Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[O:38]1[CH2:42][CH2:41][O:40][CH:39]1[CH2:43][NH:44][CH3:45]>>[O:38]1[CH2:42][CH2:41][O:40][CH:39]1[CH2:43][N:44]([CH3:45])[C:21]1[N:20]=[C:19]([O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:29]=[C:30]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:31]=[C:2]([F:1])[CH:3]=3)=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CNCC1OCCO1
Product: CN(CC1OCCO1)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and [1,3]dioxolan-2-ylmethylmethylamine according to conditions described in general procedure C. Mp: 125-127° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.57-1.61 (m, 6 H), 2.76 (bs, 1 H), 3.04 (bs, 1 H), 3.22-3.32 (m, 7 H), 3.55-3.86 (m, 4 H), 4.74-4.90 (m, 1 H), 6.26 (d, J=5.1 Hz, 1 H), 6.94-6.97 (m, 1 H), 7.15 (d, J=8.8 Hz, 1 H), 7.41 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.55-7.60 (m, 3 H), 7.82 (d, J=7.7 Hz, 1 H), 7.96-7.99 (m, 1 H), 8.24 (d, J=5.5 Hz, 1 H), 10.44 (s, 1 H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29](O)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[NH2:42][C:43]1[CH:44]=[CH:45][C:46]2[N:50]=[C:49]([S:51][CH2:52][C:53]3[N:57]([CH2:58][CH2:59][CH3:60])[CH:56]=[N:55][CH:54]=3)[N:48]([CH3:61])[C:47]=2[CH:62]=1>O1CCCC1.N1C=CC=CC=1.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:42][C:43]4[CH:44]=[CH:45][C:46]5[N:50]=[C:49]([S:51][CH2:52][C:53]6[N:57]([CH2:58][CH2:59][CH3:60])[CH:56]=[N:55][CH:54]=6)[N:48]([CH3:61])[C:47]=5[CH:62]=4)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Reactant: CCCn1cncc1CSc1nc2ccc(N)cc2n1C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc4nc(SCc5cncn5CCC)n(C)c4c2)CCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (252 mg) in tetrahydrofuran (10 ml) was added one droplet of DMF. Then, thionyl chloride (0.055 ml) was added to the mixture, and the mixture was stirred for 1 hour under nitrogen atmosphere. This solution was slowly added dropwise to a solution of 6-amino-1-methyl-2-(((1-propylimidazol-5-yl)methyl)sulfanyl)benzimidazole (158 mg) in pyridine (10 ml) at 0° C. under nitrogen atmosphere. The mixture was stirred overnight at room temperature under nitrogen atmosphere, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=1:2→ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[1-methyl-2-(((1-propylimidazol-5-yl)methyl)sulfanyl)benzimidazol-6-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (319 mg) (Compound 446) as yellow amorphous.
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][C@H:6]([OH:19])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:13][CH:14]=1)[CH3:3].C[C:21]1[CH:22]=[CH:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][CH:26]=1>CC(C)=O>[CH3:3][CH:2]([NH:4][CH2:5][C@H:6]([OH:19])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:13][CH:14]=1)[CH3:1].[C:25]1([CH3:1])[C:24]([C:27]([O-:29])=[O:28])=[CH:23][CH:22]=[CH:21][CH:26]=1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: CC(C)NC[C@H](O)COc1ccc(CC(N)=O)cc1
Solvent: CC(C)=O
Product: Cc1ccccc1C(=O)[O-]
Reaction time: 8 h

Procedure:
S-atenolol (optical purity, 91 % ee, 4.43 g) and p-toluic acid (2.28 g) are dissolved in acetone (300 ml) by heating, and the mixture is allowed to stand overnight at room temperature. The precipitated crystals are separated by filtration, and the filtrate is concentrated under reduced pressure to give S-atenolol toluate having an optical purity of 98.8% ee (5.01 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[I-:10].[Na+]>CC(C)=O>[I:10][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: [I-]
Reactant: BrCCC1CCCCC1
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCC1CCCCC1
Yield: 85.1 %

