Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:16]=3[N:17]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([NH:12][C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:16]=3[N:17]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(Nc2nc3cc([N+](=O)[O-])ccc3o2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CCC(Nc2nc3cc(N)ccc3o2)CC1
Temperature: 40 °C
Reaction time: 18 h
Yield: 98.9 %

Procedure:
To a solution of 4-(5-nitro-benzooxazol-2-ylamino)-piperidine-1-carboxylic acid ethyl ester (2.0 g, 5.98 mmol, 1.0 equiv; intermediate L/step 3 (4-(5-nitro-benzooxazol-2-ylamino)-piperidine-1-carboxylic acid ethyl ester)) in ethanol (90 mL) was added palladium on activated charcoal 10% (0.2 g, 0.19 mmol, 0.03 equiv) and the reaction vessel filled with hydrogen (3.5 bar). After stirring at 40° C. for 18 h, the reaction mixture was filtered over celite, concentrated under reduced pressure and the residue purified with column chromatography on silica eluting with ethyl acetate/hexane (2:1) containing 5% methanol to yield 1.8 g (99%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.25 (t, J=7.1 Hz, 3H), 1.44-1.54 (m, 2H), 2.07-2.10 (m, 2H), 2.92-3.01 (m, 2H), 3.72 (br s, 1H), 3.88 (br s, 1H), 4.10 (br s, 1H), 4.14 (q, J=7.1 Hz, 2H), 6.33 (dd, J=8.4 Hz, J=2.2 Hz, 1H), 6.61 (br d, J=4.6 Hz, 1H), 6.67 (d, J=2.2 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 14.61, 32.13, 42.29, 50.18, 61.37, 102.92, 107.98, 108.53, 142.04, 143.49, 143.80, 155.46, 162.14. MS (ISP): 305.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH2:9])=[O:8])[N:6]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(O)(=O)C>[C:10]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH2:9])=[O:8])[N:6]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1csc(N)n1
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(C(N)=O)cs1
Yield: 90.6 %

Procedure:
g (28 mmol) 2-Aminothiazol-4-carboxamide was dissolved in 40 ml glacial acetic acid, to which added 2.8 ml (29.6 mmol) acetic anhydride, followed by reacting under reflux for 2 hr, and naturally cooling down to precipitate a large quantity of solids, which were filtered, washed and dried to obtain 4.7 g 2-acetylaminothiazol-4-carboxamide (yield 92%) with mp>250° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Ca+2].[Br:19]Br.[OH-].[NH4+]>O>[Br:19][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1nccc(-c2ccccc2)n1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [NH4+]
Solvent: O
Product: Nc1ncc(Br)c(-c2ccccc2)n1
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
Following the method of Ziegler and Clementon (U.S. Pat. No. 2,609,372), to a stirred suspension of 5.0 g (29.2 mmol) 2-amino-4-phenylpyrimidine and 1.46 g (14.6 mmol) CaCO3 in 30 ml water at 50° C. was added dropwise 1.65 ml (32.2 mmol) bromine and stirring continued for 30 minutes. The reaction mixture was then made basic by addition of ammonium hydroxide solution and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. Recrystallisation from ethanol afforded 3.27 g (45%) 5-bromo-4-phenyl-pyrimidin-2-ylamine as a green crystalline solid. EI-MS m/e (%): 251 (M{81Br}+, 64), 249 (M{79Br}+, 64), 170 ([M—Br]+, 100).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH3:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2.N1CCCCC1>C(O)C>[CH3:14][C:7]1[NH:8][C:9]([CH:12]=[C:19]2[C:18]3[C:22](=[CH:23][CH:24]=[C:16]([CH3:15])[CH:17]=3)[NH:21][C:20]2=[O:25])=[C:10]([CH3:11])[C:6]=1[CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: Cc1ccc2c(c1)CC(=O)N2
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1ccc2c(c1)C(=Cc1[nH]c(C)c(CCC(=O)O)c1C)C(=O)N2
Yield: 64.2 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (97.5 mg), 74 mg 5-methyl-2-oxindole, and 75 μL piperidine in 3 mL of ethanol were heated at 95 ° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 104 mg (64%) of the title compound as a yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13]C)[CH:4]=1)=[O:2].[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl>[CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([OH:13])[CH:4]=1)=[O:2]
Reactant: COC(=O)c1ccc(C=O)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(C=O)cc1O
Yield: 91.1 %

