[CH2:9][CH:6]([O:5][CH2:23]/[C:24](/[CH3:25])=[CH:27]/[CH3:28])[CH2:7]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C/C=C(\C)CO
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Product: C/C=C(\C)COC1CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
A solution of 1-benzhydrylazetidin-3-yl methanesulfonate (447 mg, 1.41 mmol) in (E)-2-methylbut-2-en-1-ol (1.2 g, 14.1 mmol) was stirred under microwaves at 110° C. for 30 minutes. After concentration to dryness, the residue was purified by chromatography on silica gel using petroleum ether/ethyl acetate (9:1) as eluent. The title product was obtained as a colorless oil (290 mg, 67%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=2)[CH:7]=[N:6]1.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].C(OCC)(=O)C>O1CCCC1>[Br:16][C:12]1[N:11]=[C:10]([C:8]2[CH:7]=[N:6][N:5]([CH2:4][CH2:3][OH:2])[CH:9]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)Cn1cc(-c2cccc(Br)n2)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCn1cc(-c2cccc(Br)n2)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a cooled (0° C.) solution of methyl[4-(6-bromopyridin-2-yl)-1H-pyrazol-1-yl]acetate (196 mg, 0.66 mmol) in tetrahydrofuran (3.4 mL) was added diisobutylaluminum hydride (1.0M in hexane, 1.99 mL, 1.99 mmol) dropwise. The solution was allowed to warm to room temperature and maintained at room temperature overnight. Additional diisobutylaluminum hydride (0.66 mL, 0.66 mmol) was then added and the reaction was stirred for another 24 hours. Saturated aqueous potassium sodium tartrate (20 mL) was then added and the solution was vigorously stirred for three hours. Ethyl acetate (7 mL) was added to the solution, and it was stirred another 60 minutes. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (0-5% methanol in ethyl acetate) afforded the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4OC)[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1.NC1C=CC(C2C=NN(CCCO)C=2)=CC=1C(N(C)C)=O>>[CH3:19][N:16]([CH3:17])[C:15]([C:14]1[CH:18]=[C:10]([C:8]2[CH:7]=[N:6][N:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH:9]=2)[CH:11]=[CH:12][C:13]=1[NH:21][C:22]1[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([CH2:37][P:38](=[O:45])([O:39][CH2:40][CH3:41])[O:42][CH2:43][CH3:44])=[CH:46][CH:47]=2)[N:23]=1)=[O:20]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: CN(C)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(C)C)n2)cc1)OCC
Yield: 22 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 2-Amino-5-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-N,N-dimethylbenzamide (Compound 11C, 506 mg, 1.19 mmol) to afford 177 mg of the title compound (22%). 1H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 8.16 (s, 1H), 7.97 (s, 1H), 7.71-7.79 (m, 2H), 7.62 (d, J=1.8 Hz, 1H), 7.40 (d, J=7.8 Hz, 2H), 7.12 (d, J=5.6 Hz, 2H), 4.32 (t, J=6.9 Hz, 2H), 3.91-4.04 (m, 4H), 3.55-3.61 (m, 2H), 3.07-3.16 (d, J=21 Hz, 2H), 3.04 (s, 3H), 2.91 (s, 3H), 2.10 (t, J=6.4 Hz, 2H), 1.21 (t, J=7.1 Hz, 6H). MS (ESI): m/z 676.77 [M+H]+. UPLC: tR=1.07 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:23])=O.[NH2:24][C:25]([NH2:27])=[S:26]>CCO>[CH3:23][C:6]1[CH:7]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:24]=[C:25]([NH2:27])[S:26][CH:2]=1
Reactant: Cc1cc(Oc2ccc(C(F)(F)F)cc2)cc(C)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(Oc2ccc(C(F)(F)F)cc2)cc(C)c1-c1csc(N)n1
Yield: 62.8 %

Procedure:
A mixture of 2-bromo-1-(2,6-dimethyl-4-(4-(trifluoromethyl)phenoxy)phenyl)ethanone (2.20 g, 5.68 mmol) and thiourea (0.43 g, 5.68 mmol) in 95% EtOH (8.1 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl-4-(4-(trifluoromethyl)phenoxy)phenyl)thiazol-2-amine (1.30 g) as yellow solids in 63% yield: 1H NMR (500 MHz, CDCl3) δ 7.56 (d, J=8.5 Hz, 2 H), 7.05 (d, J=8.5 Hz, 2 H), 6.76 (s, 2 H), 6.32 (s, 1 H), 5.03 (s, 2 H), 2.17 (s, 6 H).
Reaction SMILES: C(O)(=O)C.[OH:5][C:6]1[CH:19]=[C:18]2[C:9]([CH:10]=[CH:11][C:12]3[O:13][CH:14]=[C:15]([CH:21]=O)[C:16](=[O:20])[C:17]=32)=[CH:8][CH:7]=1.Cl.[NH2:24]O.C([O-])=O.[Na+]>C(O)=O>[OH:5][C:6]1[CH:19]=[C:18]2[C:9]([CH:10]=[CH:11][C:12]3[O:13][CH:14]=[C:15]([C:21]#[N:24])[C:16](=[O:20])[C:17]=32)=[CH:8][CH:7]=1
Reactant: NO
Reactant: O=Cc1coc2ccc3ccc(O)cc3c2c1=O
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CC(=O)O
Product: N#Cc1coc2ccc3ccc(O)cc3c2c1=O

