Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[N:7][CH:8]=1.C(N(CC)CC)C.CS([Cl:45])(=O)=O>CN(C=O)C>[Cl:45][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cn2)C(OCc2ccc3ccccc3c2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCl)cn2)C(OCc2ccc3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
A solution of 70 mg (0.156 mmol) of tert-butyl (3'RS,4'RS)-5-hydroxymethyl-3'-(naphthalen-2-ylmethoxy)-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridine-1'-carboxylate in 2 ml of absolute DMF was cooled to -10° C. and treated with 26 μl (19 mg,0.187 mmol) of triethylamine. 13 μl (20 mg, 0.172 mmol) of methanesulphonyl chloride and 2 mg of N,N-dimethylaminopyridine (DMAP) were added at -10 to -15° C. and subsequently the mixture was stirred at 0° C. for 1 hour. For the working-up, the mixture was partitioned between 25 ml of ethyl acetate and 25 ml of aqueous 5% ammonium chloride solution and the organic phase was separated. The aqueous phase was extracted three times with 10 ml of ethyl acetate each time. The combined ethyl acetate phases were dried over magnesium sulphate and finally evaporated under reduced pressure. The crude product was purified by chromatography on silica gel with a 1:1 mixture of ethyl acetate and hexane as the eluent. There were obtained 22 mg (35% of theory) of tert-butyl (3'RS,4'RS)-5-chloromethyl-3'-(naphthalen-2-ylmethoxy)-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridine-1'-carboxylate as a light yellow oil; MS: 467, 469 (M+H)+.
Reaction SMILES: O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3].[CH:19]([O:24][CH3:25])([O:22][CH3:23])OC.[Cl:26][C:27]1[C:28]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[C:39](C=O)[CH:38]=2)=[N:29][N:30]([CH3:36])[C:31]=1[O:32][CH:33]([F:35])[F:34]>ClCCl>[Cl:26][C:27]1[C:28]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([CH:19]([O:22][CH3:23])[O:24][CH3:25])[CH:38]=2)=[N:29][N:30]([CH3:36])[C:31]=1[O:32][CH:33]([F:34])[F:35]
Reactant: COC(OC)OC
Reactant: Cn1nc(-c2ccc(Cl)c(C=O)c2)c(Cl)c1OC(F)F
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Solvent: O
Product: COC(OC)c1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15 g of montmorillonite K10 were added to a solution of 16 ml of trimethyl orthoformate in 80 ml of dichloromethane. A solution of 6.4 g (20 mmol) of 4-chloro-3-(4-chloro-3-formylphenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 20 ml of dichloromethane was added dropwise at 5° C. to this mixture. The mixture was then stirred at room temperature overnight. The solids were then separated off and the clear reaction solution which remained was concentrated. Yield: 6.7 g.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([NH:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][C:28]2=[O:37])[CH2:23][CH2:22]1)=[O:20])[CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[NH:13][N:12]=[CH:11]2.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CS(C)=O>[CH2:38]([N:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH:6]([NH:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][C:28]2=[O:37])[CH2:23][CH2:22]1)=[O:20])[CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[NH:13][N:12]=[CH:11]2)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2ncc[nH]2)cc2cn[nH]c12
Solvent: CS(C)=O
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nccn2Cc2ccccc2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-(1-(1H-Imidazol-2-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamide (100 mg, 0.2 mmol) and benzyl bromide (25.0 μL, 1.1 equiv) were combined in dimethyl sulfoxide (0.6 mL). After stirring at room temperature for 16 h, the reaction mixture was poured into ice water and extracted with ethyl acetate (2×). The organic layer was washed with brine (2×), dried over sodium sulfate, concentrated, and purified by column chromatography to afford 14.0 mg (12%). 1H-NMR (CD3OD, 500 MHz) δ 1.58-1.70 (m, 4H), 2.48 (s, 3H), 2.75-2.84 (m, 2H), 3.36-3.43 (m, 2H), 4.02-4.14 (m, 3H), 4.23 (s, 2H), 4.86 (m, 1H), 5.23 (s, 2H), 5.29-5.38 (m, 1H), 6.85-7.01 (m, 3H), 7.10-7.84 (m, 10H), 7.96 (s, 1H). Mass spec.: 589.16 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17]C)=O)=[CH:4][N:3]=1.[Li][NH2:20]>C1COCC1>[Cl:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([NH2:20])=[O:17])=[CH:4][N:3]=1