Procedure:
A mixture of product from Step 2 (2.6 g, 13.4 mmol) and AlCl3 (3.6 g, 26.8 mmol) in anhydrous DCM (50 mL) was refluxed for 3 minutes. The resulting mixture was cooled and poured into water (100 mL), followed by a standard aqueous/DCM workup to give Intermediate 5 (2.2 g, yield 92%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][CH2:19][C:9]=2[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)(=O)=O.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][OH:36])=[CH:30][CH:29]=1>>[OH:36][CH2:35][CH2:34][C:31]1[CH:32]=[CH:33][C:28]([NH:27][C:7]2[C:8]3[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][CH2:19][C:9]=3[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)=[CH:29][CH:30]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: O=S1(=O)CCCc2nc(-c3ccccc3)nc(OS(=O)(=O)C(F)(F)F)c21
Product: O=S1(=O)CCCc2nc(-c3ccccc3)nc(Nc3ccc(CCO)cc3)c21
Yield: 68.3 %

Procedure:
Following general procedure G, 5,5-dioxido-2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (0.123 g, 0.30 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.045 g, 0.33 mmol) to afford the desired product (0.081 g, 68%) as a light yellow solid. MW=395.47. 1H NMR (DMSO-d6, 500 MHz) δ 8.72 (s, 1H), 8.29-8.25 (m, 2H), 7.61-7.49 (m, 5H), 7.30 (d, J=8.5 Hz, 2H), 4.65 (t, J=5.5 Hz, 1H), 3.76-3.71 (m, 2H), 3.67-3.61 (m, 2H), 3.07 (t, J=6.5 Hz, 2H), 2.75 (t, J=7.0 Hz, 2H), 2.43-2.35 (m, 2H); APCI MS m/z 396 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15](OCC)=[O:16])=[C:5]2[OH:20].Cl.[C:22]([O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH2:29])([CH3:25])([CH3:24])[CH3:23].O1CCOCC1.C(N(C(C)C)C(C)C)C>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])([CH3:13])[C:7](=[O:14])[C:6]([C:15]([NH:29][C@H:28]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:31])[CH3:30])=[O:16])=[C:5]2[OH:20]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O)C(=O)OC(C)(C)C
Temperature: 140 °C
Yield: 25 %

