Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:15])[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[C:5]([CH3:16])[CH:4]=[C:3]1[CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+]>>[CH3:1][N:2]1[C:6]([C:7](=[O:15])[C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)=[C:5]([CH3:16])[CH:4]=[C:3]1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(F)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(F)cc1
Yield: 91 %

Procedure:
A suspension of 3.03 g. (0.01 mole) of ethyl 1,4-dimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetate in 11 ml. of 1N sodium hyroxide solution is heated under reflux for 30 min. The solution is filtered while hot and acidified with dilute hydrochloric acid. The precipitate is collected, air dried and recrystallised from 2-propanol to give about 2.5 g. (91% yield) of 1,4-dimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetic acid as a white solid, m.p. 176°-178°C.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:11]1[C:2]([CH3:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2ccccc2nc1C
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc2ccccc2cc1CBr
Temperature: 25 °C
Yield: 33.1 %

Procedure:
To a solution of 2,3-dimethylquinoline (0.50 g, 3.2 mmol) in carbon tetrachloride (40 ml) benzoyl peroxide (100 mg) and N-bromosuccinimide (1.14 g, 6.4 mmol) were added. The reaction mixture was refluxed for 4 hours, and then cooled to room temperature. The precipitate was removed by filtration and the filtrate was evaporated in vacuo. The residue was flash chromatographed on silica gel with ethyl acetate/petroleum ether as the eluent to give 0.25 g of 3-bromomethyl-2-methylquinoline.
Reaction SMILES: C([N:8]([CH:16]([P:25]([O:30][CH2:31][CH3:32])(=[O:29])[O:26][CH2:27][CH3:28])[P:17]([O:22][CH2:23][CH3:24])(=[O:21])[O:18][CH2:19][CH3:20])CC1C=CC=CC=1)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:8][CH:16]([P:17]([O:22][CH2:23][CH3:24])(=[O:21])[O:18][CH2:19][CH3:20])[P:25]([O:26][CH2:27][CH3:28])(=[O:29])[O:30][CH2:31][CH3:32]
Reactant: CCOP(=O)(OCC)C(N(Cc1ccccc1)Cc1ccccc1)P(=O)(OCC)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(OCC)C(N)P(=O)(OCC)OCC

Procedure:
17.1 g (35.4 mmol) of tetraethyl N,N-dibenzyl-aminomethane-1,1-bisphosphonate are dissolved in 170 ml of ethanol and 3.4 g of 5% strength Pd/C are added. Hydrogenation is carried out at normal pressure. After absorption of 100 ml of hydrogen, a further 3.4 g of 5% strength Pd/C are added and the hydrogenation is completed at normal pressure and room temperature (reaction time about 16 hours). The catalyst is then filtered off with suction. After removal of the solvent, 10.9 g of crude product are obtained. This is purified on a silica gel column using ethanol as the eluent.
Reaction SMILES: [C:1]1([CH3:9])[C:2]([NH2:8])=[CH:3][CH:4]=[CH:5][C:6]=1[NH2:7].[CH2:10]=[CH:11][C:12](=[CH2:14])[CH3:13]>CCCCC>[CH3:13][C:12]([CH3:14])=[CH:11][CH2:10][C:3]1[CH:4]=[CH:5][C:6]([NH2:7])=[C:1]([CH3:9])[C:2]=1[NH2:8]
Reactant: C=CC(=C)C
Reactant: Cc1c(N)cccc1N
Solvent: CCCCC
Product: CC(C)=CCc1ccc(N)c(C)c1N

