Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:24]([CH3:25])[C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[N:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:30]>CO.CCOCC>[ClH:30].[ClH:30].[CH3:25][N:24]1[C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[N:21]=[C:20]1[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:15]=1
Reactant: Cn1c(-c2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)c2)nc2ccccc21
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c(-c2cccc(N3CCNCC3)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-[3-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (1.30 g, 3.32 mmol) in MeOH (4 mL) was added 2M HCl in Et2O (9 mL) and the resulting solution was stirred for 6 h at room temperature.
Reaction SMILES: [C:1]1([CH:7]([CH3:12])[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:14][C:15]1[C:19]([CH2:20][N:21]2[CH:25]=[C:24]([NH2:26])[CH:23]=[N:22]2)=[C:18]([CH3:27])[O:17][N:16]=1>>[CH3:14][C:15]1[C:19]([CH2:20][N:21]2[CH:25]=[C:24]([NH:26][C:9](=[O:11])[CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:12])[CH:23]=[N:22]2)=[C:18]([CH3:27])[O:17][N:16]=1
Reactant: CC(CC(=O)O)c1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(NC(=O)CC(C)c2ccccc2)cn1
Yield: 6 %

Procedure:
Prepared as in Example 4-8 from 3-phenylbutanoic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 6%. MS M+H calculated 339.6, found 339.5.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]2[CH:18]=[C:19]([C:32]3[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=3)[C:20]([OH:31])=[C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=3)[CH:22]=2)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH2:46]([O:48][C:49](=[O:54])[CH2:50][CH2:51][CH2:52]Br)[CH3:47]>CN(C=O)C>[CH2:46]([O:48][C:49](=[O:54])[CH2:50][CH2:51][CH2:52][O:31][C:20]1[C:21]([C:23]2[CH:24]=[C:25]([CH3:30])[CH:26]=[C:27]([CH3:29])[CH:28]=2)=[CH:22][C:17]([C:15](=[O:16])[NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:18][C:19]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1)[CH3:47]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1cc(C)cc(-c2cc(C(=O)NCCCCCCCc3ccccc3)cc(-c3cc(C)cc(C)c3)c2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1c(-c2cc(C)cc(C)c2)cc(C(=O)NCCCCCCCc2ccccc2)cc1-c1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2′-Hydroxy-3,5,3″,5″-tetramethyl-[1,1′:3′,1″]terphenyl-5′-carboxylic acid (7-phenyl-heptyl)-amide (180 mg, 0.327 mmol) in 2 mL DMF was added K2CO3 (24 mg, 0.174 mmol) and the reaction mixture was stirred for 10 min at room temperature. Then 4-bromobutyric acid ethyl ester (70 mg, 0.36 mmol) was added slowly to the reaction mixture. The reaction was stirred at room temperature for 2 d then it was heated for 45 min at a temperature between 40 and 50° C. Then it was worked up as in Step 1 of Example 146. 1H NMR (CDCl3) δ 1.18 (t, J=7.36 Hz, 3H); 1.27-1.37 (m, 6H); 1.44-1.64 (m, 6H); 1.95 (t, J=8.18 Hz, 2H); 2.54 (s, 12H); 2.57 (t, J=7.36 Hz, 2H); 3.25 (t, J=6, 54 Hz, 2H); 3.41 (quartet, J=7.36 Hz, 2H); 4.00 (quartet, J=8.18 Hz, 2H); 6.04 (m, 1H); 6.00-6.08 (m, 1H); 6.99 (s, 2H); 7.10-7.26 (m, 9H); 7.66 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.Cl.CN.C([O-])(=O)C.[Na+].[N+:20]([CH3:23])([O-:22])=[O:21]>O.ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:23][N+:20]([O-:22])=[O:21])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Br)ccc1C=O
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: CN
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COc1cc(Br)ccc1C=C[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A suspension of 4-bromo-2-methoxybenzaldehyde (1.55 g; 7.2 mmol), methylamine hydrochloride (0.31 g; 50.4 mmol) and sodium acetate (0.38 g; 4.6 mmol) in 3 mL of nitromethane was stirred at ambient temperature. After stirring for 14.5 hours the mixture was diluted with 20 mL water and 40 mL dichloromethane, and the mixture was transferred to a separatory funnel. After shaking, the organic layer was dried over sodium sulfate and evaporated to give 1.74 g of 4-bromo-2-methoxy-1-(2-nitrovinyl)benzene as a light yellow solid. MS (apci, neg) m/z=257.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[C:9]([O:16]C)=[N:10][C:11]([O:14]C)=[N:12][CH:13]=2)=[CH:6][C:5]([CH3:18])=[CH:4][N:3]=1.[ClH:19]>O1CCOCC1>[ClH:19].[F:1][C:2]1[C:7]([C:8]2[C:9](=[O:16])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[CH:6][C:5]([CH3:18])=[CH:4][N:3]=1
Reactant: COc1ncc(-c2cc(C)cnc2F)c(OC)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cnc(F)c(-c2c[nH]c(=O)[nH]c2=O)c1
Yield: 83 %