Procedure:
To ethyl 6-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (2.44 g, 8.28 mmol, see Example 2) and L-alanine t-butyl ester hydrochloride (2.26 g, 12.4 mmol), were added 1,4-dioxane (5.52 mL) and N-ethyl-N-isopropylpropan-2-amine (4.33 mL, 24.8 mmol). The reaction mixture was then heated in a microwave at 140° C. for 10 minutes. The reaction mixture was diluted with 150 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 3 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (0.815 g) as a light yellow amorphous solid after flash chromatography. MS (m/z)=338 (M+H-tBu)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[C:4]=1[C:5](O)=[O:6].ClC1C=CC=CC=1.S(C)C>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:15])[F:14])[C:4]=1[CH2:5][OH:6]
Reactant: COc1cccc(C(F)(F)F)c1C(=O)O
Solvent: CSC
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cccc(C(F)(F)F)c1CO
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Into a 100-mL 3-necked round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed 2-methoxy-6-(trifluoromethyl)benzoic acid (2.2 g, 9.99 mmol, 1.00 equiv), chlorobenzene (20 mL). This was followed by the addition of BH3.SMe2(2M in tetrahydrofuran) (15.0 mL) dropwise with stirring at 0° C. The mixture was stirred 15 min at 0° C. Then the resulting solution was stirred for 2 h at 80° C. and continued stirring for 18 h at 130° C. in an oil bath. The reaction progress was monitored by TLC (PE:EtOAc=4:1). The reaction was then quenched by the addition of 20 mL of water, extracted with 3×20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 1.9 g (92%) of [2-methoxy-6-(trifluoromethyl)phenyl]methanol as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]3[N:27]4[CH:28]=[CH:29][N:30]=[C:26]4[CH:25]=[C:24]([C:31]4[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=4)[N:23]=3)[CH:19]=[N:18]2)[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)#[N:2].C(Cl)[Cl:38].Cl.O1CCOCC1>>[ClH:38].[CH3:36][N:34]1[CH:35]=[C:31]([C:24]2[N:23]=[C:22]([C:20]3[CH:19]=[N:18][N:17]([C:4]4([CH2:3][C:1]#[N:2])[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]4)[CH:21]=3)[N:27]3[CH:28]=[CH:29][N:30]=[C:26]3[CH:25]=2)[CH:32]=[N:33]1
Reactant: ClCCl
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CCN(C(=O)OC(C)(C)C)CC4)c3)n2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CCNCC4)c3)n2)cn1
Reaction time: 1.5 h
Yield: 107.8 %

Procedure:
Tert-butyl 4-(cyanomethyl)-4-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Example 21; 17 mg, 0.035 mmol) was dissolved in DCM (170 μL, 0.035 mmol) and treated with 4N HCl in dioxane (170 μL, 0.70 mmol). After 90 minutes, the reaction mixture was concentrated in vacuo to afford 2-(4-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidin-4-yl)acetonitrile hydrochloride (16 mg, 98% yield). MS (apci) m/z=388.3 (M+H).
Reaction SMILES: [C:1]([NH:5][C:6]1[N:15]([CH2:16][CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:14](=[O:23])[C:13]2[C:8](=[C:9](I)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][C@@H:26]1[C:30]2[NH:31][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:33][C:29]=2[C:28](=[O:43])[NH:27]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O>[C:1]([NH:5][C:6]1[N:15]([CH2:16][CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:14](=[O:23])[C:13]2[C:8](=[C:9]([C:32]3[NH:31][C:30]4[C@@H:26]([CH3:25])[NH:27][C:28](=[O:43])[C:29]=4[CH:33]=3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Nc1nc2c(I)cccc2c(=O)n1CCCS(C)(=O)=O
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(CCCS(C)(=O)=O)c(NC(C)(C)C)nc34)[nH]c21
Temperature: 45 °C
Yield: 79.3 %

