Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2Cl.[NH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: O=C(c1cnc2cc(F)c(Br)cc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3cc(F)c(Br)cc23)CC1

Procedure:
Following general procedure B, (6-bromo-4-chloro-7-fluoroquinolin-3-yl)(cyclopropyl)methanone (350 mg, 1.06 mmol) was reacted with tert-butyl trans-4-aminocyclohexylcarbamate (270 mg, 1.27 mmol) to afford the desired product (400 mg, 75%) as a light yellow solid: 1H NMR (300 MHz, CDCl3) δ 10.67 (d, J=8.3 Hz, 1H), 9.22 (s, 1H), 8.32 (d, J=7.3 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H), 4.42 (s, 1H), 3.91 (d, J=8.1 Hz, 1H), 3.52 (s, 1H), 2.75-2.56 (m, 1H), 2.18 (t, J=13.4 Hz, 4H), 1.72-1.62 (m, 1H), 1.59-1.50 (m, 2H), 1.45 (s, 9H), 1.30-1.18 (m, 3H), 1.13-1.01 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:10][CH2:11][CH3:12])(OCC)OCC.[NH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=CC=1O>C(O)(=O)C>[Cl:1][CH2:2][C:3]1[O:10][C:11]2[CH:12]=[CH:17][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]=2[N:13]=1
Reactant: CCOC(CCl)(OCC)OCC
Reactant: Nc1cc(C(F)(F)F)ccc1O
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc2oc(CCl)nc2c1
Temperature: 120 °C
Yield: 76.8 %

Procedure:
2-Chloro-1,1,1-triethoxyethane (410 μL, 2.15 mmol) was added to a suspension of 2-amino-4-trifluoromethylphenol (370 mg, 1.79 mmol) in acetic acid (7 mL); during the addition the solution began to clear. The solution was heated at 120° C. (external temperature). After three hours the reaction mixture was cooled and the volatiles were removed under reduced pressure. Purification by silica gel chromatography, eluting with a gradient of 0 to 10% ethyl acetate in heptanes, gave 2-chloromethyl-5-trifluoromethyl-benzoxazole as a yellow oil (324 mg, 77%). (CI, m/z): [M+H]+ 236; 1H NMR (CDCl3): δ 8.05 (s, 1H), 7.66-7.73 (m, 2H), 4.79 (s, 2H); 19F NMR (376 MHz, CDCl3): δ ppm −61.26 (s, 3F).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21](O)=[O:22])[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[O:10][C:9]([CH3:25])([CH3:24])[C:8]1=[O:26].[NH2:27][C@@H:28]1[C@H:33]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32][CH2:31][N:30]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:29]1>>[CH2:34]([C@@H:33]1[CH2:32][CH2:31][N:30]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:29][C@@H:28]1[NH:27][C:21]([C:14]1[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]2[O:10][C:9]([CH3:25])([CH3:24])[C:8](=[O:26])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:12]=2[CH:13]=1)=[O:22])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Cc2ccccc2)[C@@H](N)C1
Reactant: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)O)cc21
Product: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N[C@H]3CN(C(=O)OC(C)(C)C)CC[C@H]3Cc3ccccc3)cc21

Procedure:
Using 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid and tert-butyl (rac.)-(3R,4R)-3-amino-4-benzylpiperidine-1-carboxylate (US 2005/182095), the title compound was obtained in a similar manner to Reference Example 197.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[C:5]=1[O:6][C:7]1[CH:18]=[CH:17][C:10]2[NH:11][C:12](=[O:16])[C@@H:13]([CH3:15])[O:14][C:9]=2[CH:8]=1.O.[CH3:29]I>CN(C)C=O>[Cl:3][C:4]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[C:19]([F:27])[C:5]=1[O:6][C:7]1[CH:18]=[CH:17][C:10]2[N:11]([CH3:29])[C:12](=[O:16])[C@@H:13]([CH3:15])[O:14][C:9]=2[CH:8]=1
Reactant: CI
Reactant: C[C@H]1Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Reaction time: 0.17 h

