Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:24][CH2:23][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4].[H-].[Na+].[C:27](Cl)(=[O:29])[CH3:28]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:24][CH2:23][C:14]3[N:15]([C:27](=[O:29])[CH3:28])[C:16]4[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(C)cc4c3C2)nc1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N2CCc3c(c4cc(C)ccc4n3C(C)=O)C2)nc1
Reaction time: 0.33 h

Procedure:
From 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and Example 7 was obtained methyl-2-(8-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)pyrimidine-5-carboxylate using the method described in Example 12. To a solution of methyl-2-(8-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)pyrimidine-5-carboxylate (110 mg) in DMF (5 mL) was added sodium hydride (22 mg) at 0° C. and the mixtue was stirred for 20 min. Acetyl chloride (30 mg) was added and the reaction was allowed to attain room temperature and stirred another 3 hours. The reaction mixtue was partitioned between ethyl acetate and water. The organic layer was separated and washed with water and saturated aqueous sodium bicarbonate. The solvent was dried and evaporated and the residue purified by chromatography to give methyl-2-(5-acetyl-8-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)pyrimidine-5-carboxylate.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[N:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[N:9]1([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[N:10]1
Reactant: COc1ccc(-n2ncc3ccccc32)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(-n2ncc3ccccc32)cc1
Temperature: -40 °C
Reaction time: 5 h

Procedure:
1-(4-Methoxyphenyl)-1H-indazole (30 mg, 0.134 mmol) was dissolved in dichloromethane (0.4 mL) and cooled to −40° C. Boron tribromide (0.4 mL, 1 M solution in dichloromethane, 0.4 mmol) was added, and the reaction was warmed to rt and stirred for 5 hours. Saturated sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane. The extracts were dried over MgSO4 and concentrated to give the desired product. LC-MS (C13H10N2O calculated 210) m/z 211 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][CH:14]1[CH2:18][CH2:17][CH:16]([CH3:19])[NH:15]1>C(O)C>[CH3:13][CH:14]1[CH2:18][CH2:17][CH:16]([CH3:19])[N:15]1[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1
Reactant: CC1CCC(C)N1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(N2C(C)CCC2C)n1

Procedure:
4 g (0.0212 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 40 ml of ethanol and 4.2 g (0.042 mol) of 2,5-dimethylpyrrolidine were placed in a fully equipped round-bottomed flask.
Reaction SMILES: [OH:1][C@@H:2]([CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:16]=[C:15]([CH3:30])[CH:14]=2)[CH:10]=[N:9]1)[C:3](OC)=[O:4].[CH2:31]([CH2:33][NH2:34])[OH:32]>CO>[OH:1][C@@H:2]([CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][N:21]=3)[CH:16]=[C:15]([CH3:30])[CH:14]=2)[CH:10]=[N:9]1)[C:3]([NH:34][CH2:33][CH2:31][OH:32])=[O:4]
Reactant: NCCO
Reactant: COC(=O)[C@@H](O)Cn1cc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C[C@H](O)C(=O)NCCO)c2)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Methyl (2S)-2-hydroxy-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanoate (40 mg, 0.10 mmol) in methanol (1 mL) was treated with ethanolamine (0.03 mL, 0.48 mmol). The mixture was stirred overnight at 70° C. Upon cooling to room temperature, the mixture was filtered and purified by reverse phase HPLC (0 to 95% ACN/water with 0.1% TFA modifier) to afford (2S)-2-hydroxy-N-(2-hydroxyethyl)-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanamide. MS ESI calcd. for C20H21F3N6O3 [M+H]+ 451. found 451. 1H NMR (500 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.80 (d, J=4.9 Hz, 1H), 7.94 (s, 1H), 7.84 (t, J=5.6 Hz, 1H), 7.80 (s, 1H), 7.75 (s, 1H), 7.33 (s, 1H), 7.23 (d, J=6.3 Hz, 1H), 7.05 (s, 1H), 4.39 (dd, J=2.9 Hz, 13.7 Hz, 1H), 4.26 (d, J=7.7 Hz, 1H), 4.17-4.12 (m, 1H), 3.38 (t, J=5.9 Hz, 2H), 3.16 (q, J=6.1 Hz, 2H), 2.28 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[N+:22]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCCC2)c(C#N)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCCC2)c(C#N)cc1N