Procedure:
A 200g (1.64 mol) portion of 2,6-toluenediamine, 167g (2.45 mol) of isoprene, 200g (2.78 mol) of pentane, and 20g of powdered H-Y zeolite were reacted at 150° C. in a similar fashion as indicated in Example 3. Isolation of a catalyst free sample was obtained by hot filtration. Selective removal of all residual hydrocarbon by vacuum distillation afforded the following product mixture:
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)=[C:27]([CH:31]=1)[C:28](O)=[O:29]>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)=[C:27]([C:28]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:29])[CH:31]=1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: CN(C)c1nc(N2CC3CNCC3C2)cc(C(F)(F)F)n1
Product: CN(C)c1nc(N2CC3CN(C(=O)c4cc(F)ccc4-n4nccn4)CC3C2)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 36 and Intermediate 1. MS (ESI): mass calculated for C22H22F4N8O, 490.46; m/z found 490.9 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.00-7.92 (m, 1H), 7.78-7.64 (m, 2H), 7.26-7.20 (m, 1H), 7.17-7.11 (m, 1H), 5.87 (br s, 1H), 3.96-2.87 (m, 16H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B.C1COCC1.B.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])ccc1CO
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5.08 g (27.2 mmol) 2-methyl-4-nitrobenzoic acid in 50 ml dry THF, 41 ml (41 mmol) borane-THF complex (1M solution in THF) is added drop-wise at 0° C. After completion of the borane addition, the reaction mixture is stirred at room temperature for 20 h. After that a K2CO3 solution (1.33 g in 49 ml water) is slowly added under stirring. Then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is taken up in diethylether, vigorously stirred, and the title compound is obtained after filtration as a yellow crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.CS(O[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=O)=O.CN(C)P(N(C)C)(N(C)C)=O>O>[C:29]1([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)OCCCCCCCCCCCc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=C(O)c1ccc(NCCCCCCCCCCCc2ccccc2)cc1

Procedure:
A mixture of 16.5 g. of ethyl p-aminobenzoate, 16.3 g. of 11-phenylundecanol O-methanesulfonate (prepared as described in Example 7) and 50 ml. of hexamethylphosphoramide are heated in an oil bath at 120° C. for 20 hours. The mixture is poured into ice and water and extracted with chloroform. The extracts are washed with water, 0.1 N NaOH, saturated sodium chloride solution and water. After drying over magnesium sulfate the extract is filtered through silica gel and the silica gel is washed with chloroform. The filtrate is concentrated in vacuo to an oil which is combined with 200 ml. of ethanol-water (9:1), 15 g. of potassium hydroxide and the mixture is refluxed for 3.5 hours. The mixture is acidified with concentrated hydrochloric acid, diluted with 50 ml. of water and chilled. Dilution with 100 ml. of ethanol and 25 ml. of water and filtration gives a gummy solid which is washed with water. The solid is dissolved in hexane:ether:ethyl acetate:acetic acid (40:5:5:2) and filtered through silica gel G. The support is washed with the same solvent (2 fractions). The first fraction is concentrated in vacuo to an oil which is crystallized from hexane to give pale yellow crystals, m.p. 50°-52° C. Recrystallization from ether-hexane (1:1) gives white crystals, m.p. 53°-55° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.[CH:37]([N:40]=[C:41]=[O:42])([CH3:39])[CH3:38]>C(Cl)Cl>[CH:37]([NH:40][C:41]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5][CH2:6]1)=[O:42])([CH3:39])[CH3:38]
Reactant: CCOC(=O)c1cccc(OCCC2CCNCC2)c1
Reactant: CC(C)N=C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccc(OCCC2CCN(C(=O)NC(C)C)CC2)c1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Ethyl 3-(2-piperidin-4-yl-ethoxy)-benzoate (1.0 g of the TFA salt, 2.6 mmol) was dissolved in DCM (10 ml), wereupon DIPEA (1.3 ml, 7.7 mmol) and isopropyl isocyanate (0.33 g, 3.8 mmol) was added. The reaction mixture was shaken overnight at 20° C. Silica gel (10 ml) was added, and the solvent removed in vacuo. Flash chromatography (EtOAc/heptan 35:65→55:45) provided 0.67 g of the title compound. LC-MS (m/z): 364 (M+2).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:38][C:39]([F:49])([F:48])[C:40]1[CH:47]=[CH:46][C:43]([CH2:44]O)=[CH:42][CH:41]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:38][C:39]([F:48])([F:49])[C:40]1[CH:47]=[CH:46][C:43]([CH2:44][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:4][CH:3]=2)=[CH:42][CH:41]=1
Reactant: CN1CCN(c2cccc3ccc(O)cc23)CC1
Reactant: OCc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCN(c2cccc3ccc(OCc4ccc(C(F)(F)F)cc4)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a mixture of 7-hydroxy-1-(4-methyl-1-piperazinyl)-naphthalene (0.20 g, 0.83 mmol), triphenylphosphine (0.32 g, 1.22 mmol), and 4-trifluoromethylbenzyl alcohol (0.17 mL, 1.26 mmol)in dry THF (4 mL) was added diethyl azodicarboxylate in THF (1 mL). The mixture was stirred overnight at ambient temperature; then it was concentrated at reduced pressure. The residue was partitioned between ethyl acetate and 1N sodium hydroxide. The organic layer was washed with water and brine; then it was dried over magnesium sulfate and concentrated onto silica gel for flash chromatographic purification (1×6 inches). Elution with 75% ethyl acetate/hexane gave 0.24 g (72%) of the title compound as a nearly colorless oil. The oil was treated with HCl in ether to form the hydrochloride salt (0.23 g) which was recrystallized from chloroform/ether to give 0.14 g of a white solid thereof: mp 205°-206° C. Analysis calculated for C23H23F3N2O·HCl·0.25 H2O: C, 62.58; H, 5.59; N, 6.35. Found: C, 62.59; H, 5.63; N, 6.40.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:43])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[C:32]5[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=5)[N:26]([CH3:34])[N:25]=4)[N:22]=3)[N:17](COCC[Si](C)(C)C)[CH:16]=2)=[O:14])[CH2:9][O:10][CH3:11])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:43])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[C:32]5[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=5)[N:26]([CH3:34])[N:25]=4)[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH2:9][O:10][CH3:11])[CH2:4]1)#[N:2]
Reactant: COC[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60 %