Procedure:
Then, 60% sodium hydride (0.03 g) was suspended in dimethylformamide (5 ml), and a solution of the abovedescribed 7-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2(R)-methyl-2H-1,4-benzoxazine-3 (4H)-one (0.3 g) in dimethylformamide (5 ml) was dropwise added thereto while cooling with water. The mixture was stirred for 10 min, methyl iodide (0.1 g) was added thereto, and the mixture was stirred for an additional 10 min. Water (10 ml) was added thereto to terminate the reaction, and the reaction mixture was extracted with ethyl acetate (20 ml×2), washed with water and a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo, and the residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=3/1) to prepare the title compound (0.3 g) as a colorless crystal. The compound thus prepared was subjected to HPLC analysis for chiral separation and found to be in agreement with the first eluted fraction in the case of racemate (Example 26) modification and have an optical purity of 80%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[C:12]([CH3:16])([CH3:15])[C:13]#[CH:14].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=1[NH:27][S:28]([CH3:31])(=[O:30])=[O:29]>[Cu](I)I.CN(C=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[C:12]([C:13]1[N:27]([S:28]([CH3:31])(=[O:30])=[O:29])[C:20]2[C:19]([CH:14]=1)=[CH:24][CH:23]=[C:22]([C:25]#[N:26])[CH:21]=2)([CH3:15])[CH3:16]
Reactant: C#CC(C)(C)c1cc(OC)ccc1C(=O)OC
Reactant: CS(=O)(=O)Nc1cc(C#N)ccc1Br
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)cc1C(C)(C)c1cc2ccc(C#N)cc2n1S(C)(=O)=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To the DMF (2 ml) solution of 2-(1,1-dimethylprop-2-ynyl)-4-methoxy-benzoic acid methyl ester (Compound AA3, 134 mg, 0.577 mmol) and N-(2-bromo-5-cyanophenyl)methanesulfonamide (Compound AA3, 167 mg, 1.05 eq.), copper iodide (9 mg, 0.08 eq.) and TEA (129 μl, 1.6 eq.) were added, degassed and flushed with nitrogen gas, added with dicholorobis(triphenylphosphine) palladium (20 mg, 0.05 eq.), and then degassed and flushed again with nitrogen gas. After stirring for 2 hr at 90° C., the reaction solution was added with water, extracted with ethyl acetate. The organic layer was washed with an brine and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (white solid, 152 mg, 62%).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.[C:17](C1C=C(C#CC=C2CCN(C(OC(C)(C)C)=O)CC2)C=NC=1)#[N:18]>>[NH:14]1[CH2:13][CH2:12][C:11](=[CH:10][C:9]#[C:8][C:4]2[CH:5]=[CH:6][C:7]([C:2]#[N:3])=[N:18][CH:17]=2)[CH2:16][CH2:15]1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#Cc2cncc(C#N)c2)CC1
Product: N#Cc1ccc(C#CC=C2CCNCC2)cn1

Procedure:
The title compounds were prepared following the procedure described for the compound of Example 3 but starting respectively from the compounds of Example 45 and 46 instead of the compound of Example 2. The crudes were used in the next step without further purification.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[OH-].[Na+].[CH2:7]([C:10]1[N:11]([CH2:23][CH2:24][CH2:25][CH:26]=O)[C:12]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1)[CH2:8][CH3:9]>CO>[CH3:3][O:2][N:4]=[CH:26][CH2:25][CH2:24][CH2:23][N:11]1[C:12]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=[C:10]1[CH2:7][CH2:8][CH3:9]
Reactant: CON
Reactant: CCCc1nc2cnc3cccnc3c2n1CCCC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1nc2cnc3cccnc3c2n1CCCC=NOC
Reaction time: 8 h
Yield: 102 %