Procedure:
The title compound was prepared from (4-cyano-2-nitro-5-piperidin-1-yl-phenyl)-carbamic acid tert-butyl ester (Example C30) (2.08 g, 5.71 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as an off-white solid (1.67 g, 99%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[OH:20][S:21]([O-:23])=[O:22].[Na+:24]>CCO.O>[Na+:24].[OH:17][CH:16]([C:15]1[CH:14]=[CH:13][C:12]([C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[O:11])=[CH:19][CH:18]=1)[S:21]([O-:23])(=[O:22])=[O:20]
Reactant: O=S([O-])O
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)N1CCN(C(=O)c2ccc(C(O)S(=O)(=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-(4-isopropyl-piperazine-1-carbonyl)-benzaldehyde (20.0 g, 76.9 mmol) in EtOH (200 mL) was stirred at room temperature for 15 min. To the resulting solution was added a solution of NaHSO3 (9.6 g) in H2O (25 mL), dropwise over 30 min. The resulting suspension was stirred at room temperature for 2 h, then cooled to 0° C. and stirred for 3 h, adding EtOH periodically (total 200 mL) to aid stirring. A precipitate formed and was collected by suction filtration through a glass frit lined with filter paper. The filter cake was washed with hexane (1×50 mL), and dried under vacuum for 16 h to yield the title compound as a white solid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:5]([F:15])=[C:6]([C:9]([F:14])=[C:10]([F:13])[C:11]=1[F:12])[CH:7]=[O:8]>CO>[CH3:3][C:4]1[C:5]([F:15])=[C:6]([C:9]([F:14])=[C:10]([F:13])[C:11]=1[F:12])[CH2:7][OH:8]
Reactant: Cc1c(F)c(F)c(F)c(C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(F)c(F)c(F)c(CO)c1F
Yield: 79.2 %

Procedure:
Sodium borohydride (0.3 g) was added in small portions to a solution of 3-methyl-2,4,5,6-tetrafluorobenzaldehyde (1.5 g) in methyl alcohol (15 ml) at the ambient temperature, after which the mixture was heated at the reflux temperature for 30 minutes. The methyl alcohol was removed by evaporation under reduced pressure and the residue partitioned between dilute hydrochloric acid (20 ml of a 0.1 N solution) and ether (20 ml). The ethereal phase was separated, washed with saturated sodium bicarbonate solution and with water and then dried over anhydrous magnesium sulphate. After evaporation of the ether under reduced pressure the product was distilled in a Kugelrohr apparatus to yield 3-methyl-2,4,5,6-tetrafluorobenzyl alcohol (1.2 g)--approximate b.p. 100° C./14 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21](O)=[O:22])=[N:19][CH:20]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH2:24][OH:25])=[CH:20][N:19]=1)=[O:22])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Yield: 51 %

Procedure:
As described for example 34b, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid (75 mg, 0.22 mmol) was converted, using tert-butylamine instead of S-(+)-1-amino-2-propanol, to the title compound (45 mg, 51%), which was obtained as a colourless gum. MS: m/e=400.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[C:16]([CH:19]=[O:20])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2cccc3c2CCCC3)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Product: O=Cc1ccc(OCc2ccccc2)c2c1CCCC2

Procedure:
In analogy to the procedure described in examples 91 b], 5-benzyloxy-1,2,3,4-tetrahydro-naphthalene [J . Org. Chem. (2001), 66(5), 1775-1780] was treated with dichloromethyl methyl ether and titanium tetrachloride to give 4-benzyloxy-5,6,7,8-tetrahydro-naphthalene-1-carbaldehyde as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[BrH:14].OO>>[NH2:1][C:2]1[C:12]([CH3:13])=[CH:11][C:10]([Br:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cccc(C)c1N
Reactant: Br
Agent: OO
Product: CCOC(=O)c1cc(Br)cc(C)c1N
Yield: 89.1 %

Procedure:
The above-described method (Example 1) was repeated to react 2-ethyl 2-amino-3-methylbenzoate (16.29 g, 90.0 mmol) with hydrogen bromide (15.93 g, 94.5 mmol, 48% in water) and hydrogen peroxide (11.25 g, 99.0 mmol, 30% in water) and, following working up similar to Example 1, ethyl 2-amino-5-bromo-3-methylbenzoate (20.7 g, 89.1% of theory, >99 area % LC) was obtained as a brown oil.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCC=O
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCCCCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.70 ml (5.0 mmol) of 1-heptanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=4/1) to yield 1.82 g (87.3%, yellow oily substance) of the desired product.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])[CH3:3].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:33][C:34](=[NH:53])[C:35]1[CH:52]=[CH:51][C:38]2[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43][C:37]=2[CH:36]=1>CN(C=O)C>[CH3:3][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[O:11][N:33]=[C:34]([C:35]3[CH:52]=[CH:51][C:38]4[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH2:42][CH2:43][C:37]=4[CH:36]=3)[N:53]=2)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(=N)NO)cc2CC1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.3 %

