Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=C2C(C3C=C(C=CC=3)CNC(C3C(=O)N(CC4C=CC(F)=C(F)C=4)C=CC=3)=O)=CNC2=NC=1)#N.[F:38][C:39]1[CH:40]=[C:41]([CH:63]=[CH:64][C:65]=1[F:66])[CH2:42][N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([NH:51][CH2:52][C:53]2[CH:54]=[C:55](B(O)O)[CH:56]=[CH:57][CH:58]=2)=[O:50])[C:44]1=[O:62].[B].C[O:69][C:70]([C:72]1[CH:73]=[C:74]2[CH:80]=[CH:79][NH:78][C:75]2=[N:76][CH:77]=1)=[O:71]>>[F:38][C:39]1[CH:40]=[C:41]([CH:63]=[CH:64][C:65]=1[F:66])[CH2:42][N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([NH:51][CH2:52][C:53]2[CH:54]=[C:55]([C:80]3[C:74]4[C:75](=[N:76][CH:77]=[C:72]([C:70]([OH:71])=[O:69])[CH:73]=4)[NH:78][CH:79]=3)[CH:56]=[CH:57][CH:58]=2)=[O:50])[C:44]1=[O:62]
Reactant: O=C(NCc1cccc(B(O)O)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Reactant: COC(=O)c1cnc2[nH]ccc2c1
Agent: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: [B]
Product: O=C(O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1

Procedure:
Except where indicated, 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid was synthesized as per Example 68, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using 3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenylboronic acid as activated boron species and 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester as substituted bicyclic heterocycle, to yield the product. 1H NMR (400 MHz, DMSO-d6) d ppm 12.312 (m, 1H) 10.078 (t, J=6.0 Hz, 1H) 8.829 (d, J=1.8 Hz, 1H) 8.709 (d, J=1.8 Hz, 1H) 8.400 (dd, J=7.4, 2.2 Hz, 1H) 8.211 (dd, J=6.4, 2.0 Hz, 1H) 7.954 (d, J=2.4 Hz, 1H) 7.669 (s, 1H) 7.594 (d, J=8.0 Hz, 1H) 7.462-7.328 (m, 3H) 7.236 (d, J=7.8 Hz, 1H) 7.173-7.119 (m, 1H) 6.579 (t, J=7.0 Hz, 1H) 5.188 (s, 2H), 4.582 (d, J=5.8 Hz, 2H); MS m/z=515.29 M+H.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CO>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([N:34]1[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCN(C(=O)C(C)(C)NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-benzyloxycarbonylamino-2-methylpropionic acid (2.37 g) in tetrahydrofuran (20 mL) was added 1,1′-carbonylbis-1H-imidazole (1.78 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1-methylpiperazine (2.0 mL), and the mixture was stirred at 40° C. for 3.5 days. To the reaction mixture was added methanol, and the resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give 1-(2-benzyloxycarbonylamino-2-methylpropionyl)-4-methylpiperazine (1.99 g). This material was dissolved in methanol (10 mL). To the solution was added 10% palladium-carbon powder (0.4 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (1.14 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[F:28])[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)=[N+]=[N-]>CCOC(C)=O.[Pd]>[NH2:1][CH2:4][CH2:5][O:6][CH:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[F:28])[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(OCCN=[N+]=[N-])c2cccc(Cl)c2F)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(OCCN)c2cccc(Cl)c2F)C1
Reaction time: 8 h

Procedure:
To a solution of (R)-tert-butyl 3-((2-azidoethoxy)(3-chloro-2-fluorophenyl)methyl)-piperidine-1-carboxylate (2.6 g, 6.31 mmol) in EtOAc (50 mL) was added wetted Pd/C (0.1 g) and the mixture was stirred overnight under a hydrogen atmosphere maintained by a balloon. The reaction mixture was filtered through a pad of Celite and the solvent was removed to give (R)-tert-butyl 3-((2-aminoethoxy)(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate which was submitted to reverse phase the preparative HPLC to give (R)-tert-butyl 3-((S)-(2-aminoethoxy)(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate (990 mg, 81%) and (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate (792 mg, 65%). MS (E/Z): 387 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH3:27])=[CH:22][C:21]=1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].O>O1CCCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:27])[C:2]2[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=2)=[CH:22][C:21]=1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34]
Reactant: CNc1ccc(F)c(NC(=O)OC(C)(C)C)c1
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1ccc(F)c(NC(=O)OC(C)(C)C)c1)c1ncc([N+](=O)[O-])c(SC#N)n1
Reaction time: 1.5 h