Reactant: [Li]N
Reactant: COC(=O)c1cnc(Cl)c2c1[nH]c1ccccc12
Solvent: C1CCOC1
Product: NC(=O)c1cnc(Cl)c2c1[nH]c1ccccc12
Temperature: 100 °C

Procedure:
A mixture containing methyl 1-chloro-5H-pyrido[4,3-b]indole-4-carboxylate and LiNH2 (prepared in situ from ammonia and n-BuLi; 1.0 M in THF; 3.5 equiv) in THF (0.09 M) was heated in a microwave reactor at 100° C. for 1 min in a sealed tube. The reaction mixture was cooled to room temperature and partitioned between EtOAc and saturated NaHCO3. After separation of the organic phase, the aqueous phase was extracted again with EtOAc, and the combined organic phases were washed with brine, dried over MgSO4 and filtered. After evaporation of the organic solvent, the residue was purified by flash chromatography (10-70% EtOAc in hexanes) to provide the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([C:20]([OH:22])=[O:21])[CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl(O)(=O)(=O)=O.[H][H]>[Pd].C(O)(=O)C>[CH2:1]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([C:20]([OH:22])=[O:21])=[CH:16][CH:17]=2)[NH:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1cc2ccc(C(=O)O)cc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: CCCCCCCCCCC1Cc2ccc(C(=O)O)cc2N1
Yield: 75.3 %

Procedure:
A mixture of 2-(n-decyl)indole-6-carboxylic acid (62.5 g), perchloric acid (40 ml of strength 70% w/v) and glacial acetic acid (400 ml) were hydrogenated over palladium on charcoal (5% w/w, 8.0 g) at 80°-90° C. and atmospheric pressure. When hydrogen uptake had ceased (after 4 hours) the hot mixture was filtered and the residue was washed with hot (80° C.) glacial acetic acid (500 ml). The combined filtrates were concentrated in vacuo to 450 ml and were poured onto ice (1000 g). The mixture was adjusted to pH 9 by treatment with an aqueous solution of sodium hydroxide (strength 50% w/v) and was then adjusted to pH 4-5 with glacial acetic acid. The solid was collected, was washed with water (3×100 ml) and was dried. The solid was dissolved in boiling ethanol, treated with charcoal, and the solution was filtered. The filtrate was treated with an excess of a solution of hydrogen chloride in ethanol (90 ml of strength 37% w/v) and then the mixture was cooled and diluted with diethyl ether (750 ml). The solid was collected and treated as in Example 56 to give (RS)-2-(n-decyl)indoline-6-carboxylic acid (47.4 g), in the form of a buff solid, m.p. 123°-125° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([NH2:13])[CH:10]=[N:11][CH:12]=2)[CH2:3][CH2:2]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=2[F:25])[N:18]=[C:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[C:16]=1[CH3:33].C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:25][C:23]1[CH:22]=[C:21]([F:26])[CH:20]=[C:19]2[C:24]=1[C:15]([NH:13][C:9]1[CH:10]=[N:11][CH:12]=[C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:8]=1)=[C:16]([CH3:33])[C:17]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=[N:18]2
Reactant: Nc1cncc(C2CCOCC2)c1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cncc(C2CCOCC2)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 5-(tetrahydro-2H-pyran-4-yl)pyridin-3-amine (71.7 mg, 0.40 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (96.7 mg, 0.33 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (25.9 mg, 0.054 mmol), tris(dibenzylideneacetone)dipalladium (0) (12.8 mg, 0.014 mmol), and sodium tert-butoxide (88.8 mg, 0.92 mmol) in dry Toluene (2.0 mL) was degassed by nitrogen. The resulting reaction was heated to 100° C. and monitored with TLC and LC-MS. After 18 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (0-70% EtOAc in hexanes) to afford an impure orange residue. The light orange film was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a light yellow film as 5,7-difluoro-3-methyl-2-(pyridin-2-yl)-N-(5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-quinolin-4-amine. 