Procedure:
5-(2-Fluoro-5-methylpyridin-3-yl)-2,4-dimethoxy-pyrimidine (Prep98, 350 mg, 1.4 mmol) was dissolved in a solution of 4N HCl in dioxane solution (5 ml). After refluxing the solution for 30 minutes, the solvent was removed under vacuum to give 300 mg of the title compound as a white powder (83% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10]C)=[N:6][C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[F:20].C(O)(=O)C.Br>CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7](=[O:10])[NH:6][C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[F:20])=[O:21]
Reactant: COC(=O)c1ccc(OC)nc1Nc1ccc(Br)cc1F
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(=O)[nH]c1Nc1ccc(Br)cc1F
Temperature: 92.5 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
To 2-(4-bromo-2-fluorophenylamino)-6-methoxy-nicotinic acid methyl ester (1.00 g, 2.82 mmol) in a sealed flask was added glacial acetic acid (10 mL) and HBr (10 mL, 48 wt % in H2O). The reaction mixture was stirred at 90-95° C. for 2 hours and then cooled to room temperature. The reaction mixture was diluted with EtOAc and washed with H2O, saturated NaHCO3, saturated NaCl, dried (Na2SO4) and concentrated under reduced pressure. The crude product was triturated twice with dichloromethane/methanol and the resulting solid was collected and dried under vacuum to yield 0.756 g (79%) pure desired product as a white solid.
Reaction SMILES: [CH2:1]([N:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=1)[CH:9]([CH3:12])[CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S([Cl:38])(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl>[CH2:1]([N:8]([CH:9]([CH3:12])[CH2:10][Cl:38])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(CO)N(Cc1ccccc1)c1ccc(F)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CCl)N(Cc1ccccc1)c1ccc(F)c(Cl)c1
Reaction time: 12 h

Procedure:
2-[benzyl(3-chloro-4-fluorophenyl)amino]propan-1-ol (1-6, 0.060 g, 0.204 mmol) in CH2Cl2 was treated with triethylamine (0.028 mL, 0.204 mmol) and TsCl (0.042 g, 0.204 mmol). The resulting solution was allowed to stir 12 h. Additional TsCl (0.084 g, 0.408 mmol) was added and allowed to stir until complete. Upon completion, the reaction mixture was partitioned between NaHCO3 (sat. aq) and CH2Cl2 (3×2 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated to yield N-benzyl-3-chloro-N-(2-chloro-1-methylethyl)-4-fluoroaniline.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl.[N:28]1([C:33](=N)[NH2:34])C=CC=N1.C(#N)C>CN(C=O)C.O>[F:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:33](=[NH:28])[NH2:34])[CH2:14][CH2:13]2)=[CH:10][CH:11]=1
Reactant: FCCCc1ccc(N2CCNCC2)cc1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: N=C(N)N1CCN(c2ccc(CCCF)cc2)CC1
Temperature: 25 °C
Reaction time: 9 h
Yield: 61.9 %

