Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O/[CH:4]=[C:5](/[C:11](=O)[CH:12]([F:14])[F:13])\[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C[N:17](C)/[CH:18]=[CH:19]/[C:20]#[N:21]>CN(C=O)C>[C:20]([C:19]1[CH:18]=[N:17][C:11]([CH:12]([F:13])[F:14])=[C:5]([CH:4]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:21]
Reactant: CN(C)/C=C/C#N
Reactant: CCO/C=C(\C(=O)OCC)C(=O)C(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C#N)cnc1C(F)F
Reaction time: 12 h
Yield: 23.2 %

Procedure:
To a solution of cyanoacetic acid (2.0 g, 23.53 mmol) in 1,4-dioxane (10 mL) was added N,N-dimethylformamide dimethylacetal (3.35 g, 28.23 mmol) and the reaction mixture was heated at 80° C. for 4 h. Then the reaction mixture was concentrated, diluted with Et2O and filtered through a pad of silica. The filtrate was concentrated to afford 2.37 g of (E)-3-(dimethylamino)acrylonitrile which was taken to the next step without further purification. To a solution of (Z)-ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate (5.5 g, 24.77 mmol) in DMF (15 mL) at 65° C. was added (E)-3-(dimethylamino)acrylonitrile (2.37 g, 24.77 mmol) dropwise and the reaction mixture was heated at the same temperature for 5 h. Then NH4OAc (2.86 g, 37.15 mmol) was added to the reaction mixture and heating was continued for 12 h. Then the reaction mixture was quenched with water at rt and was extracted with Et2O. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 1.3 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 9.09 (s, 1H), 8.60 (s, 1H), 7.62-7.26 (t, J=54 Hz, 1H), 4.51-4.44 (q, J=7.2 Hz, 2H), 1.46-1.42 (t, J=7.2 Hz, 3H); MS [M+H]+: 227.38.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH3:16])[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:26])[N:15]([C:13]2[CH:14]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:10]=[CH:11][N:12]=2)[CH3:16])[CH:21]=[CH:22][CH:23]=1
Reactant: CNc1cc(Nc2ccc(F)cc2)ncn1
Reactant: O=C=Nc1cccc(Cl)c1
Product: CN(C(=O)Nc1cccc(Cl)c1)c1cc(Nc2ccc(F)cc2)ncn1

Procedure:
The title compound is prepared analogously as described in Example 121 from N-(4-fluoro-phenyl)-N′-methyl-pyrimidine-4,6-diamine and 3-chlorophenyl isocyanate.
Reaction SMILES: [CH2:1](I)[CH3:2].[OH:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][C:10](=[O:16])[NH:11]2>ClCCl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:1]([O:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][C:10](=[O:16])[NH:11]2)[CH3:2]
Reactant: CCI
Reactant: O=C1Cc2c(CCO)cccc2N1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CCOCCc1cccc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
Ethyl iodide (o.47 mL, 6 mmol) was added to a stirred mixture of silver trifluoromethanesulfonate (1.35 g, 5.2 mmol) 2,6-di-tert-butylpyridine (1 g, 5.2 mmol) and 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (0.53 g, 3 mmol) in dichloromethane (10 mL) at 0° C. The mixture was warmed to room temperature and stirred for 2 hours. The precipitate formed after 5-10 minutes changed color from yellow to brown. The reaction mixture was diluted with dichloromethane (100 mL) and washed with 1 N hydrochloric acid, saturated sodium bicarbonate and brine, dried and concentrated. The residue was chromatographed on silica gel to give 180 mg (29%) of 4-(2-ethoxy-ethyl)-1,3-dihydro-indol-2-one as a purple oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)#[N:6]>CN(C=O)C.C(OCC)(=O)C>[NH:1]1[C:5]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[N:6][N:3]=[N:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nnn[nH]2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.6 %