1H NMR (500 MHz, CDCl3) δ ppm 8.79 (1H, m), 8.23 (1H, d, J=2.4 Hz), 8.12 (1H, d, J=1.7 Hz), 7.94 (2H, m), 7.65 (1H, ddd, J=9.5, 2.4, 1.2 Hz), 7.39 (1H, ddd, J=7.5, 4.9, 1.3 Hz), 7.25 (2H, br. s.), 7.08 (2H, m), 4.12 (2H, m), 3.59 (2H, m), 2.85 (1H, m), 2.18 (3H, s), 1.86 (4H, m). Mass Spectrum (pos.) m/e: 433.1 (M+1).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([N:20]([C@H:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]([OH:25])=O)[CH3:21])=[O:19])([CH3:16])([CH3:15])[CH3:14].ON1C2N=CC=CC=2N=N1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH3:57][N:58]([CH3:66])[CH2:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1.C(N(C(C)C)C(C)C)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:19])[N:20]([C@H:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]([N:63]1[CH2:64][CH2:65][CH:60]([CH2:59][N:58]([CH3:66])[CH3:57])[CH2:61][CH2:62]1)=[O:25])[CH3:21])([CH3:14])([CH3:15])[CH3:16]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)O
Reactant: CN(C)CC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)CC1CCN(C(=O)[C@@H](Cc2ccccc2)N(C)C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 50.1 %

Procedure:
At 0° C., N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.158,g, 6.04 mmol) was added to a solution of (2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-phenylpropionic acid (149 g, 6.04 mmol) and 1-hydroxy-7-azabenzotriazole (0.822 g, 6.04 mmol) in dichloromethane (25 ml) and N,N-dimethylformamide (12 ml). The reaction mixture was stirred for 20 min at 0° C. A solution of the crude dihydrochloride salt of N,N-dimethyl-N-((piperidin-4-yl)methyl)amine (1.3 g, 6.04 mmol) in N,N-dimethylformamide (10 ml) and dichloromethane (5 ml) and ethyldiisopropylamine (6.2 ml, 36.25 mmol) were added successively. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (100 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate (100 ml). The organic layer was dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (100 g), using dichloromethane/methanol/25% aqueous ammonia (200:10:1) as eluent, to give 1.22 g of N-[(1R)-1-benzyl-2-(4-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamic acid tert-butyl ester.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([N:19]2[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:20]2)[NH:3]1.O=P(Cl)(Cl)[Cl:31]>>[Cl:31][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([N:19]2[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:20]2)[N:3]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Oc4ccccc4)ccc3c(=O)[nH]2)c1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnn(-c2nc(Cl)c3ccc(Oc4ccccc4)cc3n2)c1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A mixture of the above ethyl 1-(4-oxo-7-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate (0.31 g, 0.82 mmol), and POCl3 (3.08 mL, 32.9 mmol), was heated to reflux for 3 h. The mixture was allowed to cool to rt and then concentrated. The residue was taken up in a minimal amount of DCM and purified by FCC (0 to 25% EtOAc/hexanes) to yield the title compound (250 mg, 77%). 