Procedure:
In a 25 mL round-bottom flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amide (44 mg, 0.071 mmol) and TFA (1.8 ml, 23.4 mmol) were combined with dichloromethane (6 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (4 mL) and ethylenediamine (0.30 ml, 4.4 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (hot dichloromethane/heptane) to afford 21 mg (59%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amide as a white solid. MS: [M+H]+=492; 1H NMR (300 MHz, DMSO-d6) δ: 12.72 (br. s, 1H), 9.16 (s, 1H), 8.74 (d, J=8.7 Hz, 1H), 8.55 (d, J=8.3 Hz, 1H), 8.50 (d, J=4.9 Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 7.23 (d, J=8.7 Hz, 1H), 4.86-5.04 (m, 1H), 4.46-4.73 (m, 2H), 4.17-4.19 (m, 1H), 4.16-4.28 (m, 4H), 4.04-4.16 (m, 1H), 3.77-3.93 (m, 1H), 3.72 (dd, J=9.5, 4.9 Hz, 1H), 3.59-3.68 (m, 1H), 3.27 (app d, J=4.9 Hz, 3H).
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH3:3]>O1CCOCC1.ClCCl>[NH:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:7]=[C:6]([NH:5][C:2](=[O:4])[CH3:3])[CH:11]=[CH:10][CH:9]=2)[CH2:13][CH2:14]1
Reactant: CC(=O)Nc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.6 %