Procedure:
A mixture of 9-hydroxy-1-oxo-1H-naphtho[2,1-b]pyran-2-carboxaldehyde acetate (1 mm), hydroxylamine hydrochloride (1.3 mm) and sodium formate (2 mm) is refluxed for 30 hrs. in formic acid (3 parts). The product crystallize on cooling, is filtered and washed with acetone. The dry crystals are light beige, m.p. 289°-92° C.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:5]([CH2:20][CH3:21])[C:6](=[O:19])[C:7]1[C:12]([CH:13]=[O:14])=[CH:11][CH:10]=[CH:9][C:8]=1[Si:15]([CH3:18])([CH3:17])[CH3:16])[CH3:4]>C(O)C.CCOCC>[CH2:20]([N:5]([CH2:3][CH3:4])[C:6](=[O:19])[C:7]1[C:12]([CH2:13][OH:14])=[CH:11][CH:10]=[CH:9][C:8]=1[Si:15]([CH3:17])([CH3:16])[CH3:18])[CH3:21]
Reactant: CCN(CC)C(=O)c1c(C=O)cccc1[Si](C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCN(CC)C(=O)c1c(CO)cccc1[Si](C)(C)C
Yield: 74 %

Procedure:
Sodium borohydride (1.0 g, 26.4 mmol) was added to a solution of N,N-diethyl-2-trimethylsilyl-6-formylbenzamide, prepared in Example 97, (5.54 g, 20 mmol) in absolute ethanol (100 mL). After 3 h the mixture was diluted with ether, extracted three times with brine, dried (MgSO4), concentrated, and recrystallized from 1:1 ethyl acetate/hexanes to afford 4.12 g of N,N-diethyl-2-trimethylsilyl-6-hydroxymethylbenzamide as a white solid, a 74% yield. m.p. 81°-82.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:17]2[N:26](S(C3C=CC=CC=3)(=O)=O)[C:20]3=[N:21][CH:22]=[C:23]([F:25])[CH:24]=[C:19]3[CH:18]=2)=[CH:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][C:5]=1[F:36].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:17]2[NH:26][C:20]3=[N:21][CH:22]=[C:23]([F:25])[CH:24]=[C:19]3[CH:18]=2)=[CH:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)=[CH:6][C:5]=1[F:36]
Reactant: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
A mixture of 4-[1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-2-fluoro-benzoic acid methyl ester (2.50 g, 4.79 mmol) and tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 8 mL) was stirred at 25° C. for 16 h. The reaction was quenched with a saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (2×100 mL), washed with a saturated aqueous ammonium chloride solution (3×50 mL), brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-[2-cyclopentyl-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-2-fluoro-benzoic acid methyl ester (1.50 g, 81%) which was used in the next step without further purification: LC/MS m/e calcd for C22H20F2N2O2 [M+H]+ 383.41, observed 382.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20](=[O:22])(=[O:21])[NH2:23])[CH:15]=2)(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Product: NS(=O)(=O)c1cccc(NS(=O)(=O)c2ccc(Br)cc2Cl)c1

Procedure:
Using a method analogous to Method E, using 4-bromo-2-chlorobenzenesulfonyl chloride and 3-aminobenzenesulfonamide, the title compound was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1([CH:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:21]1[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=1)=[O:6]
Reactant: NCC(c1ccncc1)N1CCOCC1
Reactant: Cc1cccc(C(=O)O)c1C
Product: Cc1cccc(C(=O)NCC(c2ccncc2)N2CCOCC2)c1C