1H NMR (600 MHz, DMSO-d6): 9.06 (d, J=0.7 Hz, 1H), 8.35 (d, J=9.2 Hz, 1H), 8.23 (dd, J=10.6, 6.6 Hz, 1H), 7.63-7.59 (m, 1H), 7.60-7.54 (m, 2H), 7.41-7.36 (m, 1H), 7.31-7.29 (m, 2H), 7.18 (d, J=2.4 Hz, 1H), 4.30 (q, J=7.1 Hz, 2H), 1.35-1.24 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.O>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[C@@H:19]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: Cc1ccc(Sc2ccc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)C)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2ccc(S(=O)(=O)N(CCN3CCOCC3)[C@@H](C(=O)OC(C)(C)C)C(C)C)cc2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of N-[[4-[(4-methylphenyl)thio]-phenyl]sulfonyl]-D-valine, 1,1-dimethylethyl ester, from Example 2a (2.4 g ,5.5 mmole) in DMF (50 ml) was added potassium carbonate (2.28 g, 16.5 mmole) and 4-(2-chloroethyl)morpholine hydrochloride (3.07 g, 16.5 mmole). After vigorously stirring at 60° C. for 18 hours, the reaction was worked up by adding water and extracting with ethyl acetate. The combined organic extracts were washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo to give an oil which was purified on silica gel eluting with 50/50 ethyl acetate/hexane to give N-[[4-[(4-methylphenyl)thio]phenyl]sulfonyl]-N-[2-(4-morpholinyl)-ethyl]-D-valine, 1,1-dimethylethyl ester (3.62 g, 100%): anal. calc'd for C28H40N2S2O5 : C, 61.28; H, 7.35; N, 5.10. Found: C, 61.12; H. 7.69; N, 4.91. HRMS MH+ calc'd for C28H40N2S2O5 : 548.2379, found: 548.2386.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH2:7][CH2:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:47][C:48]1[S:52][C:51]([CH2:53][CH2:54][NH2:55])=[CH:50][CH:49]=1>CN(C=O)C>[CH3:47][C:48]1[S:52][C:51]([CH2:53][CH2:54][NH:55][C:9](=[O:11])[CH2:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=2)=[CH:50][CH:49]=1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(CCN)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CCNC(=O)CCc2ccc(C(F)(F)F)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of 3 g (13 mmol) 4-(trifluoromethyl)hydrocinnamic acid (commercially available) in 30 mL DMF under argon were added 4.7 g (14.37 mmol) TBTU and 11.2 mL (65.3 mmol) N-ethyldiisopropylamine. A solution of 1.85 g (13 mmol) 2-(5-methyl-thiophen-2-yl)-ethylamine in 5 mL DMF was added drop wise over a period of 2 minutes. The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with water and with a sat. NaHCO3 solution, dried over Na2SO4, filtered and concentrated in vacuo. The solid was stirred in 30 mL ether, filtered and dried. The mother liquor was concentrated in vacuo and purified on silica eluting with a gradient formed from heptane and ethyl acetate. The product containing fractions were evaporated. 3.75 g (84%) of the title compound was yielded as white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:8].C(=O)(O)[O-].[Na+]>C(O)C>[NH:8]=[C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Cn1cccc1
Reactant: CCOC(=O)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=N)c1cccn1C

Procedure:
A stream of dry halogen chloride is passed as a moderate rate through a solution of 12.5 g of N-methylpyrrole and 16.8 g of ethyl cyanoformate in 125 mls of ethanol-free chloroform at 22° C. for 31/2 hours. The reaction mixture is added dropwise with stirring to a 1.5 liter solution of 5% sodium bicarbonate. The chloroform layer is separated, dried over Na2SO4 and evaporated in vacuo at room temperature to give a brown oil (ethyl α-imino-1-methylpyrrole-2-acetate).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[CH:10][C:9]=1[F:24])=[O:6].[OH-].[NH4+:27]>>[F:24][C:9]1[CH:10]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[C:12]([F:14])=[CH:13][C:8]=1[NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:27])=[O:2]
Reactant: COC(=O)CC(=O)Nc1cc(F)c(OCc2cccc(F)c2)cc1F
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1cc(F)c(OCc2cccc(F)c2)cc1F
Yield: 56 %

Procedure:
The title compound is prepared in analogy to example 3 from N-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester and and ammonium hydroxide.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH2:7][C@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH:24]2[CH2:26][CH2:25]2)[C:18](=[O:27])[CH2:17]3)[CH2:9]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:5][O:4][C:2](=[O:3])[NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH:24]2[CH2:26][CH2:25]2)[C:18](=[O:27])[CH2:17]3)[CH2:9]1