Procedure:
To a suspension of 2-chloro-5-nitropyrimidin-4-yl thiocyanate (2.73 g, 12.6 mmol) and sodium hydrogen carbonate (2.76 g, 32.9 mmol) in tetrahydrofuran (80 mL) was added a solution of tert-butyl [2-fluoro-5-(methylamino)phenyl]carbamate (2.63 g, 11.0 mmol) produced above in tetrahydrofuran (20 mL), and the mixture was stirred for 1.5 hr. To the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate (100 mL, 30 mL). The combined organic layer was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl {2-fluoro-5-[methyl(5-nitro-4-thiocyanatopyrimidin-2-yl)amino]phenyl}carbamate as a yellow amorphous solid. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1.[CH3:29][O:30][C:31]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:32]=1[C:33](O)=[O:34]>>[CH3:29][O:30][C:31]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:32]=1[C:33]([N:23]1[CH2:24][CH2:25][CH:20]([N:18]2[C:17](=[O:26])[C:16]([CH3:28])([CH3:27])[C:15]([C:7]3[C:8]4[CH2:9][C:10]([CH3:14])([CH3:13])[O:11][C:12]=4[C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)=[N:19]2)[CH2:21][CH2:22]1)=[O:34]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Reactant: COc1ccc(C(=O)O)c(OC)c1
Agent: Cl
Product: COc1ccc(C(=O)N2CCC(N3N=C(c4ccc(OC)c5c4CC(C)(C)O5)C(C)(C)C3=O)CC2)c(OC)c1

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B5) and 2,4-dimethoxybenzoic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11](Cl)=[O:12].[Br:16][C:17]1[CH:18]=[C:19]([N:24]2[CH2:28][CH2:27][CH:26]([NH:29]CC)[C:25]2=[O:32])[CH:20]=[CH:21][C:22]=1[F:23].O>ClCCl.C(OCC)C>[Br:16][C:17]1[CH:18]=[C:19]([N:24]2[CH2:28][CH2:27][CH:26]([NH:29][C:11](=[O:12])[CH2:10][C:9]([CH3:15])([CH3:14])[CH3:8])[C:25]2=[O:32])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: CCNC1CCN(c2ccc(F)c(Br)c2)C1=O
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)CC(=O)NC1CCN(c2ccc(F)c(Br)c2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.28 ml), followed by 3,3-dimethylbutanoyl chloride (0.46 ml) was added to a solution of 1(3-bromo-4-fluorophenyl)3-ethylaminopyrrolidin-2-one, (0.5 g, prepared as in Step 3 of Example 15) in dichloromethane. The mixture was stirred for three hours at room temperature, and then left to stand overnight. It was then poured into water and the mixture extracted with dichloromethane and the extract dried (magnesium sulphate) and evaporated to leave a yellow oil. This was dissolved in diethyl ether and the solution passed through a column of silica using ether as the eluent. Fractions of 25 ml were collected. Fractions 3-8 were combined and evaporated to give the title compound as a clear oil. The NMR, IR, and mass spectra of the product were consistent with the structure assigned.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]3[CH2:13][N:14]([CH3:16])[CH2:15][C@H:9]23)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>O.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].C1(C)C=CC=CC=1>[CH3:16][N:14]1[CH2:13][C@@H:10]2[C@@H:9]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[CH:3][CH:4]=3)[CH2:12][CH2:11]2)[CH2:15]1
Reactant: CN1C[C@H]2CCN(c3ccc(Br)cc3)[C@H]2C1
Reactant: C1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CN1C[C@H]2CCN(c3ccc(N4CCNCC4)cc3)[C@H]2C1
Temperature: 140 °C