Procedure:
Dissolve (2-bromo-ethyl)-cyclohexane (10.0 g, 52.3 mmol) in 500 mL acetone, add sodium iodide (15.6 g, 104.6 mmol) and reflux over night. Filter the reaction mixture, add water to the filtrate and extract with hexane. Dry the organic phases over sodium sulfate, filter and concentrate to an oil. Further purify this material by distillation to afford the title compound (10.6 g). 1H-NMR (CDCl3) δ=0.83-1.00 (m, 2H), 1.07-1.48 (m, 4H), 1.61-1.80 (m, 7H), 3.16-3.27 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24]CC)=[O:23])[CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>>[ClH:1].[C:22]([C:18]1[CH:17]=[C:16]([NH:15][C:13](=[O:14])[C@@H:12]([NH:11][S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[CH:21]=[CH:20][CH:19]=1)([OH:24])=[O:23]
Reactant: CCOC(=O)c1cccc(NC(=O)[C@H](Cn2ccnc2)NS(=O)(=O)c2ccc(Cl)cc2)c1
Agent: Cl
Product: O=C(O)c1cccc(NC(=O)[C@H](Cn2ccnc2)NS(=O)(=O)c2ccc(Cl)cc2)c1
Yield: 66.7 %

Procedure:
The procedure described in Example 92 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide (53.1 mg) was hydrolyzed, and then reacted with HCl to obtain (S)-N-(3-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride (18.03 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOCC>[NH2:6][C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:20](=[S:21])[NH:19][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NC(=O)c1ccccc1N
Solvent: CCOCC
Product: NC(=O)c1ccccc1NC(=S)NC(=O)c1ccccc1
Reaction time: 48 h
Yield: 95 %

Procedure:
To a stirred mixture of 13.6 g of 2-aminobenzamide and 200 ml of ether Was added dropwise, a solution of 16.3 g of benzoyl isothiocyanate in 100 ml of ether over 30 minutes. After standing 48 hours, the solid Was collected, giving 28.4 g of the desired product as grey crystals, mp 190°-192° C.
Reaction SMILES: [N+:1]([C:4]1[C:13]([CH3:14])=[CH:12][C:7]([C:8]([NH:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH3:15])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[C:5]([CH3:15])=[CH:6][C:7]([C:8]([NH:10][CH3:11])=[O:9])=[CH:12][C:13]=1[CH3:14]
Reactant: CNC(=O)c1cc(C)c([N+](=O)[O-])c(C)c1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1cc(C)c(N)c(C)c1
Yield: 99.4 %

Procedure:
4-Nitro-3,5,N-trimethyl-benzamide (1.0 g, 4.8 mmol) is suspended in methanol (10 mL) and hydrogenated at 3 bar for 3 hours using 10% Palladium on activated carbon (100 mg) as the catalyst. The mixture is filtered through celite and the solvent removed under vacuum to give the title compound (Yield 850 mg).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:33])=[C:11]([CH2:16][C:17]([O:19][CH:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[C:12]=3[O:14][CH3:15])[C:7](=[O:34])[C:6]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:5]2)[CH2:3][CH2:2]1.C=O.[C:42](=O)([O-])O.[Na+].C(OCC)(=O)C>CS(C)=O.O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:33])=[C:11]([C:16]([C:17]([O:19][CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:18])=[CH2:42])[C:12]=3[O:14][CH3:15])[C:7](=[O:34])[C:6]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(CC(=O)OC(c3ccccc3)c3ccccc3)c(F)cc2c1=O
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: C=C(C(=O)OC(c1ccccc1)c1ccccc1)c1c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c2c1OC
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 1462.5 %

