Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C@H:10]2[CH2:9][C@H:8]([C:6]3[O:7][NH:29][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])=[CH:20][CH:21]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(F)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 64.6 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorobenzyl)piperidine-1-carboxylate (0.454 g, 1.24 mmol) (from example 97, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.050 g, 1.24 mmol) dissolved in water (1 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.076 mL, 1.24 mmol) was added during 5 min. The resulting solution was stirred at −40° C. for 2 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (6 mL, 36.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a slightly yellow oil. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Trans-methyl 2-(4-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.268 g, 64.5%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 1.47-1.75 (m, 2H), 1.85-2.14 (m, 2H), 2.71-3.00 (m, 2H), 3.02-3.16 (m, 2H), 3.40-3.76 (m, 3H), 4.22 (d, br., 1H), 4.59 (d, br., 1H), 5.64 (s, 1H), 6.95-7.03 (m, 2H), 7.15 (s, br., 2H). MS m/z 335 (M+H)+
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C:10](=[O:11])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].Cl.[F:18][C@H:19]1[CH2:23][CH2:22][NH:21][CH2:20]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[C:2]([O:5][C:6]([N:8]1[CH2:9][C:10](=[O:11])[CH2:12][C@H:13]1[C:14]([N:21]1[CH2:22][CH2:23][C@H:19]([F:18])[CH2:20]1)=[O:16])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: F[C@H]1CCNC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
N-tert-Boc-4-oxo-L-proline (2.29 g, 10 mmol), (S)-3-fluoropyrrolidine hydrochloride (1.38 g, 11 mmol) and TEA (2.09 mL, 15 mmol) were mixed in anhydrous methylene chloride (30 mL) under nitrogen. HOBT (2.03 g, 15 mmol) was added and the mixture cooled to 0° C. in an ice bath before addition of EDC (2.10, 11 mmol). The reaction mixture was allowed to warm to RT and stirred overnight. The mixture was washed with saturated sodium bicarbonate and brine and dried over magnesium sulfate. The crude material (3.15 g) was recrystallized from hexane:EtOAc (2:1) to give the title compound as light yellow needles (2.18 g, 73%). MS m/z 301.3 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@:40]1([C:49]([N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][O:52]2)=[O:50])[CH2:42][C@@H:41]1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:67][CH2:68][CH2:69][CH2:70][CH2:71][C:72]([OH:74])=[O:73].C([BH3-])#N.[Na+].Cl>O1CCOCC1.O>[C:72]([CH2:71][CH2:70][CH2:69][CH2:68][CH2:67][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@:40]1([C:49]([N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][O:52]2)=[O:50])[CH2:42][C@@H:41]1[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:12])[CH3:13])([OH:74])=[O:73]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=CCCCCC(=O)O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCC(=O)O)C(C)C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
10 mg (0.011 mmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetate (Intermediate 16) were dissolved in 2 ml of dioxane/water, and 2.8 mg (0.022 mmol) of 6-oxohexanoic acid were added. The reaction mixture was subsequently stirred at 100° C. for 1 h. After cooling to RT, 0.75 mg (0.012 mmol) of sodium cyanoborohydride was added and the mixture was adjusted to a pH of 3 by adding 0.1 N hydrochloric acid. The reaction mixture was then stirred at 100° C. for a further hour. After cooling, another 2.8 mg (0.022 mmol) of 6-oxohexanoic acid were added and the reaction mixture was again stirred at 100° C. for 1 h. A further 0.75 mg (0.012 mmol) of sodium cyanoborohydride was added and 0.1 N hydrochloric acid was subsequently used to adjust the pH back to 3. The reaction mixture was then stirred at 100° C. for another 1 h. This procedure was then repeated for a third time. The reaction mixture was finally concentrated and the crude product was purified by means of preparative HPLC. This gave 6.4 mg (64% of theory) of the title compound in the form of a colourless foam.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:12]=2[N:13]=1.[CH2:22]([SH:24])[CH3:23].O>CN1C(=O)CCC1>[CH2:22]([S:24][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:12]=2[N:13]=1)[CH3:23]
Reactant: FC(F)(F)c1ccc2oc(-c3sccc3Br)nc2c1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCSc1ccsc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.11 g of sodium hydride (60%) was added to a solution of 0.65 g of 2-(3-bromothiophen-2-yl)-5-(trifluoromethyl)benzoxazole and 0.2 ml of ethanethiol in NMP 6 ml at 0° C., and the mixture was stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous hydrochloric acid solution and a saturated aqueous salt solution and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.8 g of 2-(3-ethylthiothiophen-2-yl)-5-(trifluoromethyl)benzoxazole (Compound of Present Invention (36)).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:21]=[C:22]([CH:26]([CH:34]2[CH2:36][CH2:35]2)[NH:27][S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])[CH:23]=[N:24][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[C:8]([C:20]2[CH:21]=[C:22]([CH:26]([CH:34]3[CH2:36][CH2:35]3)[NH:27][S:28]([CH:31]([CH3:33])[CH3:32])(=[O:29])=[O:30])[CH:23]=[N:24][CH:25]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)S(=O)(=O)NC(c1cncc(Br)c1)C1CC1
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)NC(c1cncc(-c2ccc(C#N)c(Cl)c2)c1)C1CC1
Temperature: 100 °C
Yield: 66.7 %