Procedure:
Methoxylamine hydrochloride (3.39 g, 40.6 mmol, 2 eq) and 6M sodium hydroxide solution (7.5 mL, 44.7 mmol. 2.2 eq) were added sequentially to a solution of 4-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyraldehyde (5.73 g, 20.3 mmol, 1 eq) in methanol (80 mL) and stirred overnight. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (100 mL) and water (60 mL). The pH of the mixture was adjusted to 7 and the layers were separated. The aqueous layer was extracted with dichloromethane (2×20 mL) and the combined organics were washed with brine (75 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 6.45 g of 4-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyraldehyde O-methyloxime as an orange oil with an E/Z ratio of 77:23. The material was used in subsequent steps without any further purification.
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:10])([F:9])[CH2:7][NH2:8].C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])=[N:24][O:25][C:26]=2[CH3:27])=[N:16][CH:15]=1.O>O1CCOCC1>[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:23]1[C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([C:13]([NH:8][CH2:7][C:6]([F:10])([F:9])[F:5])=[O:12])=[CH:15][N:16]=2)=[C:26]([CH3:27])[O:25][N:24]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3F)noc2C)nc1
Reactant: NCC(F)(F)F
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2F)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.5 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 1.17 mL, 2.3 mmol) was added dropwise (exothermic) to a solution of 2,2,2-trifluoroethylamine (188 μL, 2.3 mmol) in dioxane (15 mL) and the resulting mixture was stirred at room temperature for 1.5 h. Then 6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.58 mmol) was added. The resulting mixture was then heated at 85° C. for 2 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=2:1 to 1:1) afforded the title compound (210 mg, 88%) which was obtained as a colourless oil. MS: m/e=410.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)C(C)(C)O
Product: CCOC(=O)C(C)(C)OC(=O)c1cc([N+](=O)[O-])ccc1Cl

Procedure:
Analogously to the procedure described in Example 74, from 2-chloro-5-nitro-benzoic acid via its acid chloride and ethyl α-hydroxy-isobutyrate there is obtained ethyl 2-(2-chloro-5-nitro-benzoyloxy)-2-methyl-propionate, m.p. 64°-66° C., which is subsequently reduced to ethyl 2-(5-amino-2-chloro-benzoyloxy)-2-methyl-propionate. B.p. 200°-230° C./0.1 torr;
Reaction SMILES: [CH3:1][S-:2].[Na+].[N+:4]([C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C:14](=[O:17])[CH2:15]Br)([O-:6])=[O:5]>CO>[N+:4]([C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C:14](=[O:17])[CH2:15][S:2][CH3:1])([O-:6])=[O:5]
Reactant: O=C(CBr)c1cccc(Cl)c1[N+](=O)[O-]
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSCC(=O)c1cccc(Cl)c1[N+](=O)[O-]
Yield: 36.3 %

Procedure:
1.5 g (0.0061 mol) of 2'-nitro-3'-chloro-2-(methylthio)acetophenone are prepared by addition at 0° C. of 1.3 g (0.018 mol) of sodium methanethiolate in solution in 10 ml of methanol to 4.7 g (0.0168 mol) of 2'-nitro-3'-chloro-2-bromoacetophenone obtained above.
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:6][C:7]=1B(O)O)=[O:2].Br[C:22]([CH3:24])=[CH2:23].[F-].[Cs+]>O1CCOCC1>[C:22]([C:7]1[CH:6]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:4][C:3]=1[CH:1]=[O:2])([CH3:24])=[CH2:23]
Reactant: C=C(C)Br
Reactant: O=Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1B(O)O
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: C=C(C)c1cc(-c2ccc(C(F)(F)F)cc2)sc1C=O