Procedure:
The product of Example 72B (200 mg, 0.71 mmole), piperazine (200 mg, 2.33 mmole), tris(dibenzylideneacetone)dipalladium (20 mg, 0.022 mmole), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (28 mg, 0.045 mmole), sodium tert-butoxide (140 mg, 1.46 mmole) and 7 ml of toluene were mixed under N2 in a Emrys process vial. The vial was sealed heated in the microwave for 15 minutes at 140° C. using the Emrys Creator. The mixture was diluted with Water and extracted with dichloromethane (4×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product which was purified by column chromatography (10% methanol and 1% ammonium hydroxide in dichloromethane) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 6.84-6.94 (m, 2H) 6.53-6.60 (m, 2H) 4.00-4.07 (m, 1H) 3.44-3.51 (m, 1H) 3.11-3.20 (m, 1H) 2.99-3.09 (m, 9H) 2.88-2.96 (m, 1H) 2.68 (dd, J=9.66, 2.54 Hz, 1H) 2.48-2.59 (m, 2H) 2.31 (s, 3H) 2.09-2.19 (m, 1H) 1.89 (m, 1H). MS: (M+H)+=287.
Reaction SMILES: O[C:2]1([CH2:13][NH:14][CH:15]=O)[CH2:8][O:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[ClH:25].Cl.OC1(CNC)COC2C=CC=CC=2OC1>C(O)C.O.CCOCC>[ClH:25].[CH3:15][NH:14][CH2:13][CH:2]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH2:3]1
Reactant: O=CNCC1(O)COc2ccccc2OC1
Agent: CNCC1(O)COc2ccccc2OC1
Agent: Cl
Agent: [Al+3]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CNCC1COc2ccccc2OC1

Procedure:
3-hydroxy-3-formamidomethyl-3,4-dihydro-2H-1,5-benzodioxepin (5.8 g.) in 200 ml. anhydrous ether is added to lithium aluminum hydride (2.0 g.) in 40 ml. of anhydrous ether dropwise in one hour. The mixture then is refluxed for 2 hours and the excess lithium aluminum hydride then decomposed with water (5.0 ml.) followed by 10% sodium hydroxide (3.6 ml.) followed by 6.0 ml. of water. The white solid formed is filtered and the filtrate dried over magnesium sulfate then over calcium sulfate. It is stripped affording 3.8 g. of oil. The oil is acidified with 11N hydrochloric acid in ethanol to give 3.7 g. of 3-hydroxy-3-methylaminomethyl-3,4-dihydro-2H-1,5-benzodioxepin hydrochloride, m.p. 189°-205°C. Following several recrystallizations from ethanol, the product melts at 217-219°C.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:24][CH3:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])C1C=CC=CC=1.Br.[OH-].[Na+]>CC(O)=O.O>[CH2:24]([N:14]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[CH2:13][CH2:12][CH2:11][NH2:10])[CH3:25]
Reactant: CCN(CCCNC(=O)OCc1ccccc1)Cc1ccccc1OC
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCN(CCCN)Cc1ccccc1OC
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a solution of {3-[ethyl-(2-methoxy-benzyl)-amino]-propyl}-carbamic benzyl ester acid (1.4 g; 3.9 mmol) in 15 ml of glacial CH3COOH, 3.5 ml of a 33% solution of HBr in CH3COOH was added cautiously. It was left in agitation for 2 h, then the hydrobromate was precipitated with 100 ml of diethyl ether. The white solid formed was solubilised in H2O, basified with NaOH 2N and extracted with CHCl3 (5×20 ml). The anhydrified organic phase was evaporated in a vacuum to give 0.87 g of the compound XI as pure transparent oil on TLC (eluant CHCl3/MeOH/NH4OH 9.0:1.0:0.1); quantity yield; 1H NMR (free base; CDCl3) δ: 1.07 (t, 3H), 1.50 (s enlarged, 2H exchangeable with D2O), 1.57-1.71 (m, 2H), 2.55 (q, 4H), 2.73 (t, 2H), 3.60 (s, 2H), 3.84 (s, 3H), 6.83-6.99 (m, 2H), 7.19-7.44 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[H-].[Na+].Cl[CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1.C(#N)C.O>C1COCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:23][C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Reactant: ClCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cccs1
Temperature: 68 °C