Procedure:
2.64 g of ethyl 1-cyclopropyl-7-diphenylmethoxycar-bonylmethyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quino-linecarboxylate was suspended in 20 ml of dimethylsulfoxide. Then 0.85 g of a 35% aqueous solution of formaldehyde and 21 mg of sodium hydrogencarbonate were added thereto and the mixture was stirred at 50° C. for 1.5 hours. To the reaction mixture, 100 ml of ethyl acetate and 50 ml of water were added and then the organic layer was collected. The organic layer thus collected was successively washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the obtained residue was dissolved in 25 ml of methylene chloride. Under ice-cooling, 0.57 g of methanesulfonyl chloride and 1.0 mg of triethylamine were successively dropped thereinto slowly and the resulting mixture was stirred at room temperature for 3 hours. 20 ml of water was added to the reaction mixture and the pH value of the mixture was regulated to 1 with 2N hydrochloric acid. Then the organic layer was collected, successively washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the oily product thus obtained was crystallized by adding ethanol and the crystals were collected by filtration. Thus 1.98 g of ethyl 1-cyclopropyl-7-(1-diphenylmethoxycarbonylvinyl)-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylate was obtained (yield: 73.1%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][C:26]([N:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.[I-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][C:26]([N:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:27])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(CCCl)N(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1)N(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 88.8 %

Procedure:
A mixture of 12.0 g (0.040 mole) of α,α-bis(4-fluorophenyl)-4-piperidine methanol, 10.3 g (0.040 mole) of 3-chloro-N,N-diphenylpropanamide, 17.0 g (0.160 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in 100 ml of N,N-dimethylformamide was heated on a steam bath for 16 h. The mixture was poured into 2 L of water and a solid precipitated. After standing 3 h, the solid was collected by filtration, washed with water, dried and recrystallized from benzene-petroleum ether (30°-60° C.) to yield 18.7 g (90%) of a white solid, mp 160°-162° C.
Reaction SMILES: Cl[CH2:2][CH2:3][OH:4].[SH:5][C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1>[OH-].[Na+]>[OH:4][CH2:3][CH2:2][S:5][C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1
Reactant: Cn1ccnc1S
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Product: Cn1ccnc1SCCO
Temperature: 100 °C
Yield: 82.2 %

Procedure:
2-Chloroethanol (3 g, 37 mmol) was added to a solution of 2-mercapto-1-methylimidazole (3.45 g, 30 mmol) in 2M aqueous sodium hydroxide solution (30 ml) and the mixture heated at 100° C. for 2 hours. The mixture was allowed to cool and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and the solvent removed by evaporation to give 2-(2-hydroxyethylthio)-1-methylimidazole (3.9 g, 82%).
Reaction SMILES: C[O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12](=O)[CH2:13][C:14](=O)[CH3:15])[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:18][NH:19][NH2:20].O>CO>[OH:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[CH:13]=[C:14]([CH3:15])[N:19]([CH3:18])[N:20]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2oc(C(=O)CC(C)=O)cc12
Reactant: CNN
Solvent: O
Solvent: CO
Product: Cc1cc(-c2cc3c(O)cccc3o2)nn1C
Temperature: -40 °C
Yield: 86.5 %

Procedure:
1-(4-Methoxybenzo(b)furan-2-yl)butan-1,3-dione (1.0 g) was dissolved in methanol (30 ml) and methylhydrazine (0.3 g) was added thereto. The mixture was refluxed under heating for 20 min. The reaction solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/acetone). To the obtained oil was added methylene chloride (30 ml), and the mixture was cooled to −40° C., and boron tribromide (1 ml) was added dropwise. After the completion of the reaction, the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and after filtration, the solvent was evaporated under reduced pressure to give 3-(4-hydroxybenzo(b)furan-2-yl)-1,5-dimethylpyrazole (0.85 g) as a brown oil. Using this and (S)-glycidyl nosylate (0.75 g) and in the same manner as in Starting Material Synthesis Example 1, the title compound (0.53 g) was obtained as a brown oil.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:33])[C:16]([N:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][C@@H:19]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][C:37]([S@:40]([NH2:42])=[O:41])([CH3:39])[CH3:38]>C1COCC1.C(Cl)Cl.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]([N:15]([CH3:33])[C:16]([N:18]2[CH2:23][CH2:22][C:21](=[N:42][S:40]([C:37]([CH3:39])([CH3:38])[CH3:36])=[O:41])[CH2:20][C@@H:19]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:34])([F:1])[F:35])[CH:8]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: Cc1cc(F)ccc1[C@H]1CC(=O)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(F)ccc1[C@H]1CC(=NS(=O)C(C)(C)C)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 45.6 %