Procedure:
Sodium azide (228 mg, 3.50 mmol) was added to a stirred, cooled RT mixture of tert-butyl 4-cyanopiperidine-1-carboxylate (243 mg, 1.167 mmol) in DMF (5 ml) and the mixture was stirred at 100° C. for 48 h. The mixture was cooled, diluted with ethyl acetate (100 mL), washed with brine (3×50 mL), dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 40S, eluting with 10% methanol in dichloromethane to afford the title compound (197 mg, 75%) as a colorless liquid. ESI-MS calculated for C11H19N5O2: Exact Mass: 253.13. Found 254.12.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH2:10])[N:6]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:4]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl>[F:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:10][CH2:9][C:7]2[N:6]=[C:5]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COc1cc(CN)nc(-c2ccccn2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CNS(=O)(=O)c2ccc(F)cc2)nc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
A mixture of C-(4-Methoxy-[2,2′]bipyridinyl-6-yl)-methylamine (62.0 mg, 0.29 mmol), triethylamine (55.1 μL, 0.43 mmol), 4-Fluoro-benzenesulfonyl chloride (72.0 mg, 0.371 mmol) and dichloromethane (3 mL) was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the crude purified by column chromatography on silica gel (0-100% Ethyl acetate in Hexane) to afford 4-Fluoro-N-(4-methoxy-[2,2′]bipyridinyl-6-ylmethyl)-benzenesulfonamide as a white solid (48.1 mg, 38%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=2)[O:3]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>ClCCl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)[CH:10]=2)=[O:26])=[CH:20][C:19]=1[C:27]([F:28])([F:29])[F:30]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Solvent: ClCCl
Product: CC1(C)OB(c2cccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c2)OC1(C)C
Yield: 98.7 %

Procedure:
To a solution of 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (100 mg, 0.46 mmol) in dichloromethane (4 mL), 1-chloro-4-isocyanato-2-trifluoromethyl-benzene (100 mg, 0.46 mmol) was added. The mixture was stirred until disappearance of the starting material. The solvent was evaporated to dryness to give 200 mg of 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]urea in quantitative yield.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1)([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>>[CH:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:10]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=2)[C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[CH:16][CH:15]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1ccc(CBr)cc1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)c1ccc(CN(Cc2ccc(C(C)C)cc2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 4-isopropylbenzylbromide (469 mg; 0.376 ml; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.147 g (36.9%); MS m/z: 398.4 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.16 (d, 12H, 3J=7.0 Hz); 2.83 (hept, 2H, 3J=7.0 Hz); 4.62 (s, 4H); 6.69 (br s, 1H); 6.73 (dd, 1H, 4J=2.4 Hz, 3J=8.9 Hz); 7.16-7.20 (m, 8H); 7.32 (d, 1H, 3J=8.9 Hz); 7.89 (s, 1H); 11.90 (br s, 1H); HPLC (METHOD [A]): rt 19.95 min (94.4%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]2[CH2:17][OH:18])=[CH:4][CH:3]=1.[F:19][C:20]1[CH:21]=[C:22]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:23]=[C:24]([F:27])[C:25]=1O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[C:9]2[CH2:17][O:18][C:25]2[C:24]([F:27])=[CH:23][C:22]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:21][C:20]=2[F:19])=[CH:6][CH:7]=1
Reactant: OCc1c(C(F)(F)F)ccn1-c1ccc(Cl)cc1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1cc(F)c(OCc2c(C(F)(F)F)ccn2-c2ccc(Cl)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of the product prepared in Step D (1.33 g, 4.84 mmol, 1 eq), ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (1.78 g, 7.74 mmol, 1.6 eq), 1,1′-(azodicarbonyl)dipiperidine (2.52 g, 9.68 mmol, 2 eq) and tri-n-butylphosphine (3.08 mL, 12.1 mmol, 2.5 eq) in toluene (85 mL) was heated to 60° C. under N2. After 3 hr, heptane (170 mL) was added and the resulting suspension allowed to cool to room temperature over 30 min. The resulting white solid byproduct was filtered, washed with heptane, and the filtrate concentrated. The resulting residue was purified by flash chromatography (120 g column) eluting with 2 to 12% EtOAc/heptane to yield ethyl 3-(4-((1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrrol-2-yl)methoxy)-3,5-difluorophenyl)propanoate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[O:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:19]=[CH:18][C:17]3[O:20][C:21]4[C:26]([C:27]5([C:35]6[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=6)[C:29]([NH2:36])=[N:28]5)[C:16]=3[CH:15]=2)=[CH:25][C:24]([C:37]2[C:38]([F:43])=[N:39][CH:40]=[CH:41][CH:42]=2)=[CH:23][CH:22]=4)[CH2:10][CH2:9]1>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:43][C:38]1[C:37]([C:24]2[CH:25]=[C:26]3[C:27]4([C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:29]([NH2:36])=[N:28]4)[C:16]4[CH:15]=[C:14]([CH:11]5[CH2:12][CH2:13][O:8][CH2:9][CH2:10]5)[N:19]=[CH:18][C:17]=4[O:20][C:21]3=[CH:22][CH:23]=2)=[CH:42][CH:41]=[CH:40][N:39]=1
Reactant: NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3cnc(C4=CCOCC4)cc32)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3cnc(C4CCOCC4)cc32)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.8 %