Procedure:
4-[(1-Methylethyl)oxy]-3-(trifluoromethyl)benzoic acid (Preparation 39) (744 mg, 3.00 mmol), HOBT (446 mg, 3.30 mmol) and EDC (630 mg, 3.30 mmol) were stirred in DMF (28 ml) under argon for 20 minutes. 1,1-dimethylethyl 7-[(hydroxyamino)(imino)methyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 41) (915 mg, 3.00 mmol) was added and the mixture stirred at room temperature for 2 hrs before it was heated to 80° C. for 20 hrs. The reaction mixture was partitioned between EtOAc and water and the organic layer washed with aqueous sodium bicarbonate before it was dried in the usual manner and evaporated. The residue was purified by Biotage Horizon, reverse phase cartridge, eluting with 5-100% acetonitrile in water to give the title compound (749 mg, 1.45 mmol). δH (d6DMSO, 400 MHz): 8.40 (1H, dd), 8.31 (1H, d), 7.89 (1H, br.s), 7.86 (1H, dd), 7.58 (1H, d), 7.37 (1H, d), 4.98 (1H, septet), 3.54-3.46 (4H, m), 3.00-2.92 (4H, m), 1.41 (9H, s), 1.36 (6H, d).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>O1CCOCC1>[S:20]1[CH:24]=[CH:23][C:22]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=3)=[CH:18][CH:17]=2)=[CH:21]1
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Reactant: OB(O)c1ccsc1
Solvent: C1COCCO1
Product: O=C(O)c1csc(COc2ccc(-c3ccsc3)cc2)n1

Procedure:
A solution of 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of Intermediate 2; 78 mg, 0.2 mmol) in dioxane (2 mL) was degassed with nitrogen and then added to a reaction vial containing thiophene-3-boronic acid (available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). The solution was sonicated and degassed and a solution of potassium carbonate (1.5 M, 0.4 mL) was added, followed by bis(tri-cyclo-hexylphosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 7 mg, 0.01 mmol) was added. The mixture was degassed and then heated in a microwave oven at 170 degrees for 25 min. The reaction mixture was evaporated in the Genevac to give 2-(4-thiophen-3-yl-phenoxymethyl)-thiazole-4-carboxylic acid. Mass spectrum MH+=318.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Br:9][C:10]1[C:11]([CH3:18])=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14]>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][C:10]1[C:11]([CH2:18][Br:8])=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14]
Reactant: Cc1c(Br)cccc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cccc(Br)c1CBr
Temperature: 25 °C
Yield: 86.9 %

Procedure:
A mixture of NBS (3.45 g), dibenzoyl peroxide (100 mg) and 3-bromo-2-methylbenzonitrile (3.47 g) in carbon tetrachloride (40 ml) was heated at reflux under nitrogen for 48 h. The mixture was then cooled to room temperature, filtered and concentrated in vacuo to give a pale yellow solid. Chromatography eluting with dichloromethane gave the title compound as a white solid (4.23 g) m.p. 90°-93° C.
Reaction SMILES: [F:1][CH:2]([F:32])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([O:12][C:13]1[CH:17]=[C:16]([N:18]2[C:26]3[CH:25]=[C:24]([CH2:27][OH:28])[N:23]=[CH:22][C:21]=3[N:20]=[CH:19]2)[S:15][C:14]=1[C:29]([NH2:31])=[O:30])[CH3:11].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH3:33][S:34]([O:28][CH2:27][C:24]1[N:23]=[CH:22][C:21]2[N:20]=[CH:19][N:18]([C:16]3[S:15][C:14]([C:29](=[O:30])[NH2:31])=[C:13]([O:12][CH:10]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[O:3][CH:2]([F:1])[F:32])[CH3:11])[CH:17]=3)[C:26]=2[CH:25]=1)(=[O:36])=[O:35]
Reactant: CC(Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1OC(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1OC(F)F

Procedure:
In a similar manner as described for example 49 (step 1), 511 mg of 3-{(1-[2-(difluoromethoxy)phenyl]ethoxy}-5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxamide, 252 mg of methanesulfonyl chloride, and 223 mg of triethylamine in 11 ml dichloromethane give [1-(5-carbamoyl-4-{1-[2-(difluoromethoxy)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: ClCCCN(C)[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2=[N:16][N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:8]2[N:7]=1.[I-].[K+].[C-:30]#[N:31].[K+]>C(O)C>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[N:8]3[N:7]=[C:6]([CH2:30][NH:31][CH2:13][CH2:14][CH2:15][C:6]#[N:7])[C:15]4[C:10]([C:9]3=[N:16][N:17]=2)=[CH:11][CH:12]=[CH:13][CH:14]=4)=[CH:24][CH:23]=1
Reactant: [C-]#N
Reactant: COc1ccc(-c2nnc3c4ccccc4c(N(C)CCCCl)nn23)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(-c2nnc3c4ccccc4c(CNCCCC#N)nn23)cc1
Yield: 70 %