Procedure:
To a room temperature suspension of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (330.0 mg, 1.00 mmol)) and NaH (48.0 mg, 2.0 mmol) in THF (3.0 mL) was added 2-(chloromethyl)thiophene (461 mg, 3.97 mmol). The resulting suspension was stirred and heated to 68° C. for 12 hours until complete consumption of starting material by LCMS analysis. The reaction mixture was then diluted with ethyl acetate (400 mL), water washed (3×200 mL). The resulting organic extract was separated, Na2SO4 dried, and concentrated. The resulting dark residue was subjected to SiO2 chromatography with ethyl acetate/hexanes (4:6) to furnish a solid. 1H NMR (400 MHz, d4-MeOH) δ 7.58 (app q, J=8.2 Hz, 1H), 7.30 (app dd, J=5.1, 1.2 Hz, 1H), 7.05 (d, J=2.6 Hz, 1H), 7.01 (app t, J=8.1 Hz, 2H), 6.93 (dd, J=5.1, 3.4 Hz, 1H), 6.43 (s, 1H), 5.49 (s, 2H), 5.25 (s, 2H), 2.51 (s, 3H); LC/MS C-18 column, tr=2.74 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 426 (M+H). ES-HRMS m/z 425.9936 (M+H calcd for C18H15BrF2NO2S requires 425.9969).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>CN(C=O)C.C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:24][C:23]2[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a solution of 4-(tert-butoxycarbonyl)-2-piperazinone (600 mg) in DMF (9 ml) was added sodium hydride in oil (120 mg), and the mixture was stirred at room temperature for 1 hour. To the mixture was added dropwise a solution of 4-nitrobenzyl bromide (648 mg) in THF (5 ml) at ° C., and the mixture was stirred for 30 minutes. The reaction solution was diluted with water, extracted with ethyl acetate, washed with water and brine, dried and concentrated, and the residue was crystallized from diisopropylether to give colorless crystals of 4-(tert-butoxycarbonyl)-1-(4-nitrobenzyl)-2-piperazinone (755 mg).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)=[C:12]([C:28]([F:31])([F:30])[F:29])[CH:11]=1)(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:27][N:26]1[C:22]([C@H:18]2[CH2:19][CH2:20][CH2:21][C@@H:17]2[O:16][C:13]2[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)(=[O:8])=[O:9])=[CH:11][C:12]=2[C:28]([F:31])([F:29])[F:30])=[CH:23][CH:24]=[N:25]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCC[C@@H]3c3ccnn3C)c(C(F)(F)F)c2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)cc1C(F)(F)F
Yield: 53.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)-3-(trifluoromethyl)benzenesulfonamide (123 mg, 0.199 mmol) prepared in Example 21b, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (50.0 mg, 54%) as a colorless solid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@H:2]1[CH2:11][C:12]([CH:14]1[S:18][CH2:17][NH:16][C@@H:15]1[C:19]([OH:21])=O)=[O:13].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@H:2]1[CH2:11][C:12]([CH:14]1[S:18][CH2:17][NH:16][C@@H:15]1[C:19]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])=[O:13]
Reactant: C1CCNC1
Reactant: O=C(C[C@@H]1CCc2ccccc2C1)C1SCN[C@@H]1C(=O)O
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: O=C(C[C@@H]1CCc2ccccc2C1)C1SCN[C@@H]1C(=O)N1CCCC1
Yield: 31 %