Procedure:
A flask containing a solution of 3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)spiro[chromeno[2,3-c]pyridine-5,1′-isoindol]-3′-amine 2,2,2-trifluoroacetate (30 mg, 0.051 mmol) and MeOH (4 mL) was evacuated and backfilled with nitrogen. Pd/C (10 weight %, 100 mg, Aldrich) was added and the flask was evacuated and backfilled with H2 gas. The flask was fitted with a balloon filled with H2 gas (1 atm) and the reaction mixture was stirred at RT for 3 h. The reaction mixture was filtered through a pad of celite and the celite was washed with EtOAc. The solvent was removed under reduced pressure and the remaining residue was purified by reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 20 min to obtain the title compound (7.8 mg, 25.9%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][C:9](O)=[O:10])=[CH:4][CH:3]=1.B.O1CCCC1.O>O1CCCC1>[F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: O=C(O)CCOc1ccc(F)cc1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: OCCCOc1ccc(F)cc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
3-(4-Fluorophenoxy)propanoic acid (16.6 g, 90 mmol) was stirred in 100 mL of tetrahydrofuran under a nitrogen atmosphere. The solution was cooled to 5° C. and borane (120 mL, 120 mmol, 1M in tetrahydrofuran) was added dropwise at a rate to keep the temperature of the reaction near 5° C. Once the addition was complete, the solution was allowed to stir at room temperature overnight. The reaction was then cooled below 10° C. and 18 mL of a tetrahydrofuran/water mixture was added. The tetrahydrofuran was removed by evaporation under reduced pressure and the resulting cloudy mixture was diluted with about 200 mL of water. This mixture was extracted three times with diethyl ether. The combined extracts were washed with water, twice with 10% aqueous sodium bicarbonate, and once with brine. The combined extracts were then dried over sodium sulfate, filtered, and concentrated to give 15.24 g of a product oil. Yield: 99%. MS(FD) M+171.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH:7]2[CH3:12].B(O)O>>[CH3:12][CH:7]1[C:8]2[C:3](=[C:2]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:3]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][NH:6]1
Reactant: CC1NCCc2c(Br)cccc21
Agent: OBO
Product: CC1NCCc2c(-c3cccnc3)cccc21

Procedure:
In close analogy to the procedure described above, 5-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12.[CH3:25][N:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27](=[O:32])[CH2:28][C:29](O)=[O:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:29](=[O:30])[CH2:28][C:27]([N:26]([CH3:25])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: CN(C(=O)CC(=O)O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.9 %