Procedure:
The compound of example 106 (2.5 g) is dissolved in ethanol (20 ml) and added of potassium iodide (0.4 g) and potassium cyanide (0.75 g). The mixture is refluxed for about 8 hours. The reaction mixture is then hot filtered, and the filtrate is concentrated to dryness. The residue is taken up with water and extracted with methylene chloride (2×25 ml). The pooled organic layer is dried over sodium sulfate and concentrated to dryness. The residue, which is the compound of the title, crystallizes from methanol. Yield: 70%. M.p. 117°-119° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH2:13])=O)=[CH:4][CH:3]=1>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]#[N:13])=[CH:6][CH:7]=1
Reactant: NC(=O)CCCc1ccc(F)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#CCCCc1ccc(F)cc1
Reaction time: 2 h
Yield: 97.1 %

Procedure:
4-(4-Fluorophenyl)-butyramide (Int. A4) (2.63 g) was dissolved in trifluoroacetic anhydride (10 ml) and stirred for 2 h. The solution was concentrated and then dissolved in dichloromethane and washed with 2N sodium hydroxide solution. The organics extracts were isolated, dried (MgSO4) and concentrated to yield the product (2.3 g, 100%) which contained ˜5% starting amide as an impurity. 1H-NMR (CDCl3) δ 1.96 (2H, app q), 2.31 (2H, t), 2.75 (2H, t), 6.98 (2H, m), 7.14 (2H, m). MS (APCI+) M+1=164, C10H10FN requires 163.
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+].CO>C(O)(C)(C)C>[CH:10](=[C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCCCCCC1
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)(C)O
Product: O=C1C(=Cc2ccccc2)CCCCCC1=Cc1ccccc1

Procedure:
An alternative procedure for preparing 2,8-dibenzylcyclooctanones involves the corresponding 2,8-dibenzylidenecyclooctanones as the intermediates. Thus, a mixture comprising 12.5 grams of cyclooctanone, 27 grams of benzaldehyde, 15 grams of potassium hydroxide and 300 milliliters of methanol is stirred at reflux temperatures for 4 hours. To the hot, stirred mixture are slowly added 400 milliliters of t-butyl alcohol with simultaneous removal of the methanol by distillation. The mixture is then cooled, water is added and the product is extracted with ether. The crude product obtained from the ether extract is chromatographed on activated alumina to give 2,8-dibenzylidenecyclooctanone. This intermediate is hydrogenated at 60 p.s.i.g. in ethanol using 5 percent palladium on carbon. Fractional crystallization of the hydrogenation product from methanol affords the isomeric 2,8-dibenzylcyclooctanones, m.p. 75°-77° C. and 66°-68° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[CH3:10].[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=2[CH3:10])[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(CO)ccc1Br
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc(CO)cc2C)c1

Procedure:
Following the procedure described for Example 13, step A, but using the product from step A above and 3-methoxybenzene-boronic acid as starting materials the title product was obtained.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:36])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21](O)=[O:22])[CH:18]=2)[NH:13][CH:12]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:10][C:11]1([CH3:36])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:18]=2)[NH:13][CH:12]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCNCC2)c1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1cccc(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
To a suspension of 60% sodium hydride (196 mg, 4.9 mmol) in N,N-dimethylformamide (1.5 mL) was added cyclopropanesulfonamide (605 mg, 5.0 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-(3-piperazin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (180 mg, 0.5 mmol) and 1,1′-carbonyldiimidazole (162 mg, 1.0 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [3,3-dimethyl-2-(3-piperazin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (74 mg, 32%) as a light yellow solid: LC/MS m/e calcd for C25H32N4O3S (M+H)+: 469.61, observed: 469.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=S)=[CH:15][CH:14]=1)([O-:12])=[O:11].CC(N=C=NC(C)C)C>CN(C=O)C>[Cl:9][C:3]1[C:2]2[NH:1][C:20]([NH:19][C:16]3[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=3)=[N:8][C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: Nc1ccnc(Cl)c1N
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Nc2nc3ccnc(Cl)c3[nH]2)cc1
Reaction time: 6 h
Yield: 82.9 %

Procedure:
3.1 A solution of 0.72 g of 3,4-diamino-2-chloropyridine, 0.9 g of 4-nitrophenyl isothiocyanate and 0.78 ml of N,N-diisopropylcarbodiimide in 30 ml of DMF is stirred at room temperature for 16 hours, then at 500 for 6 hours. The solvent is separated off, and the residue is crystallised from methanol, giving 1.2 g of 4-chloro-2-(4-nitrophenylamino)-3H-imidazo-[4,5-c]pyridine (“6”).