Procedure:
A solution of HCl in dioxane (4N, 5 mL) was added to tert-butyl 4-[3-(acetylamino)-phenyl]-1-piperidinecarboxylate (660 mg) in dry dichloromethane (15 mL). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo, giving the desired product (550 mg): mp 102-104° C.; 1H NMR δ 2.02 (d, J=13.2 Hz, 2H), 2.11-2.45 (m, 5H), 2.67-2.77 (m, 1H), 3.00-3.10 (m, 2H), 3.51 (d, J=10.5 Hz, 2H), 6.94 (d, J=7.5 Hz, 1H), 7.20-7.46 (m, 3H), 7.60 (s, 1H)
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH:16]=[O:17])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].C(OCC)C>C(O)C.CO.ClCCl>[C:24]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[N:10]=[CH:9]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=CCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: CCO
Product: OCCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 4 h
Yield: 57.6 %

Procedure:
A solution of the product from step c (16.1 g, 42.4 mmol) in ethanol (300 ml) was cooled under an atmosphere of argon to 0° C. Sodium borohydride (1.57 g, 42.4 mmol) was added, the mixture stirred for 4 h and carefully quenched with saturated ammonium chloride. The mixture was extracted with dichloromethane (3×100 ml). The combined extracts were dried over magnesium sulfate, filtered and evaporated to give a white solid, which was dissolved in a 5% methanol/dichloromethane and preciptated with diethyl ether. Thus, the product was isolated as a colourless crystalline solid (9.34 g, 58%).
Reaction SMILES: COC1C=CC=CC=1C([NH:7][C@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=O.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=1>>[N:10]12[CH2:15][CH2:14][CH:13]([CH2:12][CH2:11]1)[C@@H:8]([NH:7][C:26]([C:25]1[CH:24]=[N:23][C:22]([C:21]([F:20])([F:32])[F:31])=[CH:30][CH:29]=1)=[O:28])[CH2:9]2
Reactant: COc1ccccc1C(=O)N[C@@H]1CN2CCC1CC2
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(C(F)(F)F)nc1

Procedure:
Title compound was synthesized according to the procedure used in the synthesis of Compound 19S, using 6-(trifluoromethyl)nicotinic acid in place of o-methoxybenzoic acid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.84 (s, 1H), 8.34 (dd, J=8 Hz, 1H), 8.23 (s, 1H), 8.12 (dd, J=8 Hz, 1H), 4.18 (m, 1H), 3.39 (ddd, J=10, 14 Hz, 1H), 2.95-2.87 (m, 4H), 2.67 (ddd, J=16 Hz, 1H), 2.06 (m, 1H), 1.79-1.74 (m, 3H), 1.50 (m, 1H). C14H16F3N3O=299.12 LCMS (M+H): m/z 300
Reaction SMILES: O=[C:2]([CH2:13][CH3:14])[CH:3]([CH2:9][C:10](=O)[CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([F:23])[CH:22]=1)[NH2:19]>C(O)(=O)C>[F:15][C:16]1[CH:17]=[C:18]([N:19]2[C:10]([CH3:11])=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]2[CH2:13][CH3:14])[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CCOC(=O)C(CC(C)=O)C(=O)CC
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)n(-c2cc(F)cc(F)c2)c1CC
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 98 %