Procedure:
Colorless crystals of 1-{3-[(R)-(+)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl]-L-thioprolyl}pyrrolidine were prepared in the same manner as in Example 1, except that 3-[(R)-(+)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl]-L-thioproline prepared in Reference Example 34 and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 31%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9](Cl)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CN1C(=O)C[CH2:19][CH2:18]1.C([Mg]Br)C>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH2:18][CH3:19])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCCC1=O
Reactant: Cc1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CCc1cc(C(=O)OC(C)(C)C)cc(C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a red solution of 2-chloro-6-methyl-isonicotinic acid tert.-butyl ester (2.95 g, 13.0 mmol), Fe(acac)3 (512 mg, 1.45 mmol) and NMP (1.58 g, 16.0 mmol) in THF (400 mL), a solution of ethylmagnesium bromide (1.81 g, 13.6 mmol) in THF is slowly added at −77° C. The brown solution turns green-grey. The suspension is warmed to rt, stirred for 30 min before the yellow solution is again cooled to −70° C. and another portion of the Grignard reagent (1.38 g, 10.4 mmol) is added. The reaction mixture is warmed to rt, stirred for 16 h and then carefully quenched with 1 N aq. HCl (100 mL) and diluted with diethyl ether. The org. layer is separated and the aq. phase is extracted with diethyl ether. The combined org. extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by MPLC on silica gel to give 2-ethyl-6-methyl-isonicotinic acid tert.-butyl ester as a yellow oil which is dissolved in 4 N HCl in dioxane (50 mL). The solution is stirred at 50° C. for 16 h before the solvent is evaporated to give 2-ethyl-6-methylisonicotinic acid hydrochloride as a beige powder; LC-MS: tR=0.28 min; [M+1]+=166.25; 1H NMR (CDCl3): δ 8.19 (s, 2H), 3.12 (q; J=7.6 Hz, 2H), 2.84 (s, 3H), 1.43 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH2:24][CH2:25][CH2:26][CH2:27][F:28])[C:7]([CH2:9][N:10]3[C:14]4[CH:15]=[N:16][CH:17]=[CH:18][C:13]=4[N:12]([CH2:19][C:20](O)=[O:21])[C:11]3=[O:23])=[N:8][C:4]=2[CH:3]=1.C([N:34]([CH:37]([CH3:39])[CH3:38])CC)(C)C.C1(N)CC1.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH2:24][CH2:25][CH2:26][CH2:27][F:28])[C:7]([CH2:9][N:10]3[C:14]4[CH:15]=[N:16][CH:17]=[CH:18][C:13]=4[N:12]([CH2:19][C:20]([NH:34][CH:37]4[CH2:39][CH2:38]4)=[O:21])[C:11]3=[O:23])=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(O)Cn1c(=O)n(Cc2nc3cc(Cl)ccc3n2CCCCF)c2cnccc21
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1c(=O)n(Cc2nc3cc(Cl)ccc3n2CCCCF)c2cnccc21)NC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
In a 100 ml dry flask, (3-{[5-chloro-1-(4-fluorobutyl)-1H-benzimidazol-2-yl]methyl}-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)acetic acid (P67, 300 mg, 0.69 mmol), diisopropylethylamine (0.29 mL, 2.08 mmol, 3 eq.), cyclopropylamine (60 μL, 0.83 mmol, 1.2 eq.) and 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate Methanaminium (HATU, 316.9 mg, 0.83 mmol, 1.2 eq.) were dissolved in DMF (50 mL). The solution was placed under N2 atmosphere and stirred at room temperature during 1 hour. The reaction mixture was diluted with water (20 ml) and extracted with dichloromethane (50 mL). The organic layer was dried with MgSO4 and evaporated. The residue was further crystallized in diisopropylether/acetonirile. The solid was filtered off and dried into the oven for 16 hours which gave 2-(3-{[5-chloro-1-(4-fluorobutyl)-1H-benzimidazol-2-yl]methyl}-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)-N-cyclopropylacetamide (P68, 86 mg, 26%) as a white solid; LCMS m/z=471 (M+H)+
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].[H-].[Na+].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>C1COCC1>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][N:15]=[C:14]2[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: O=C1Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2ncnc(C3C(=O)Nc4ccccc43)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12 %

Procedure:
A solution of oxindole (266 mg, 2.0 mmol) in THF (2 ml) was added dropwise under nitrogen to a stirred suspension of sodium hydride (80 mg, of a 60% dispersion in mineral oil, 2.0 mmol) in THF (1 ml). After stirring the resulting mixture for 15 minutes at ambient temperature, a solution of 4-chloro-6,7-dimethoxyquinazoline (449 mg, 2.0 mmol), (prepared as described for the starting material in Example 1), in THF (20 ml) was added. The mixture was stirred at ambient temperature for 2 hours, quenched with water and the volatiles removed by evaporation. The resulting solid was purified by flash chromatography eluting with methylene chloride/methanol (19/1). The purified product was triturated with methanol, collected by filtration, washed with ether and dried under vacuum to give 6,7-dimethoxy-4-(oxindol-3-yl)quinazoline (77 mg, 12%).