Procedure:
To a solution of 1-(4-(3-fluoropropyl)phenyl)piperazine hydrochloride (50 mg, 0.22 mmol) and diisopropylethylamine (82 μL, 0.47 mmol) in DMF (1 mL) was added 1H-pyrazole-1-carboximidamide hydrochloride (36 mg, 0.25 mmol). After stirring at room temperature for 9 h, the reaction mixture was purified via HPLC using a Phenomenex Luna C-18 (2) column (10μ, 250×21.2 mm, gradient method 15-55% B over 40 min., where B=90% ACN in water using 0.1% TFA as a modifier and A=water using 0.1% TFA as a modifier) with a flow rate of 20 mL/min afforded 4-(4-(3-fluoropropyl)phenyl)piperazine-1-carboximidamide as a white solid (36 mg, 42% yield). 1H NMR (300 MHz, DMSO-d6): δ 7.53 (br s, 3H), 7.09 (d, 2H, J=8.6 Hz), 6.92 (d, 2H, J=8.6 Hz), 4.50 (t, 1H, J=6.0 Hz), 4.34 (t, 1H, J=6.0 Hz), 3.57 (dd, 4H, J=5.3, 4.8 Hz), 3.17 (dd, 4H, J=5.2, 4.9 Hz), 2.58 (dd, 2H, J=8.1, 6.4 Hz), 1.98-1.80 (m, 2H); 19F NMR (282.4 MHz, DMSO-d6): δ−217.97 (m, 1F); 13C NMR (150 MHz, DMSO-d6): δ 156.1, 148.5, 132.1, 128.8, 116.2, 83.6 (82.5), 47.8, 44.8, 31.7 (31.6), 29.7 (29.6); HRMS calcd. for C14H21FN4: 265.18230 found 265.18240.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:26]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27]1.CCN=C=NCCCN(C)C>>[S:26]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:33])=[CH:27]1
Reactant: O=C(O)Cc1ccsc1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccsc4)c3)c2c1
Yield: 4.7 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (250 mg, 0.74 mmol) with 3-thiopheneacetic acid (0.13 g, 0.89 mmol) and EDCI (0.21 g, 1.11 mmol) furnished 13 mg (5% yield) of the title compound. 1H NMR (DMSOd6) δ 13.4 (br s, 1H), 10.2 (s, 1H), 8.6 (s, 1H), 8.2 (s, 1H), 8.1 (br s, 1H), 7.92 (d, 1H), 7.8-7.7 (m, 2H), 7.6 (d, 1H), 7.54-7.44 (m, 2H), 7.35 (m, 2H), 7.14 (m, 1H), 3.7 (s, 2H); ES-MS (m/z) 377 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH3:12])=[O:10].[OH:13][C:14]([CH3:44])([CH3:43])[CH2:15][C@@:16]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:21][C:20](=[O:22])[N:19]([C@H:23]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[CH3:24])[CH2:18][CH2:17]1>ClCCl>[CH3:12][O:11][C:9]([N:34]1[CH2:35][CH2:36][CH:31]([C:28]2[CH:27]=[CH:26][C:25]([C@@H:23]([N:19]3[CH2:18][CH2:17][C@:16]([CH2:15][C:14]([OH:13])([CH3:43])[CH3:44])([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[O:21][C:20]3=[O:22])[CH3:24])=[CH:30][CH:29]=2)[CH2:32][CH2:33]1)=[O:10]
Reactant: C[C@@H](c1ccc(C2CCNCC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCC(c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (0.10 mL) and methyl chloroformate (24 μL) were added consecutively to (S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-[(S)-1-(4-piperidin-4-yl-phenyl)-ethyl]-[1,3]oxazinan-2-one (0.12 g) dissolved in dichloromethane (5 mL) at room temperature. The resulting solution was stirred at room temperature overnight and then diluted with dichloromethane. The resulting solution was washed with water and brine and dried (Na2SO4). After removal of the solvent, the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 99:1→90:10) to afford the title compound as a foam-like solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:13][C@@H:14]1[CH2:19][C@H:18]([NH2:20])[C@H:17]([CH3:21])[CH2:16][C@@H:15]1[NH2:22]>>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:20][C@H:18]3[CH2:19][C@@H:14]([CH3:13])[C@@H:15]([NH2:22])[CH2:16][C@H:17]3[CH3:21])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: C[C@@H]1C[C@H](N)[C@H](C)C[C@@H]1N
Product: C[C@@H]1C[C@H](N)[C@H](C)C[C@@H]1Nc1ccnc2cc(Cl)ccc12
Temperature: 150 °C