Procedure:
To a mixture of 2-Formyl-5-(4-trifluoromethyl-phenyl)-thiophene-3-boronic acid (0.330 g, 1.10 mmole), 2-Bromo-propene (0.399 g, 3.30 mmole) and cesium fluoride (0.585 g, 3.85 mmole) in dioxane (5 mL), is bubbled with nitrogen gas for 15 minutes. The catalyst PdCl2 (dppf) (0.033 g) is then added to the mixture. The reaction is heated under reflux for 16 hours. The solvent is removed on rota vapor, and the resulting residue is partitioned between ethyl acetate (20 ml) and water (20 mL). The aqueous layer is extracted with more ethyl acetate (20 mL). The combined organic solution is washed with brine (3×50 mL), dried over Na2SO4 and concentrated. The crude product is purified on a silica gel column, eluting with 0-15% ethyl acetate in hexane and concentrated to provide the titled compound as pale yellow crystalline.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@@H:14]([NH2:17])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>ClCCl.CCOCC>[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:17][C@@H:14]2[C@@H:12]3[C@@H:11]([CH2:10][N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[N:8]=4)[CH2:13]3)[CH2:16][CH2:15]2)=[O:29])=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Nc1ccc(F)cc1)N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 264 Step A (0.050 g, 0.184 mmol) in dichloromethane (0.1 mL) was added 1-fluoro-4-isocyanatobenzene (0.025 mL, 0.221 mmol). The reaction was stirred at ambient temperature for 30 minutes. The reaction was diluted with ether and sonicated, then filtered and washed with ether to give the title compound: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.45 (s, 1H), 7.63 (dd, J=9.1, 4.9, 2H), 7.46 (t, J=7.9, 1H), 7.00 (t, J=8.8, 2H), 6.93 (d, J=8.8, 1H), 6.51 (d, J=7.7, 1H), 6.21 (d, J=6.7, 1H), 4.27-4.12 (m, 1H), 3.73-3.44 (m, 3H), 3.28 (dd, J=11.0, 4.0, 1H), 2.77-2.57 (m, 2H), 2.12 (td, J=12.7, 6.8, 1H), 1.87 (td, J=13.3, 7.9, 1H), 1.57 (dq, J=12.8, 7.8, 1H), 1.37 (dtd, J=13.2, 7.8, 5.3, 1H); MS (ESI+) m/z 409 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH2:13].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:13]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(N)c1N
Yield: 90.3 %

Procedure:
To a solution of 2-amino-3-nitro-benzoic acid methyl ester (2 g, 10 mmol) in methanol, a suspension of 10% Pd/C (300 mg) in methanol 5 mL was added and hydrogenated with a hydrogen balloon over a period of 8 h. The reaction mass was filtered and the filtrate was concentrated under reduced pressure to obtain 1.5 g of the required compound as a brown coloured solid (88%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:8]([OH:10])=O)[NH:6][CH:7]=1)#[N:2].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([N:31]3[CH2:36][CH2:35][CH:34]([CH3:37])[CH2:33][CH2:32]3)[CH:25]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:8]([C:5]3[NH:6][CH:7]=[C:3]([C:1]#[N:2])[CH:4]=3)=[O:10])=[C:26]([N:31]3[CH2:36][CH2:35][CH:34]([CH3:37])[CH2:33][CH2:32]3)[CH:25]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: N#Cc1c[nH]c(C(=O)O)c1
Reactant: CC1CCN(c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2N)CC1
Product: CC1CCN(c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2NC(=O)c2cc(C#N)c[nH]2)CC1

Procedure:
Prepared according to the procedure from Example 53 using 4-cyano-1H-pyrrole-2-carboxylic acid (as prepared in Example 2) and 4-[4-amino-3-(4-methyl-piperidin-1-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester as prepared in Example 15, step (c). Purification of the resulting residue by silica gel preparative TLC eluting with 20% ethyl acetate in dichloromethane afforded the title compound in 47% as an off-white solid. 1H-NMR (400 MHz, CDCl3): δ 11.13 (br s, 1H), 9.05 (s, 1H), 8.29 (d, 1H, J=8.9), 7.48 (dd, 1H, J=3.0, 1.3 Hz), 6.88 (s, 1H), 6.84 (d, 1H, J=2.6 Hz), 6.76 (dd, 1H, J=8.9, 2.2 Hz), 3.62 (m, 4H), 3.13 (m, 4H), 3.01-2.98 (m, 2H), 2.73 (m, 2H), 1.88-1.85 (m, 2H), 1.61-1.56 (m, 2H), 1.51 (s, 9H), 1.50-1.37 (m, 2H), 1.10 (d, 3H, J=6.5 Hz). LC-MS (ESI, m/z): Calcd. for C27H37N6O3, 493.3 (M+H); found: 493.1.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([F:28])([F:27])/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CN(C)C=O>[Br:1][C:2]1[C:3]2[O:11][CH:20]([C:19]([F:18])([F:28])[F:27])[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5][C:4]=2[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: O=Cc1cc(Cl)cc(Br)c1O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=Cc2cc(Cl)cc(Br)c2OC1C(F)(F)F