Procedure:
From 2,3-dimethylbenzoic acid and (2-morpholin-4-yl-2-pyridin-4-ylethyl)amine.
Reaction SMILES: [CH3:1][N+:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:35])[NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17](=[O:34])[CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]([CH2:31][CH2:32][Cl:33])[CH2:28][CH2:29][Cl:30])=[CH:23][CH:22]=3)[CH2:12][CH2:11]2)[CH:3]=1.C(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].C(OCC)(=O)C>C(#N)C.O>[CH3:1][N:2]1[CH:7]=[CH:6][CH2:5][C:4]([C:8](=[O:35])[NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17](=[O:34])[CH2:18][CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([N:27]([CH2:31][CH2:32][Cl:33])[CH2:28][CH2:29][Cl:30])=[CH:25][CH:26]=3)[CH2:12][CH2:11]2)=[CH:3]1
Reactant: C[n+]1cccc(C(=O)NC2CCC(OC(=O)CCCc3ccc(N(CCCl)CCCl)cc3)CC2)c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CN1C=CCC(C(=O)NC2CCC(OC(=O)CCCc3ccc(N(CCCl)CCCl)cc3)CC2)=C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
The quaternary salt prepared in Example 81 (0.34 g, 0.0005 mol) was dissolved in 0.5 mL of acetonitrile and taken up in 20 mL of degassed water (bubbling N2) cooled to 0° C. To the stirring solution, sodium bicarbonate (0.27 g, 0.003 mol) was added, followed first by 0.37 g (0.002 mol) of sodium dithionite and then by 20 mL of ethyl acetate. After 90 minutes, the organic phase was removed and the aqueous phase was extracted 3 to 4 times with ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate and evaporated in vacuo. The residual solid was washed several times with anhydrous ether and dried. The residue thus obtained was applied to a neutral alumina column and eluted with chloroform under pressure. Evaporation of chloroform left 0.18 g (65%) of a hygroscopic yellow solid of the formula ##STR114## The identity of the product was confirmed by UV analysis.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[C:10]([NH2:22])=[CH:11][C:12]2[CH2:13][C:14]3[C:19]([C:20]=2[CH:21]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[Br:8][C:9]1[C:10]([N:22]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:11][C:12]2[CH2:13][C:14]3[C:19]([C:20]=2[CH:21]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Ic1ccccc1
Reactant: Nc1cc2c(cc1Br)-c1ccccc1C2
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Brc1cc2c(cc1N(c1ccccc1)c1ccccc1)Cc1ccccc1-2

Procedure:
8.0 g (42.2 mmol) of copper(I) iodide and 11.7 ml (97.5 mmol) of trans-cyclohexanediamine are added to a vigorously stirred suspension of 47.7 g (234 mmol) of iodobenzene, 26 g (100 mmol) of 3-bromo-9H-fluoren-2-ylamine and 416.4 g (1961 mmol) of potassium phosphate in 1170 ml of dioxane, and the mixture is heated under reflux for 16 h. After cooling, the precipitated solid is filtered off with suction, washed three times with 50 ml of toluene, three times with 50 ml of ethanol:water (1:1, v:v) and three times with 100 ml of ethanol. Yield: 33 g (80 mmol), 80%.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:4]=1[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1)=[O:6].[C:23](Cl)(=[O:25])[CH3:24].C(N(C(C)C)CC)(C)C>O1CCCC1>[C:23]([NH:2][C:3]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:4]=1[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1)=[O:6])(=[O:25])[CH3:24]
Reactant: Nc1ccc(Cl)cc1C(=O)NCc1ccc2c(c1)OCO2
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Cl)cc1C(=O)NCc1ccc2c(c1)OCO2
Yield: 84 %

Procedure:
2-Amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide hydrochloride (100 mg) was reacted with 40 μl of acetyl chloride in 5 ml of tetrahydrofuran in the presence of 150 μl of diisopropylethylamine. The reaction mixture was subjected to extraction with ethyl acetate and water and recrystallization from ethyl acetate/hexane to give 85 mg of 2-acetamido-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide (yield: 84%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH:37]([NH:40][CH3:41])([CH3:39])[CH3:38]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:40]([CH:37]([CH3:39])[CH3:38])[CH3:41])=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CNC(C)C
Reactant: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CN(C)C(C)C)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-7-(methyl-propyl-amino)-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 29) (219 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with N-isopropyl-methylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (129 mg, 52%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:18]([CH2:24][CH2:25][CH3:26])=[N:17][C:11]=3[C:12]([NH2:16])=[N:13][C:14]=2[CH:15]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:37]=[C:38]=[O:39])(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(Cl)(Cl)Cl>[NH2:16][C:12]1[C:11]2[N:17]=[C:18]([CH2:24][CH2:25][CH3:26])[N:19]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:38]([NH:37][S:34]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)(=[O:35])=[O:36])=[O:39])=[CH:15][C:14]=2[N:13]=1
Reactant: CCCc1nc2c(N)nc3cc(OCCCN)ccc3c2n1CC(C)C
Reactant: O=C=NS(=O)(=O)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(OCCCNC(=O)NS(=O)(=O)c4ccc(F)cc4)ccc3c2n1CC(C)C
Yield: 85.5 %

Procedure:
A solution of 7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.41 mmol) in chloroform (15 mL) was cooled to 0° C.; 4-fluorobenzenesulfonyl isocyanate (0.548 g, 2.72 mmol) was added in three portions over a period of 30 minutes. A white precipitate was present and was isolated by filtration, washed with chloroform, and dried overnight in a vacuum oven at 60° C. to provide 0.671 g of N-{[(3-{[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)amino]carbonyl}-4-fluorobenzenesulfonamide as a white powder, mp 194-198° C.