Procedure:
A glass microwave reaction vessel was charged with 2-(tert-butylamino)-8-iodo-3-(3-(methylsulfonyl)propyl)quinazolin-4(3H)-one (105 mg, 0.227 mmol) and (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705) (89 mg, 0.272 mmol) in 1,4-dioxane (1.0 mL)/water (0.2 mL) followed by potassium phosphate (0.056 mL, 0.680 mmol) and XPhos precatalyst II (8.92 mg, 0.011 mmol, Sigma Aldrich, St. Louis, Mo.). The reaction mixture was stirred and heated in an oil bath at 45° C. for 2 h, then another 0.3 equiv. of boronic ester 705 was added and the reaction was stirred at RT overnight. More boronic ester 705 (0.3 equiv) was added and the reaction was stirred at 45° C. for 1 h. The mixture was cooled to RT and diluted with water (15 mL). The suspension was filtered and the solid was purified with silica gel chromatography (eluted with 1-4% MeOH in DCM) to give (R)-2-(tert-butylamino)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(3-(methylsulfonyl)propyl)quinazolin-4(3H)-one (85 mg, 0.180 mmol, 80% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 472 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (1H, s), 7.83-7.93 (2H, m), 7.60 (1H, s), 7.19 (1H, t, J=7.6 Hz), 6.68 (1H, d, J=1.4 Hz), 5.95 (1H, s), 4.52 (1H, q, J=6.6 Hz), 4.28 (2H, t, J=7.2 Hz), 3.21 (2H, t, J=7.5 Hz), 3.02 (3H, s), 2.00-2.10 (2H, m), 1.50 (9H, s), 1.36 (3H, d, J=6.7 Hz).
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[NH:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])=O)(C)(C)C>CCOC(C)=O>[ClH:1].[C:14]1([C@H:13]2[C@@H:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:11][C:10]([NH:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[F:35])=[N:9]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C(NCCc2ccccc2F)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccccc1CCNC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride is bubbled into a solution of 91 (0.37 g, 0.81 mmol) in EtOAc (10 mL) for 1 min, and the solution is stirred at RT overnight. The solvent is removed by rotary evaporation, and the residue crystallized from dichloromethane and Et2O to give 0.21 g of the product 92. 1H NMR (DMSO-d6) δ 9.10 (t, 1H), 8.43 (s, 1H), 8.58 (s, 1H), 7.40 (t, 1H), 7.30-7.15 (m, 1H), 7.15-6.90 (m, 8H), 6.80-6.55 (m, 4H), 5.15 (s, 2H), 3.80-3.45 (m, 2H), 3.10-2.85 (m, 2H); MS: m/z 360 (M++1).
Reaction SMILES: Cl[C:2]([C:4]1[C:5]([CH:21]2[CH2:24][CH2:23][CH2:22]2)=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:7]([CH:14]([F:16])[F:15])=[N:8][C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:3].[CH3:25][CH:26]([SH:28])[CH3:27]>>[F:16][CH:14]([F:15])[C:7]1[C:6]([C:17]([O:19][CH3:20])=[O:18])=[C:5]([CH:21]2[CH2:22][CH2:23][CH2:24]2)[C:4]([C:2]([S:28][CH:26]([CH3:27])[CH3:25])=[O:3])=[C:9]([C:10]([F:12])([F:11])[F:13])[N:8]=1
Reactant: CC(C)S
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)Cl)c1C1CCC1
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)SC(C)C)c1C1CCC1

Procedure:
Methyl 5-chlorocarbonyl-4-cyclobutyl-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate prepared similarly to the procedure in step 7 of U.S. Pat. No. 4,988,384 was reacted with 2-propanthiol according to the procedure in example 141 of U.S. Pat. No. 4,692,184 to give the product as an oil, nD25 1.4946.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12]C)=[CH:4][C:3]=1[O:14][CH:15]1[CH2:20][CH2:19][C:18]([CH:25]([NH2:28])[CH2:26][CH3:27])([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]1.CC(O)C.Cl>O>[NH2:28][CH:25]([C:18]1([C:21]([F:23])([F:24])[F:22])[CH2:17][CH2:16][CH:15]([O:14][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:2]=2[Cl:1])[C:9](=[O:12])[NH:8][CH:7]=[CH:6]3)[CH2:20][CH2:19]1)[CH2:26][CH3:27]
Reactant: CCC(N)C1(C(F)(F)F)CCC(Oc2cc3ccnc(OC)c3cc2Cl)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CCC(N)C1(C(F)(F)F)CCC(Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Yield: 0.1 %