Procedure:
To a solution of the amine 9 (80 mg, 0.235 mmol), acid 31 (47 mg, 0.235 mmol), and BOP (114.6 mg, 0.254 mmol) in DMF (2.4 mL), DIPEA (0.164 mL, 0.941 mmol) was added and the mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with EtOAc (100 mL), water (50 mL) was added and the mixture filtered through paper filter. The organic phase was separated, washed with water (50 mL), brine (20 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent EtOAc/MeOH 10:1) to afford the title compound 32 (36.2 mg, 30% yield) as a creamy solid. 1H NMR (DMSO-d6) δ (ppm): 10.29 (s, 1H), 8.49 (d, J=5.5 Hz, 1H), 7.87 (s, 1H), 7.77 (d, J=12.7 Hz, 1H), 7.46-7.30 (m, 8H), 7.03 (s, 1H), 6.66 (d, J=5.5 Hz, 1H), 3.98 (s, 3H), 3.22 (s, 2H), 2.52 (3H, s). MS (m/z): 516.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.Cl[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=[O:14]>C(OCC)C>[CH2:21]([CH:18]1[CH2:17][CH2:16][N:15]([C:13](=[O:14])[CH2:12][NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[CH:5]3)[CH2:20][CH2:19]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C(CCl)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: O=C(CNc1ccc2[nH]ncc2c1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 5-aminoindazol and 2-chloro-1-(4-benzyl-piperidin-1-yl)-ethanone according to the method described in Example 142b. Melting Point: 153-155° C. (diethylether)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][C:35](=O)[N:34]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:33]=3[CH:44]=2)=[CH:7][CH:6]=1)=O.B1C2CCCC1CCC2.C(CN)O>O1CCCC1>[OH:2][CH2:3][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][CH2:35][N:34]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:33]=3[CH:44]=2)=[CH:9][CH:10]=1
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(=O)OC)cc3)cc21
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Solvent: NCCO
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CO)cc3)cc21
Temperature: 25 °C

Procedure:
The solution of 2.0 g of benzyl 4-(4-methoxycarbonylphenyl)-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 235d) in 16 ml of tetrahydrofuran is admixed with 52.1 ml of 9-BBN and stirred at reflux over 24 hours. The reaction mixture is cooled to room temperature, admixed with 1.58 ml of ethanolamine and concentrated by evaporation. The residue is stirred in 50 ml of ethyl acetate-hexane (1:1) over 1 hour and clarified by filtration, and the filtrate is concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (3:1 EtOAc-heptane); Rt=4.74.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1CCC(N=C=NC2CCCCC2)CC1.[CH2:32](O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:4]([O:3][C:1]([N:8]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:9]1[C:10]([O:12][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:11])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of N-Boc-trans-4-fluoro-L-proline (4.5 g, 19.29 mmol) in CH2Cl2 (68 mL) were added DCC (4.78 g, 23.15 mmol), DMAP (0.236 g, 1.93 mmol) and benzyl alcohol (2 mL, 19.29 mmol). The resulting white suspension was stirred at RT for 48 h and filtered. The filtrate was concentrated to give a colorless oil which was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 4-1) to give the desired compound. TLC, Rf (c-hexane/EtOAc 3:1)=0.3; MS: 346.0 [M+Na]+; tR (HPLC conditions a): 3.85 min.
Reaction SMILES: F[C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([CH3:18])[C:5]([C:16]#[N:17])=[C:6]2[C:10]=1[O:9][C:8]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[N:7]2.C(N(CC)CC)C.[CH3:32][N:33]([CH3:39])[C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1>CS(C)=O.ClCCl>[CH3:32][N:33]([CH3:39])[C@H:34]1[CH2:38][CH2:37][N:36]([C:2]2[C:3]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:4]([CH3:18])[C:5]([C:16]#[N:17])=[C:6]3[C:10]=2[O:9][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:7]3)[CH2:35]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N3CCCC3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CCCC3)nc2c1C#N
Temperature: 150 °C
Reaction time: 4 h
Yield: 29.5 %