Procedure:
Ethyl 3-oxo-2-(2-oxopropyl)pentanoate (200 mg) and 3,5-difluoroaniline (380 mg) were dissolved in acetic acid (10 mL), and stirred at 80° C. for 2.5 hours. The reaction liquid was cooled to room temperature, then the solvent was evaporated off, the residue was diluted with chloroform, and washed with aqueous saturated sodium hydrogencarbonate solution. The extract was washed with saturated saline water, then dried with anhydrous sodium sulfate, then the solvent was evaporated off, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain the entitled compound (287 mg) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([O:15][CH2:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].CN1CCOCC1>C(Cl)Cl.C(OCC)(=O)C>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:3][CH:4]=2)=[CH:9][C:10]=1[O:15][CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(-c2cnc(N)c(OCc3c(Cl)cccc3Cl)c2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CS(=O)(=O)Nc1ccc(-c2cnc(N)c(OCc3c(Cl)cccc3Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(4-amino-phenyl)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (100 mg, 0.28 mmol) in methylene chloride (5 mL) at 0° C., was added methanesulfonyl chloride (0.021 mL, 0.28 mmol) and 4-methylmorpholine (0.16 mL). The mixture was stirred at room temperature for 2 hr, and diluted with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified with a silica gel column eluting with hexane-ethyl acetate (5:1) to give N-{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-methanesulfonamide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:30]([C:31](=[O:42])[NH:32][C:33]3[CH:41]=[CH:40][C:36]4[N:37]=[CH:38][S:39][C:35]=4[CH:34]=3)=[CH:29][C:17]3[N:18]=[C:19]([NH:21][C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=4)[NH:20][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[S:39]1[C:35]2[CH:34]=[C:33]([NH:32][C:31]([C:30]3[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:15][C:16]4[NH:20][C:19]([NH:21][C:22]5[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=5)=[N:18][C:17]=4[CH:29]=3)=[O:42])[CH:41]=[CH:40][C:36]=2[N:37]=[CH:38]1
Reactant: Cc1cccnc1Nc1nc2cc(C(=O)Nc3ccc4ncsc4c3)c(N3CCN(C(=O)OC(C)(C)C)CC3)cc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cccnc1Nc1nc2cc(C(=O)Nc3ccc4ncsc4c3)c(N3CCNCC3)cc2[nH]1

Procedure:
The product from Example 165 was treated with 4M HCl in dioxane employing the procedure described for Example 156 to afford 2-(3-Methyl-pyridin-2-ylamino)-6-piperazin-1-yl-1H-benzoimidazole-5-carboxylic acid benzothiazol-6-ylamide as a hydrochloride salt. MS: m/z 485 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:26][CH:27]1[CH2:31][CH2:30][O:29][CH2:28]1>>[O:29]1[CH2:30][CH2:31][CH:27]([NH:26][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH2:24][OH:25])[CH:16]=2)=[O:23])[CH2:28]1
Reactant: NC1CCOC1
Reactant: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)O
Product: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)NC1CCOC1
Yield: 61 %

Procedure:
As described for example 107, 5-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.28 mmol) was converted, using rac-3-aminotetrahydrofuran instead of 2-amino-2-methyl-1-propanol, to the title compound (73 mg, 61%) which was obtained as a colorless gum. MS: m/e=433.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([OH:15])[CH:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25].N1C=CN=C1>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:14][CH:13]([O:15][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29])[CH:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(Cc2ccccc2)CCOC1c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CN(Cc2ccccc2)CCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a solution of (6RS,7SR)-4-benzyl-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-ol (27.7 g) in DMF (154 mL) were added tert-butylchlorodimethylsilane (17.8 g) and imidazole (10.7 g), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water-ethyl acetate for partitioning, and the organic layer was washed with distilled water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (37.0 g).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22]([O:24]C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:26]>C1COCC1.[OH-].[NH4+]>[CH:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22](=[O:24])[NH2:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2CC1CCCCC1
Reactant: N
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2CC1CCCCC1
Temperature: 35 °C
Yield: 70 %

Procedure:
A solution of 9-[(cyclohexyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (205 mg, 0.608 mmol) in 5 mL of THF and 20 mL of concentrated aqueous ammonium hydroxide was treated with a stream of NH3 gas to ensure saturation. The reaction vessel was capped, and the mixture was heated at 35° C. with stirring until tlc indicated complete consumption of starting material (20 hrs). The THF was evaporated, and the aqueous layer was filtered. The green solid precipitate was dissolved in THF and purified by radial chromatography on silica gel (elution with CH2Cl2). The resultant foam was triturated with ether to afford 138 mg (70%) of the title compound as an off-white solid. IR (KBr, cm−1) 3418, 3200, 3131, 1629, 1600, 1443, 1261, 778. 'FAB HRMS m/e, Calcd for C20H23N2O2: 323.1760. Found: 323.1760 (M+1).