Procedure:
229 mg (480 mmol) of 1-[4-(7-Chloro-1-methoxy-isoquinolin-6-yloxy)-1-trifluoromethyl-cyclohexyl]-propylamine (75) were dissolved using 2 ml of 2-propanol and 2 ml of a 1N aqueous solution of HCl. The mixture was treated for 1 h at 100° C. under microwave irradiation. Afterwards, the mixture was diluted using 50 ml of water and lyophilized to yield 195 mg of Example 103 as the hydrochloride. Rt=0.64 min (Method P). Detected mass: 403.10 (M+H+).
Reaction SMILES: [C:1]12([O:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[C:24]([NH:26][C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=3)[C:30](O)=[O:31])=[O:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.[CH2:37]([O:44][NH2:45])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>>[CH2:37]([O:44][NH:45][C:30]([C:29]1[CH:28]=[C:27]([NH:26][C:24]([C:14]2[N:15]=[C:16]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[NH:17][C:13]=2[CH2:12][O:11][C:1]23[CH2:2][CH:3]4[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]4)[CH2:8]2)[CH2:10]3)=[O:25])[CH:35]=[CH:34][CH:33]=1)=[O:31])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)c1cccc(NC(=O)c2nc(C3CCCCC3)[nH]c2COC23CC4CC(CC(C4)C2)C3)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(NOCc1ccccc1)c1cccc(NC(=O)c2nc(C3CCCCC3)[nH]c2COC23CC4CC(CC(C4)C2)C3)c1
Yield: 82.2 %

Procedure:
3-{[5-(Adamantan-1-yloxymethyl)-2-cyclohexyl-1H-imidazole-4-carbonyl]-amino}-benzoic acid (Example 216) (910 mg, 1.90 mmol) was reacted with O-benzylhydroxylamine hydrochloride (455 mg, 2.85 mmol) in the presence of triethylamine (0.40 ml, 2.85 mmol) according to the procedure of Example 20, step d. The crude material was purified by flash column chromatography (silica, DCM/methanol 95:5) to afford a colourless foam (910 mg, 84%). 1H NMR (300MHz, CDCl3) 9.25 (1H, br s), 9.06 (1H, s), 8.64 (1H, s), 8.01 (1H, s), 7.84 (1H, m), 7.41 (6H, m), 5.06 (2H, s), 4.98 and 4.81 (2H, 2×s), 2.72 (1H, m), 2.19 (3H, br s), 2.07 (2H, m), 1.90-1.36 (20H, m).
Reaction SMILES: Br[CH:2]([CH:5]=[O:6])[CH:3]=O.[Br:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:15])=[N:12][C:13]=1[CH3:14]>C(#N)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:2]([CH:5]=[O:6])=[CH:3][N:15]=2)[C:13]=1[CH3:14]
Reactant: O=CC(Br)C=O
Reactant: Cc1nc(N)ccc1Br
Solvent: CC#N
Product: Cc1c(Br)ccc2ncc(C=O)n12
Yield: 28 %

Procedure:
Bromomalonaldehyde (464 mg, 3.07 mmol) was added to a solution of 5-bromo-6-methylpyridin-2-amine (500 mg, 2.67 mmol) in acetonitrile. The reaction mixture was refluxed for 1 hour. After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated and the product was purified by column chromatography using up to 0.5% methanol in chloroform gradient to obtain the title compound. Yield: 28%; 1H NMR (DMSO-d6; 300 MHz): δ 10.06 (s, 1H), 8.51 (s, 1H), 7.86-7.83 (d, 1H, J=9.3 Hz), 7.68 (d, 1H, J=9.3 Hz), 3.03 (s, 3H); MS: m/z 240.1 (M+1)+.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].Br[CH2:13][CH2:14]Br>CN(C)C=O>[N:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1([C:10]#[N:11])[CH2:14][CH2:13]1
Reactant: N#CCc1cnccn1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(c2cnccn2)CC1
Reaction time: 18 h
Yield: 31.4 %