Reactant: NC[C@@H]1CN(c2cc(F)c3c(c2)CC(=O)N3C2CC2)C(=O)O1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NC[C@H]1CN(c2cc(F)c3c(c2)CC(=O)N3C2CC2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (0.055 ml, 0.715 mmol) is added dropwise to (R)-5-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-1-cyclopropyl-7-fluoro-1,3-dihydro-indol-2-one (Example 50, Step 5, 0.200 g, 0.476 mmol) and diisopropylethylamine (0.349 ml, 1.90 mmol) in dichloromethane (5 ml) at 0° C. The reaction is stirred at 0° C. for 30 minutes and then allowed to warm at room temperature. The reaction mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated. The residue is purified by PTLC (5% MeOH/DCM) to give the title compound as a yellow solid. HPLC r.t. 4.05 min; 1H NMR (300 MHz, CDCl3) 7.23 (m, 1H), 7.18 (m, 1H), 5.12 (t, 1H), 4.77 (m, 1H), 4.02 (t, J=8.7 Hz, 1H), 3.79 (dd, J=6.6, 9 Hz, 1H), 3.69 (s, 3H), 3.51 (m, 2H), 2.85 (m, 1H), 0.97 (m, 2H); MS for C17H18FN3O5 m/z 364.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:19]([CH2:20][CH2:21]O)[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.CS(Cl)(=O)=O.O>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:11]3=[N:12][C:13]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[N:19]3[CH2:20][CH2:21]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Nc2nc3cccnc3n2CCO)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCn3c2nc2cccnc23)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To a solution of 2-{2-[(4-nitrophenyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}ethanol (2.2 g) and triethylamine (10 mL) in THF (100 mL) was added methanesulfonyl chloride (1.1 mL) at 0° C., and the mixture was stirred at 0° C. for 2 h. The mixture was poured into water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. A mixture of the residue and potassium carbonate (3.1 g) in NMP (30 mL) was stirred at 100° C. overnight. After cooling to room temperature, the mixture was diluted with water. The formed crystals were collected by filtration to give the title compound (1.7 g).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH2:9][O:10][CH2:11][CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:36]1[CH2:41][CH2:40][CH2:39][C@@H:38]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:37]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH2:45]([O:44][C:42]([C@@H:38]1[CH2:39][CH2:40][CH2:41][N:36]([CH2:12][CH2:11][O:10][CH2:9][CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:37]1)=[O:43])[CH3:46]
Reactant: OCCOCC=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H]1CCCN(CCOCC=C(c2ccccc2)c2ccccc2)C1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
A solution of 2-(3,3-diphenyl-2-propen-1-yloxy)ethanol (3.0 g, 11.8 mmol) in dry THF (30 ml) kept under a nitrogen atmosphere was cooled to 10° C. and a solution of n-butyllithium in hexanes (5.0 ml, 2.5 M) was added dropwise. The reaction mixture was stirred for 0.5 h at room temperature and p-toluenesulphonyl chloride (2.3 g, 12.1 mmol) was added. The mixture was stirred at room temperature for 1 h. Ethyl (R)-3-piperidinecarboxylate (2.7 g, 17.7 mmol) and potassium carbonate (2.5 g, 17.7 mmol) were added and the mixture was heated at reflux temperature for 5 h. The cooled reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (2×75 ml). The combined organic phases was washed with water and a sodium citrate buffer solution (2×100 ml, pH 6). The organic phase was then extracted with a 5% citric acid solution (3×75 ml) and the combined acidic aqueous extracts was washed with ethyl acetate (25 ml). To the acidic aqueous solution was added a 4 N sodium hydroxide solution until pH 11 and this solution was immediately extracted with ethyl acetate (3×50 ml). The combined organic extracts was dried over sodium sulphate and the solvent evaporated in vacuo to give 1.5 g (33%) of the title compound as an oil. TLC: rf=0.20 (SiO2 ; n-heptane/THF=7:3). 1H NMR (CDCl3)δ 4.08 (d, 2H); 6.22 (t, 1H).