Procedure:
A mixture of 2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (198 mg, 0.75 mmol), N-((5-bromopyridin-3-yl)(cyclopropyl)methyl)propane-2-sulfonamide (250 mg, 0.75 mmol), PdCl2(PPh3)2 (43 mg, 0.06 mmol) and Na2CO3 (2 M in water, 0.94 mL, 1.88 mmol) in DMF (6 mL) was heated at 100° C. for 2 h. After concentration, the resulting residue was dissolved in DCM and filtered. The filtrates were concentrated and purified by flash column (EtOAc/Heptane, v/v, 0-40%) to give the title compound (195 mg, 67%); ESI-MS m/z: 390 [M+1]+; 1H-NMR (MeOD, 400 MHz) δ 8.84 (1H, s), 8.71 (1H, s), 8.25 (1H, s), 8.05 (1H, bs), 7.98 (1H, d, J=8.0 Hz), 7.86 (1H, d, J=8.0 Hz), 3.97 (1H, d, J=9.2 Hz), 3.16-3.09 (1H, m), 1.37-1.33 (1H, m), 1.36 (3H, d, J=7.2 Hz), 1.29 (3H, d, J=7.2 Hz), 0.81-0.76 (1H, m), 0.66-0.63 (2H, m), 0.53-0.48 (1H, m); Enantiomers were separated by chiral HPLC (ChiralPak IA-H, EtOH/Heptane, v/v, 60/40) to give the first peak (enantiomer 1, t=10.11 min) and the second peak (enantiomer 2, t=12.95 min).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:27])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)=[O:2].S([CH2:38][N+:39]#[C-:40])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CO>[O:2]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[C:10](=[O:27])[N:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:14]=2)=[CH:40][N:39]=[CH:38]1
Reactant: O=Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=c1c(-c2ccccc2-c2cnco2)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
13 mg of 3-(2-formylphenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 10 ml of methanol. To the mixture were added 11 mg of tosylmethylisocyanide and 8 mg of potassium carbonate, followed by heating under reflux overnight. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. It was filtered through NH silica gel and silica gel, and the filtrate was evaporated. The resulting precipitates were washed with ether and dried, to give 9 mg of the title compound.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([NH:10][CH:11]([C:13]2[N:18]=[N:17][C:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:15][CH:14]=2)[CH3:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH:1]1([CH2:7][C:8]2[N:18]3[C:13]([CH:14]=[N:15][C:16]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)=[N:17]3)=[C:11]([CH3:12])[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)CC3CCCCC3)nn2)cc1
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(Nc2ncc3c(C)nc(CC4CCCCC4)n3n2)cc1
Yield: 71.7 %

Procedure:
Applying the Cyclization Procedure 2, using 2-cyclohexyl-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]acetamide (Intermediate 69) (100 mg, 0.27 mmol), pyridine (25 mL), 1,2,4 triazole (56 mg, 0.81 mmol) and phosphorus oxychloride (0.040 mL, 0.43 mmol), to afford 7-(cyclohexylmethyl)-5-methyl-N-[4-(methyloxy)phenyl]-imidazo[5,1-f][1,2,4]triazin-2-amine (68 mg) as a yellow solid. MS m/z 352 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[CH:6]=[CH:5][N:4]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>ClCCl.O>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:12]2[CH:13]=[C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=3)[CH:10]=[N:11]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CSc1nccc(-c2cn[nH]c2)n1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cn2cc(-c3ccnc(SC)n3)cn2)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-(methylthio)-4-(1H-pyrazol-4-yl)pyrimidine (200 mg, 1 mmol) in dichloromethane (3 mL) and H2O (1 mL) was added 4-methoxybenzylchloride (200 mg, 1.28 mmol) at 0° C. The mixture was stirred at R1 overnight. The organic layer was separated, washed with brine and concentrated in vacuo to give crude 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine. 1H NMR (300 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.50, (d, J=5.4 Hz, 1H), 8.16 (s, 1H), 7.40 (d, J=5.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 5.30 (s, 2H), 3.72 (s, 3H), 2.51 (s, 3H); MS (ESI) m/z: 313 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH3:24])=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:25]#[N:26])[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[NH4+].CO>O.C(OCC)(=O)C.[Fe]>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:23][CH3:24])[N:13]=[CH:12][C:11]([C:25]#[N:26])=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Yield: 75.9 %