Procedure:
A mixture of 4,7-dichloroquinoline (500 mg, 2.5 mmol) and (1S,2R,4S,5R)-2,5-dimethylcyclohexane-1,4-diamine (750 mg, 5.2 mmol) was heated at 150° C. for 5 hours, cooled to room temperature, and flash chromatographed through silica gel column with dichloromethane and methanol (3:1 ratio by vol) to provide the titled compound. MS(ESI(+)Q1MS m/z 304 (M+H)+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+]([C:17]1C=CC=C[C:18]=1C(O)=O)([O-])=O.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=[C:9]2[C:10]=1[NH:11][CH:18]=[CH:17]2
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cc[nH]c2c1Cl
Temperature: -45 °C
Yield: 90 %

Procedure:
A two liter 3-neck flask was assembled with an overhead stir, flame dried and flushed with nitrogen. To this was added 1.0 equivalent of 2-chloro-3-nitrobenzoic acid (30 grams, 148.8 mmol) in 300 mL dry THF. The flask was then cooled to −45° C. with the aid of an ethanol/dry ice bath. 4.0 equivalents of cold Vinyl Grignard reagent (Aldrich, 1M Sure/Seal™ bottles) was then cannulated into the solution of nitrobenzoic acid. An additional 100 mL of dry THF was then added via cannula to the very thick solution. The flask was allowed to slowly warm to room temperature overnight. In the morning, the flask was cooled to 0° C. with an ice bath and 400 mL of saturated NH4Cl was added in four portions. The mixture was stirred for one hour then transferred to a separatory funnel and extracted with ethyl acetate (300 mL×3). The organic layers were combined, washed with brine (100 mL), dried over MgSO4 and evaporated to dryness on the rotovap. The aqueous layer was acidified to pH=2 with 2M HCl. The resulting solid was filtered, combined with the above isolated solid and dried in a vacuum desiccator over night to yield 26.32 grams (90%) of a tan powder that was used without further purification. 1H NMR (300 MHz): (CD3OD) δ 7.59 (d, J=8.42 Hz, 1H), 7.49 (d, J=8.42 Hz, 1H), 7.42 (d, J=2.93 Hz, 1H), 6.53 (d, J=2.93 Hz, 1H); Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=195.92, 197.92, HPLC Rt=1.018 min.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[OH:9].[C:10](O)([CH3:13])([CH3:12])[CH3:11].S(=O)(=O)(O)O>CCCCCCC>[C:10]([C:7]1[CH:6]=[C:4]([OH:5])[C:3]([OH:9])=[C:2]([CH3:1])[CH:8]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1cccc(O)c1O
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Product: Cc1cc(C(C)(C)C)cc(O)c1O
Temperature: 80 °C
Yield: 99.9 %