Procedure:
To a suspension of sodium hydride (0.386 g, 16.1 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added dropwise a solution of 2-(pyrazin-2-yl)acetonitrile (0.55 g, 4.6 mmol) and 1,2-dibromoethane (2.25 g, 11.9 mmol) in anhydrous N,N-dimethylformamide (8 mL) over a period of 10 min at room temperature. The mixture was stirred for 18 h, then was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 100% dichloromethane) to afford 1-(pyrazin-2-yl)cyclopropanecarbonitrile (210 mg, 31%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:8][C:7]=1[Br:21].N#N>O=[Pt]=O.CCO.C1COCC1>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])=[CH:8][C:7]=1[Br:21]
Reactant: COC(=O)/C=C/c1ccc(S(=O)(=O)c2ccccc2)cc1Br
Agent: O=[Pt]=O
Agent: N#N
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(S(=O)(=O)c2ccccc2)cc1Br
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
To a solution of (E)-3-(4-benzenesulfonyl-2-bromo-phenyl)-acrylic acid methyl ester (8.52 g) in a mixture EtOH/THF (2/1, 150 mL) was added under N2 atmosphere PtO2 (0.45 g). A balloon filled with H2 was set up and N2 was replaced with H2, the reaction was then stirred for 4 h 30 min. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified via flash chromatography (hexane/EtOAc, 85/15) affording 3-(4-benzenesulfonyl-2-bromo-phenyl)-propionic acid methyl ester (6.73 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[O:24][CH3:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[O:24][CH3:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 65 h
Yield: 50.9 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-methoxynitrobenzene (4.36 g) in methanol (60 ml) was added palladium on carbon (0.25 g) and the mixture was stirred under a hydrogen atmosphere at room temperature for 65 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=1/1 as an eluant to give the desired compound (2.03 g, yield 51%) as a pale red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18]C=CN=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:24][O:25][C:26]1[CH:31]=C(NN)C=C[N:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:27]=[C:26]([O:25][CH3:24])[CH:31]=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Reactant: COc1cc(NN)ccn1
Agent: Cl
Product: COc1cc(-n2nc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)ccn1

Procedure:
500 mg (1.53 mmol) of the compound of Example 1A is reacted analogously to the synthesis of the compound of Example 20A with 295 mg (1.68 mmol) of 2-methoxypyridin-4-yl-hydrazine hydrochloride. After hydrolysis, 8 mg (1.5% of theory) of the title compound is obtained.
Reaction SMILES: O[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:12]1([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[CH2:16]1[CH2:17][CH:12]([O:18][C:5]2[N:4]=[CH:3][CH:2]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:13][CH2:14][CH2:15]1
Reactant: COC(=O)c1cncc(O)c1
Reactant: OC1CCCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cccnc1OC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.2 %

Procedure:
To a stirred solution of methyl 5-hydroxynicotinate (2.40 g, 15.7 mmol) in methylene chloride (40 mL) was added cyclohexanol (1.73 g, 1.80 mL, 17.2 mmol) and triphenylphosphine (5.75 g, 21.9 mmol). The solution was treated with diethyl azodicarboxylate (3.20 mL, 20.4 mmol), resulting in a mild exotherm and development of an orange colored solution. The reaction mixture was allowed to stir at room temperature. After 16 hours, the cloudy yellow suspension was filtered, and the filtrate was washed with saturated sodium bicarbonate solution and brine, dried (magnesium sulfate), filtered, and concentrated to provide a yellow oil. Flash chromatography over silica (hexanes/ethyl acetate) afforded 1.08 g (29%) of the desired product as a colorless oil: 1H NMR (CDCl3) δ 8.77 (d, J=1.7 Hz, 1H), 8.43 (d, J=2.9 Hz, 1H), 7.74 (dd, J=1.7, 2.9 Hz, 1H), 4.37-4.31 (m, 1H), 3.94 (s, 3H), 2.01-1.93 (m, 2H), 1.85-1.75 (m, 2H), 1.62-1.49 (m, 3H), 1.46-1.31 (m, 3H) ppm. 13C NMR (CDCl3) δ 166.2, 154.0, 144.2, 142.9, 126.6, 122.3, 76.3, 52.7, 31.6, 25.6, 23.7 ppm.