Procedure:
A mixture of 4.88 g (13 mmol) of 4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-nitro-quinoline-3-carbonitrile, 5.2 g (97.5 mmol) of ammonium chloride, and 3.3 g (58.5 mmol) iron was stirred at reflux in 60 ml of water and 60 ml of methanol for 4.5 hours. The mixture was diluted with 500 ml of hot ethyl acetate and the hot mixture was filtered. The filtration was washed with saturated sodium chloride solution and then the organic layer was dried over sodium sulfate. The solvent was removed and the residue was chromatographed on silica gel eluting with mixture of ethyl acetate and methanol to give 3.38 g of yellow solid: mass spectrum (electrospray, m/e): M+H 343.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([O:54][CH3:55])[C:40]=1[OH:56]>>[NH2:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:42]=[C:41]([O:54][CH3:55])[C:40]([OH:56])=[C:39]([Cl:38])[CH:44]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(Nc4ccc(N5CCC[C@@H](N)C5)nc4)c3c2)cc(Cl)c1O
Yield: 32.4 %

Procedure:
Following general procedure D, (R)-tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.17 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (74 mg, 0.26 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (30 mg, 32% over 2 steps) as an orange-yellow solid: 1H NMR (500 MHz, MeOD+TFA-d) δ 9.40 (br s, 1H), 8.28-8.20 (m, 2H), 8.10 (br s, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.65 (dd, J=9.1, 2.8 Hz, 1H), 7.05 (d, J=9.1 Hz, 1H), 6.99 (s, 1H), 6.83 (br s, 1H), 4.55-4.49 (d, J=11.6 Hz, 1H), 4.04-3.95 (m, 1H), 3.91 (s, 3H), 3.28-3.18 (m, 3H), 2.87 (br s, 1H), 2.22-2.14 (m, 1H), 1.96-1.87 (m, 1H), 1.76-1.62 (m, 2H), 1.28-1.16 (m, 4H).; ESI MS m/z 544 [C30H30ClN5O3+H]+; HPLC>99.0% (AUC), tR=10.74 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([OH:20])=O)[C:13]2[C:8](=[CH:9][C:10]([CH3:21])=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2].FC1C(O)=C(F)C(F)=C(F)C=1F.[N:34]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N1CCOCC1)C>CN(C=O)C.C(Cl)Cl.C(Cl)CCl>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([N:37]2[CH2:36][CH2:35][N:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38]2)=[O:20])[C:13]2[C:8](=[CH:9][C:10]([CH3:21])=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(OCC(=O)O)c2ccc(C)cc2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN1CCOCC1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1cc(OCC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(C)cc2n1

Procedure:
To a solution of 990 mg 4-Carboxymethoxy-7-methyl-quinoline-2-carboxylic acid ethyl ester in 5 ml DMF were added 945 mg pentafluorophenol and 984 mg EDC. The mixture was stirred under exclusion of moisture until LCMS indicated complete conversion to the corresponding pentafluorophenolester. Tert-Butyl 1-piperazinecarboxylate (437 mg) was mixed with 0.8 ml N-ethylmorpholine and 10 ml DMF and this mixture added dropwise to the solution of the pentafluorophenolester. After 12 h the reaction mixture was diluted with DCM and washed with aqueous LiCl (4%) and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica eluting with ethyl acetate/heptane gradient. Yield: 988 mg.
Reaction SMILES: C[CH2:2][O:3]C(C1N(C(OC(C)(C)C)=O)C2=NC=C(OC(=O)C3C=CC=CC=3)C=C2C=1)=O.[C:31]([O:35][C:36]([N:38]1[CH2:50][C@@H:49]([CH3:51])[N:48]2[C@H:40]([CH2:41][C:42]3[C:47]2=[N:46][C:45]([C@@H:52]([O:54][CH3:55])[CH3:53])=[C:44](Br)[CH:43]=3)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:50][C@@H:49]([CH3:51])[N:48]2[C@H:40]([CH2:41][C:42]3[C:47]2=[N:46][C:45]([C@@H:52]([O:54][CH3:55])[CH3:53])=[C:44]([CH:2]=[O:3])[CH:43]=3)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CO[C@@H](C)c1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reactant: CCOC(=O)c1cc2cc(OC(=O)c3ccccc3)cnc2n1C(=O)OC(C)(C)C
Product: CO[C@@H](C)c1nc2c(cc1C=O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 15, intermediate c) from (4R,9aR)-7-bromo-6-(1-(S)-methoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 51, intermediate).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1CCCC1>CO>[CH:12](=[C:6]1/[C:7](=[O:11])[NH:8][C:9]2[C:5]/1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccccc1