Procedure:
A 1000 mL three neck flask equipped with stirrer, condenser and thermometer is charged with 3-methylcatechol (25.0 g, 0.20 mole), tert-butanol (38.0 mL, 0.40 mole) and 500 mL of heptane; followed by addition of sulfuric acid (98%, 20 g) slowly. The mixture is heated to 80° C. for 6 hrs until gas chromatography (GC) indicates the completion of the reaction. The solvent is removed in vacuo, and the residue is dissolved in CH2Cl2 and washed with water, NaHCO3 (aq.), brine and dried (Na2SO4). Filtration and concentration yield 5-tert-butyl-3-methylcatechol (36 g, 84%). 1H NMR: 6.79 (s, 1H), 6.75 (s, 1H), 5.01 (br, 1H), 2.29 (s, 3H), 1.29 (s, 9H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[OH:15])[CH3:2].C(NC(C)C)(C)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[CH2:27]([O:26][C:24](=[O:25])[N:3]([CH2:1][CH3:2])[CH2:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[OH:15])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCNCc1cc(S(C)(=O)=O)ccc1O
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCN(Cc1cc(S(C)(=O)=O)ccc1O)C(=O)OCc1ccccc1

Procedure:
To 2-ethylaminomethyl-4-methanesulfonyl-phenol (0.229 g, 1.0 mmol) and diisopropylamine (0.94 mL, 2.5 mmol) in CH2Cl2 (10 mL) was added benzyl chloroformate (0.16 mL, 1.1 mmol). Some over-acylation product was observed, so additional benzyl chloroformate (0.21 mL) was added to convert all of the product to the diacylated product. After aqueous work-up, the organic layer was concentrated, and the residue was dissolved in MeOH (10 mL) and treated with 1N aqueous LiOH (4 mL). Once the hydrolysis was complete, the mixture was worked-up, and the residue was purified to give the title compound.
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH:9]2[CH2:14][CH:13]([C:15]([O:17]C)=[O:16])[CH2:12][CH2:11][N:10]2[C:19]([O:21][CH3:22])=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[CH:1]1([O:7][CH2:8][CH:9]2[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][CH2:11][N:10]2[C:19]([O:21][CH3:22])=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CCN(C(=O)OC)C(COC2CCCCC2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(C(=O)O)CC1COC1CCCCC1
Yield: 100.2 %

Procedure:
Dimethyl 2-(cyclohexyloxymethyl)piperidine-1,4-dicarboxylate (2.54 g, 8.1 mmol) was dissolved in acetonitrile (35 mL) and water (0.7 mL), then lithium bromide (5.63 g, 64.80 mmol) was added. Triethylamine (4.49 mL, 32.40 mmol) was added and the resulting suspension was heated under reflux for 4 h. MTBE (100 mL) and water (50 mL) were added, the phases separated and the organic layer was extracted with water. The combined aqueous layers were acidified to pH 1 with 3.8 M HCl and extracted with MTBE. The combined organic layers were dried with Na2SO4 and evaporated. 2-(Cyclohexyloxymethyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (2.43 g, quant.) was isolated. MS m/z 300 (M+H)+
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3=[N:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:21](=[O:22])[C:11]3=[N:10]2)=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[C:21](=[O:22])[C:11]2=[N:10][N:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:3][CH:4]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]2=[N:19]1
Reactant: C1COCCN1
Reactant: Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(Br)nc3)nc-2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(N4CCOCC4)nc3)nc-2c1=O
Temperature: 25 °C
Reaction time: 9 h

Procedure:
5-[(6-Bromopyridin-3-yl)methyl]-2-(2-methylphenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one [(Example 22), 60 mg, 0.13 mmol] was dissolved in dimethyl sulfoxide (1 mL) and treated with morpholine (35 mg, 0.40 mmol, 3 equiv) and potassium carbonate (19 mg, 0.13 mmol, 1 equiv). The vessel was sealed and placed into an oil bath preheated at 100° C. for 9 hours. The mixture was cooled to ambient temperature, poured into water (5 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed three times with water and once with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 94:6; chloroform:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.29 (1H, br s), 7.69-7.59 (3H, m), 7.57-7.51 (2H, m), 7.44 (1H, m), 7.38-7.29 (3H, m), 6.59 (1H, d, J=9.1 Hz), 5.73 (2H, s), 3.79 (4H, m), 3.50 (4H, m), 2.35 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 453.2038 [(M+H)+; calculated for C26H25N6O2: 453.2034].
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:23][C:24]([NH2:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([S:30](Cl)(=[O:32])=[O:31])[CH2:28][CH3:29].C(N(CC)CC)C.O.N>ClCCl>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][S:30]([CH2:27][CH2:28][CH3:29])(=[O:32])=[O:31])=[CH:20][CH:21]=2)[N:12]=[CH:11][C:10]=1[CH2:23][C:24]([NH2:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: NC(=O)Cc1cnc(Nc2ccc(N)cc2)cc1NCc1ccccc1
Agent: N
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc(Nc2cc(NCc3ccccc3)c(CC(N)=O)cn2)cc1
Reaction time: 0.08 h
Yield: 23.6 %