Procedure:
To a solution of (2R)—N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-oxo-1-piperidinecarboxamide (WO0232867) (4 g, 7.93 mmol) and Titanium(IV) ethoxide (8 mL) in THF (10 mL) was added at 25° C., under Nitrogen, (R)-(+)-2-Methyl-2-propanesulfinamide (1.15 g, 9.52 mmol, Aldrich) and the reaction mixture was heated to 100° C. It was stirred at this temperature for 3 hrs, then it was diluted with DCM and brine (2 mL) was added. A white precipitate was formed and it was filtered-off. The resulting solution was dried (Na2SO4) and evaporated to dryness. The crude was purified by silica cartridge (25 g) (from 1:0 to 0:1 Cyclohexane/EtOAc) to give the title compound (2.2 g, 3.62 mmol, 45% yield) as a yellow gum. A further purification of the crude fractions containing the desired compound by flash chromatography on Companion CombiFlash (from 1:0 to 0:1 Cyclohexane/EtOAc) gave further title compound (848 mg, 1.40 mmol, 17.6% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.68-8.07 (m, 3H) 6.70-7.43 (m, 3H) 4.80-5.35 (m, 2H) 3.10-3.79 (m, 2H) 2.42-2.95 (m, 7H) 2.19-2.30 (m, 3 H) 1.46-1.62 (m, 3H) 1.01-1.22 (m, 9H); mixture of E+Z isomers
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].[CH2:33](I)[CH3:34]>CN(C)C=O>[CH2:33]([N:23]1[CH2:24][CH2:25][CH2:26][CH:22]1[C:19]1[CH:20]=[CH:21][C:16]([NH:15][CH:14]=[C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=3)[C:8](=[O:12])[NH:7][C:6]2=[O:13])=[CH:17][CH:18]=1)[CH3:34]
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNc1ccc(C2CCCN2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCCC1c1ccc(NC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1

Procedure:
6-Iodo-4-[(4-pyrrolidin-2-yl-phenylamino)-methylene]-4H-isoquinoline-1,3-dione (250 mg, 0.54 mmol) and K2CO3 (170 mg, 1.23 mmol) and EtI (155 mg, 0.99 mmol) in N,N-dimethylformamide (5 mL) were stirred at room temperature for 2 hours. After TLC suggested no starting material left, the N,N-dimethylformamide is removed through an aqueous work up, and the desired product is isolated through chromatography (125 mg, 48%). MS (ESI): 488.0 (M+1)+1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[O:16])[N:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:6]=1[Br:7].CC(C)=[O:19].[Mn]([O-])(=O)(=O)=O.[K+]>O>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:19])=[O:16])[N:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:6]=1[Br:7]
Reactant: CC(C)=O
Reactant: O=Cc1cc(Br)c(Br)n1-c1ncccc1Cl
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(Br)c(Br)n1-c1ncccc1Cl
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of 1.0 g of 4,5-dibromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carbaldehyde, 15 ml of acetone and 7 ml of water was slowly added 1.3 g of potassium permanganate at 40° C. The resulting mixture was stirred at 60° C. for 2 hours. Precipitates in the reaction mixture were removed by filtration. The resulting filtrate was washed with chloroform two times. The aqueous layer was adjusted to around pH 3 by an addition of 2N hydrochloric acid and then extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 0.69 g of 4,5-dibromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid of the formula:
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:5])[OH:4])[CH3:2].CC(C)=[O:11].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH2:1]([P:3]([OH:4])([CH2:6][C:7]([OH:11])=[O:8])=[O:5])[CH3:2]
Reactant: CCP(=O)(O)CCO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CCP(=O)(O)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
13.8 g (0.1 mol) of ethyl-(2-hydroxyethyl)phosphinic acid (produced as in Example 8) in 500 ml of acetone were admixed with 0.11 mol of Jones reagent (12.7 g of chromium trioxide in 36.7 ml of water and 11.0 ml of concentrated sulfuric acid) at 0° C. by dropwise addition. The reaction mixture was additionally stirred for 3½ hours with ice cooling and for 1 hour at room temperature. After 12 ml of isopropanol have been added, the mixture is poured onto ice-water. Volatile constituents are subsequently distilled off in vacuo. The residue was taken up in tetrahydrofuran and extracted. Insoluble salts were filtered off. The solvent of the filtrate was removed in vacuo and the residue was recrystallized from acetone to obtain 12.3 g (81% of theory) of 2-(ethylhydroxyphosphinyl)acetic acid as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH2:15])[C@H:10]([F:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC1C([O:24][C:25]([C:27]2[N:28]=[N:29][C:30]([CH2:46][CH2:47][CH2:48][CH3:49])=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)=[CH:35][CH:34]=3)[CH:32]=2)=O)=C(F)C(F)=C(F)C=1F>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][C:25]([C:27]2[N:28]=[N:29][C:30]([CH2:46][CH2:47][CH2:48][CH3:49])=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH:40]4[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]4)=[CH:35][CH:34]=3)[CH:32]=2)=[O:24])[C@H:10]([F:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)[C@H](F)C1
Reactant: CCCCc1nnc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1-c1ccc(OC2CCCCC2)cc1
Solvent: ClCCl
Product: CCCCc1nnc(C(=O)NC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2F)cc1-c1ccc(OC2CCCCC2)cc1