Procedure:
7-Fluoro-5-methyl-6-phenyl-2-(pyrrolidin-1-yl)-1,3-benzoxazole-4-carbonitrile (I-135) (0.10 g, 0.31 mmol) was suspended in dimethyl sulfoxide (3.5 ml), then triethylamine (90.0 μl, 0.65 mmol) and (3S)-3-(dimethylamino)pyrrolidine (88.0 μl, 0.69 mmol) were added, followed by stirring in a sealed tube at an external temperature of about 150° C. for 4 hours. This was diluted with dichloromethane, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=20:1), then ether and a small amount of hexane were added, and the insoluble matter was collected by filtration to obtain a beige solid (38 mg, 29%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.Cl.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[CH:28][C:27]=1[N+:36]([O-:38])=[O:37]>C(Cl)(Cl)Cl>[N+:36]([C:27]1[CH:28]=[N:29][C:30]2[C:35]([C:26]=1[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:34][CH:33]=[CH:32][CH:31]=2)([O-:38])=[O:37]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CCOC(=O)CCCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCCNc1c([N+](=O)[O-])cnc2ccccc12
Reaction time: 4 h
Yield: 99.3 %

Procedure:
Potassium carbonate (66.23 g, 479.3 mmol), triethylamine (167 mL, 1.20 mol), and ethyl 5-aminovalerate hydrochloride (104.4 g, 575.2 mmol) were added to a solution of 4-chloro-3-nitroquinoline (100.0 g, 479.3 mmol) in chloroform (1000 mL) according to the method described in Part B of Example 6. The reaction was run for four hours and provided 151 g of ethyl 5-(3-nitroquinolin-4-ylamino)pentanoate.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH3:19])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[C:29](ON1C(=O)C2C=CC=CC=2N=N1)(=[O:33])[CH:30]([CH3:32])[CH3:31].C(O)(=O)C(C)C>>[F:1][C:2]1[C:3]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:4]([CH:12]=[C:13]([CH2:16][N:17]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[O:18][CH3:19])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CC(C)C(=O)On1nnc2ccccc2c1=O
Reactant: CONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Solvent: CC(C)C(=O)O
Product: CON(Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F)C(=O)C(C)C
Yield: 77 %

Procedure:
The title compound was prepared by a procedure similar to that in Example 41. Namely, 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-benzamide obtained in Example 15 was reacted with 4-oxo-4H-benzo[d][1,2,3]triazin-3-yl isobutyrate prepared from isobutyric acid to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(isobutyryl-methoxy-amino)-methyl]-benzamide (88.9 mg, 77%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]3)=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[CH:24]=3)[C:15]=2[CH3:38])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O>FC(F)(F)C(O)=O.ClCCl>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]3)=[C:16]([C:23]3[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=3)[O:29][CH2:30][C:31]([OH:33])=[O:32])[C:15]=2[CH3:38])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(-c3cccc(OCC(=O)OC(C)(C)C)c3)c3ccccn23)ccc1N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)c2c(C)c(-c3cccc(OCC(=O)O)c3)c3ccccn23)ccc1N
Yield: 90.2 %

Procedure:
The solution of 3.68 g (6.65 mmol) of methyl 2-amino-5-({1-[3-(2-tert-butoxy-2-oxoethoxy)phenyl]-2-methylindolizin-3-yl}carbonyl)benzoate in 11 ml of trifluoroacetic acid and 35 ml of dichloromethane at ambient temperature for 4 hours. The reaction medium is poured into water and the mixture is extracted with dichloromethane. The organic phase is partially concentrated, and the yellow precipitate formed is filtered and washed with diisopropyl ether and then dried, to give 2.75 g (92%) of a yellow powder.