Procedure:
In a manner similar to the method described in example 1a, 6-chlorooxindole (1.0 g, 5.7 mmol) was reacted with benzaldehyde (0.6 g, 5.7 mmol) (Aldrich) and pyrrolidine (0.4 g, 5.7 mmol) in methanol to give a mixture of E- and Z-3-benzylidene-6-chloro-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.5 g, 100%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[CH:17]=O.[C:26](#[N:30])[CH2:27][C:28]#[N:29].C1N2CCN(CC2)C1>C(O)C.O>[NH2:30][C:26]1[O:1][C:2]2[C:3]([CH:17]([C:16]3[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:14]([Br:13])[CH:15]=3)[C:27]=1[C:28]#[N:29])=[CH:4][C:5]([OH:12])=[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=21
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: Oc1ccc(O)c2ccccc12
Reactant: N#CCC#N
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CCO
Product: COc1cc(C2C(C#N)=C(N)Oc3c2cc(O)c2ccccc32)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,4-Dihydroxy-naphthalene (704 mg, 4.4 mmol), 3-bromo-4,5-dimethoxy-benz-aldehyde (1077 mg, 4.4 mmol) and malononitrile (295 mg, 4.4 mmol) were taken in 40 ml ethanol at room temperature, charged with DABCO (48.4 μl, 1.46 mmol) and then refluxed with stirring under LC-MS control for 18 h. The reaction mixture was then cooled down to room temperature. The mixture was diluted with water to about 100 ml, stirred at room temperature for 1 h and the precipitates were separated by filtration. It was washed well with 50% aqueous ethanol and dried under vacuum (1.68 g, 3.7 mmol, 84%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.CS(O)(=O)=O.N1C2C(=CC=CC=2)C=CC=1.[C:29](Cl)(Cl)=[O:30].C1(C)C=CC=CC=1.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:49](=[O:57])[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[NH2:56])=[CH:44][CH:43]=1>C(Cl)Cl>[CH3:40][O:41][C:42]1[CH:43]=[CH:44][C:45]([NH:48][C:49](=[O:57])[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[NH:56][C:29]([O:13][CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:30])=[CH:46][CH:47]=1
Reactant: COc1ccc(NC(=O)c2ccccc2N)cc1
Reactant: OC1CCN(c2ccncc2)CC1
Reactant: O=C(Cl)Cl
Agent: CS(=O)(=O)O
Solvent: c1ccc2ncccc2c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2ccccc2NC(=O)OC2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0 h
Yield: 46 %

Procedure:
To a mixture of 1-(4-pyridyl)-4-hydroxypiperidine (536 mg, 3.01 mmol) and methylene chloride (45 mL) was added methanesulfonic acid (0.2 ml, 3.1 mmol). After stirring for 15 seconds, quinoline (0.45 mL, 3.8 mmol) was added, immediately followed by 1.93 M phosgene in toluene (2 mL, 3.9 mmol). After 5 minutes, the reaction was placed in a 35° C. oil bath for 45 minutes. The reaction was cooled to room temperature and N-(4-methoxyphenyl)-2-aminobenzamide (728 mg, 3.0 mmol) and quinoline(0.45 mL, 3.8 mmol) were added. After stirring overnight, the reaction was diluted with CH2Cl2(150 mL) and washed with sat'd sodium carbonate (2×25 mL). The organic layer was concentrated and the crude residue was chromatographed to give 617 mg (46%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:25])[CH:6]=[C:7]([CH2:23][CH3:24])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[CH3:2].[Cl:26][C:27]([Cl:31])=[CH:28][CH2:29]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([C:7]1[CH:6]=[C:5]([O:25][CH2:29][CH:28]=[C:27]([Cl:31])[Cl:26])[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[CH3:24]
Reactant: ClCC=C(Cl)Cl
Reactant: CCOC(COCCCCOc1c(CC)cc(O)cc1CC)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(COCCCCOc1c(CC)cc(OCC=C(Cl)Cl)cc1CC)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.6 %

Procedure:
Then, 19.9 g of 3,5-diethyl-4-(4-(2,2-diethoxyethoxy)butyloxy)phenol, 9.20 g of 1,1,3-trichloro-1-propene, 9.15 g of potassium carbonate, and 200 ml of N,N-dimethylformamide were placed in a reaction vessel. After stirring at room temperature for 24 hours, the reaction mixture was poured into water, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium, and concentrated to give a residue. This residue was subjected to silica gel chromatography, which afforded 25.4 g (yield, 91%) of 3,5-diethyl-1-(3,3-dichloro-2-propenyloxy)-4-(4-(2,2-diethoxyethoxy)butyloxy)benzene, nD26.0 1.4991.