Procedure:
To a stirred solution of (±)-cis-4-aminomethyl-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (0.65 mmol, 150 mg) in dichloromethane (3 mL) was added 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester (Example 93, 0.75 mmol, 400 mg) and TEA (1.3 mmol, 0.2 mL). After stirring the reaction at room temperature for 8 h, dichloromethane (5 mL) was added. The reaction was washed with saturated sodium bicarbonate solution (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Crude product was purified using hexane:ethyl acetate on 12 g normal phase ISCO flash column to provide (±)-cis-4-({[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-methyl)-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCOCC5)c(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)ccc1N1CCOCC1
Yield: 18.2 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-morpholinophenyl) methanesulfonamide (240 mg, 0.342 mmol) was hydrolyzed by lithium hydroxide (143 mg, 3.42 mmol), THF/Methanol/water (20/8/8 mL) to yield 34 mg (18%) of the titled compound. 1H NMR (DMSO-D6, 400 MHz): δ 11.8 (s, 1H), 8.618 (s, 1H), 8.469-8.464 (m, 1H), 8.421 (s, 1H), 8.317-8.313 (d, 1H), 7.963 (s, 1H), 7.782-7.777 (d, 1H), 7.649-7.645 (d, 1H), 7.58-7.52 (m, 1H), 7.44-7.366 (m, 2H), 7.16-7.08 (m, 3H), 5.402 (s, 2H), 3.80.3-3.791 (m, 4H), 3.197 (s, 3H), 2.898-2.887 (m, 4H). MS: m/z=546.8 (M+1); HPLC: 96.04% in method B.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15]Br.[OH-].[K+]>CO>[O:10]1[CH2:15][CH2:14][O:11][C:6]2[CH:5]=[C:4]([C:3]([O:2][CH3:1])=[O:12])[CH:9]=[CH:8][C:7]1=2
Reactant: BrCCBr
Reactant: COC(=O)c1ccc(O)c(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)OCCO2
Yield: 13 %

Procedure:
A mixture of 3,4-dihydroxybenzoic acid methyl ester (5.2 g, 31 mmol), 1,2-dibromoethane (2.9 mL, 34 mmol), and pulverized KOH (3.8 g, 68 mmol) in MeOH was heated at reflux for 30 hrs. After removal of the solvent under reduced pressure, the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, dried over MgSO4, concentrated in vacuo and purified by purified by column chromatography on silica gel eluting with 40% ethyl acetate in hexane to yield methyl 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (780 mg, 13%) along with the unreacted starting material (2.6 g). 1H NMR (DMSO-d6, 600 MHz) δ 7.45 (d, 1H, J=8.4 Hz), 7.39 (s, 1H), 6.96 (d, 1H, J=8.4 Hz), 4.33-4.28 (m, 4H), 3.80 (s, 3H); MS (ES+) m/z 195.1 (M+H)+