Procedure:
A mixture of 3-bromo-5-chlorosalicylaldehyde (1.9 g, 4.2 mmol), potassium carbonate (0.58 g, 4.2 mmol), and ethyl 4,4,4-trifluorocrotonate (0.79 g, 4.7 mmol) was stirred in N,N-dimethylformamide (5 mL) at 95° C. for 18 h. Water (100 mL) was added and the mixture was extracted with ether (3×50 mL). The combined organic extracts were washed with sodium hydroxide (10 mL) and water (2×50 mL). After drying over MgSO4 and concentrating, the mixture filtered through of a pad of silica eluting with ethyl acetate-hexanes (1:4). The eluant was concentrated and a light yellow solid was crystallized from cold hexane (0.43 g, 26%): mp 101.0–102.2° C. 1H NMR (acetone-d6/300 MHz) 7.90 (s, 1H), 7.65 (d, H, J=2.4 Hz), 7.61 (d, H, J=2.4 Hz), 6.03 (qH-F, 1H, J=6.9 Hz), 4.34 (m, 2H), 1.33 (t, 3H, J=7.5 Hz). ESHRMS m/z 384.9435 (M−H, Calc'd 384.9454). Anal. Calc'd for C13H9BrClF3O3: C, 40.50; H, 2.35. Found: C, 40.61; H, 2.40.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:19]([OH:27])[CH2:20]C2CCOCC2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)[O:41][C:39](=O)[C:38]2[CH:37]=[CH:36][CH:35]=CC1=2)=O>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](=[O:27])[CH2:20][CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39][O:41]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: O=S(=O)(c1ccccc1)n1c(C(O)CC2CCOCC2)cc2cccnc21
Solvent: ClCCl
Product: O=C(CC1CCCCO1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
To a solution of 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-ethanol (2.1 g, 11 mmol) in dichloromethane (75 mL) was added Dess-Martin periodinane (8.3 g, 39 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 2 h and then quenched with a saturated aqueous sodium bicarbonate solution (100 mL). The mixture was extracted with dichloromethane (50 mL), washed with a saturated aqueous sodium bicarbonate solution (3×100 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-2-yl)-ethanone (2.0 g, 93%) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C20H20N2O4S [M+H]+ 385.46, observed 385.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([O:13][C:14]([C:16]1[C:17]([CH3:24])=[C:18]([CH:22]=O)[NH:19][C:20]=1[CH3:21])=[O:15])[CH3:12]>N1CCCCC1.C(O)C>[CH3:21][C:20]1[NH:19][C:18]([CH:22]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[C:17]([CH3:24])[C:16]=1[C:14]([O:13][CH2:11][CH3:12])=[O:15]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccccc32)c1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
A reaction mixture of 134.0 mg of oxindole, 234.3 mg of the 4-ethoxycarbonyl-3,5-dimethylpyrrole-2-carboxaldehyde, and 3 drops of piperidine in 3 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 244.6 mg (79%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([CH:31]=O)=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:31][C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[N:22]([CH3:21])[CH:23]=[CH:24]3)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: Cn1ccc2cc(C=O)ccc21
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc2c(ccn2C)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 1-methyl-1H-indole-5-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 378.93 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][CH:11]=[C:10]([O:17][CH3:18])[C:8]=2[N:9]=1.[BH4-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3](=[O:19])[NH:4][C:5]1[S:6][C:7]2[C:13]([CH:14]([OH:16])[CH3:15])=[CH:12][CH:11]=[C:10]([O:17][CH3:18])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(C(C)=O)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)Nc1nc2c(OC)ccc(C(C)O)c2s1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
0.05 g of (7-acetyl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester (0.00018 Mol) were dissolved in ethanol (30 ml) and 0.028 g of NaBH4 (0.00072 Mol) were added. After stirring at 40° C. for 24 hrs. the reaction mixture was diluted with water, extracted with CH2Cl2, the organic phase washed with brine and dried over MgSO4. After chromatography on silicagel with CH2Cl2/MeOH 97:3 the title compound was obtained as a white solid (38%); F.p.: 179° C. (dec.).