Procedure:
39 mg of 4-(benzylamino)-6-{(4-aminophenyl)amino) pyridine-3-carboxyamide (the compound of Example 65), 83 mg of 1-propanesulfonyl chloride and 67 mg of triethylamine in 1.5 mL of dichloromethane were stirred at room temperature for 1 hour. Under ice cooling, ammonia water was added to the reaction mixture, and stirred for 5 minutes. The reaction mixture was extracted with chloroform, and the extract was dried on anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (chloroform:ammonia methanol=10:1) to obtain 12 mg (19%) of the title compound as a light brown crystalline powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH2:15]([C@@H:22]1[CH2:27][C@@H:26]([N:28]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]=[CH:38][CH:37]=2)[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[CH2:25][CH2:24][NH:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>>[CH2:15]([C@@H:22]1[CH2:27][C@@H:26]([N:28]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]=[CH:38][CH:37]=2)[C:29](=[O:34])[C:30]([F:32])([F:33])[F:31])[CH2:25][CH2:24][N:23]1[C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1cccc(Br)c1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(c1cccc(Br)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 94.9 %

Procedure:
141 mg (0.70 mmol) of m-bromobenzoic acid are reacted in analogy to Example 2a first with 2 ml (27 mmol) of thionyl chloride and subsequently with 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine and 118 μl (0.842 mmol) of triethylamine to give the title compound (271 mg, 95%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.71, FD-MS: M+ =609, 611.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[O:17][C:16]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C@H:27]4[CH2:32][CH2:31][C@H:30]([CH2:33][C:34]([O:36]C)=[O:35])[CH2:29][CH2:28]4)=[CH:23][CH:22]=3)=[O:19])=[N:15][N:14]=2)=[CH:8][CH:7]=1)[CH3:5].Cl>O.C1COCC1.CO>[CH2:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[O:17][C:16]([C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C@H:27]4[CH2:32][CH2:31][C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)=[CH:25][CH:26]=3)=[O:19])=[N:15][N:14]=2)=[CH:8][CH:7]=1)[CH3:5]
Reactant: CCc1ccc(Nc2nnc(C(=O)Nc3ccc([C@H]4CC[C@H](CC(=O)OC)CC4)cc3)o2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(Nc2nnc(C(=O)Nc3ccc([C@H]4CC[C@H](CC(=O)O)CC4)cc3)o2)cc1
Reaction time: 24 h

Procedure:
A solution of lithium hydroxide monohydrate (110 mg, 2.64 mmol.) in water (1.4 mL) was added to a suspension of methyl (trans-4-{4-[({5-[(4-ethylphenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phenyl}cyclohexyl)acetate (152 mg, 0.33 mmol) in THF (1.6 mL) and MeOH (2.6 mL). After 24 h, 1M aqueous HCl (5 mL) was added followed by water (10 mL). The solid was filtered off and washed with water (2×5 mL), Et2O (2×5 mL) then hexane (2×5 mL) to give the title compound as a solid (105 mg, 71%); 1H NMR δ 1.04-1.19 (5H, m), 1.37-1.51 (2H, m), 1.65-1.85 (5H, m), 2.11-2.15 (2H, m), 2.39-2.47 (1H, m), 2.57 (2H, q), 7.21 (4H, m), 7.49 (2H, d), 7.68 (2H, d), 10.84 (1H, s), 10.91 (1H, s), 11.99 (1H, s); MS m/e MH+ 449.