Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH3:12])[NH:7][C:6]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][CH2:30]Cl>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:11][CH3:12])[N:7]([CH2:28][O:29][CH3:30])[C:6]=2[CH:21]=1
Reactant: COCCl
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(Br)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(Br)cc2n1COC
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.9 %

Procedure:
To a solution of (S)-tert-butyl (1-(6-bromo-1H-benzo[d]imidazol-2-yl)propyl)carbamate (Preparation 18, 0.97 g, 2.7 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (1.35 g, 9.77 mmol) and chloromethyl methyl ether (0.40 mL, 5.3 mmol), and the reaction was stirred at room temperature for 16 hours. The reaction was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-100% ethyl acetate/hexanes gradient to afford the title compound (580 mg, 53%) as a white solid.
Reaction SMILES: C(O[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]([OH:23])=[C:8]([C:24]([O:26][CH3:27])=[O:25])[N:7]=1)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>[Pd].C(OCC)(=O)C>[OH:23][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=2)[C:6]([CH3:5])=[N:7][C:8]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1nc(COC(C)=O)c2ccc(Oc3ccccc3)cc2c1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C)c2ccc(Oc3ccccc3)cc2c1O
Temperature: 60 °C
Reaction time: 7 h

Procedure:
A glass lined Parr pressure reactor vessel equipped with a 4-blade impeller can be charged with 2c, Pd/C (about 0.4 to 0.5 molar equivalents), anhydrous Na2CO3 (about 0.5 molar equivalents), and ethyl acetate. The flask can then be vacuum-purged with nitrogen (3×) and vacuum-purged with hydrogen (3×). The flask can then be pressurized with hydrogen to set point 60 psi and stirred at 60° C. for 6-8 hrs until completion of reaction (2c <0.5%). The flask can then be cooled to 20-25° C., the pressure released to ambient, the head space purged with nitrogen three times and filtered through glass microfiber filter paper. The filtrate can be concentrated and precipitated from cold methanol and dried under vacuum at 50±5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])([F:32])[F:31])=[CH:26][CH:25]=1>>[F:32][C:30]([P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])([F:31])[C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11](=[O:12])[NH:13][CH3:14])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=2)=[CH:25][CH:26]=1
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(N)cc1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)cc1
Yield: 6 %

Procedure:
The title product was prepared according to the procedure for Example 102 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 104A, 40.0 mg, 0.12 mmol) and diethyl [(4-aminophenyl)(difluoro)methyl]-phosphonate (Compound 188A, 40.5 mg, 0.15 mmol). The crude product was purified by silica gel chromatography (5% 7 N NH3 in MeOH in DCM) to afford the desired product as a white solid (4.1 mg, yield: 6%). 1H NMR (CD3OD, 400 MHz): δ=1.32 (t, J=7.2 Hz, 6 H), 2.90 (s, 3 H), 4.14-4.25 (m, 4 H), 7.22 (t, J=8.4 Hz, 1 H), 7.45 (d, J=8.4 Hz, 2 H), 7.51 (dt, J=1.2, 7.2 Hz, 1 H), 7.66 (dd, J=1.2, 7.6 Hz, 1 H), 7.79 (d, J=8.8 Hz, 2), 8.39 (s, 1 H), 8.47 (d, J=8.4 Hz, 1 H). MS (ES+): m/z 574.12 [MH+]. HPLC: tR=4.13 min (OpenLynx, polar—5 min).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:21]=[CH:20][C:11]([CH:12]=[C:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[O:18]=[C:16]1[NH:15][C:14](=[O:19])[C:13](=[CH:12][C:11]2[CH:20]=[CH:21][C:8]([N:3]3[CH2:4][CH2:5][CH:6]([NH:22][CH2:23][CH:24]([C:26]4[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=4)[OH:25])[CH2:7][CH2:2]3)=[CH:9][CH:10]=2)[S:17]1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Reactant: O=C1NC(=O)C(=Cc2ccc(N3CCCCC3=O)cc2)S1
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(C=C4SC(=O)NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidine-1-yl)-benzylidene]-thiazolidine-2,4-dione (which was obtained in Example 36) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 73 as a pale yellowish solid; mp >200° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.45-1.60 (m, 2H), 1.90-2.05 (m, 2H), 2.70-3.50 (m, 5H), 2.94 (s, 3H), 3.88 (brd, J=9.9 Hz, 2H), 4.67 (dd, J=7.2, 2.1 Hz, 1H), 6.87 (d, J=6.3 Hz, 1H), 7.00 (d, J=6.8 Hz, 2H), 7.06 (dd, J=6.3, 1.5 Hz, 1H), 7.23 (d, J=1.5 Hz, 1H), 7.33 (s, 1H), 7.38 (d, J=6.8 Hz, 2H); MS (ES) m/z: 533.0 (MH+); HRMS Calcd. for C24H29N4O6S2 (MH+): 533.1529. Found: 533.1544.
Reaction SMILES: [C:1]12[C:14](=[O:15])[O:13][C:11](=O)[C:2]=1[CH2:3][CH2:4][C:5]1[C:10]2=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:16]([CH2:18][NH2:19])[OH:17]>C(O)(=O)C>[OH:17][CH2:16][CH2:18][N:19]1[C:11](=[O:13])[C:2]2[CH2:3][CH2:4][C:5]3[C:10]([C:1]=2[C:14]1=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: O=C1OC(=O)C2=C1CCc1ccccc12
Reactant: NCCO
Solvent: CC(=O)O
Product: O=C1C2=C(C(=O)N1CCO)c1ccccc1CC2

Procedure:
A solution of 70 g (0.35 mol) of 3,4-dihydronaphthalene-1,2-dicarboxylic acid anhydride [prepared according to Org. Synthesis, Col., Vol. 2, 194 (1943)] and 23.5 g (0.385 mol) of ethanolamine in 1.7 liters of glacial acetic acid is kept under reflux for 24 hours. The glacial acetic acid is then removed by distillation, the residue is dissolved in 2 liters of absolute ethanol, 50 g of an ion exchanger ("Dowex 50 W" from Fluka AG) are added and the suspension is kept under reflux for 24 hours. The ion exchanger is then filtered off, the ethanol is distilled off and the residue is recrystallised from diethyl ether/ethanol. This yields 61.8 g (73% of theory) of N-(2'-hydroxyethyl)-3,4-dihydronaphthalene-1,2-dicarboximide; melting point 120.5°-121° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.OS(O)(=O)=O.[CH3:17]O>C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Br)cc1C

Procedure:
To a solution of 4-bromo-2-methyl benzoic acid (25 g, 0.116 mol) in methanol (680 mL) was added H2SO4 (12.15 mL) and this reaction mixture was refluxed for about 16 h. The reaction mixture was cooled and the solvent was evaporated to obtain a residue, which was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulphate and filtered. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [NH:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[SH:4](=[O:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:3]1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](Cl)=[O:33])=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[Cl:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32]([N:1]=[C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[SH:4](=[O:17])([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:3]2)=[O:33])=[CH:28][CH:27]=1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: N=C1N[SH](=O)(c2ccccc2)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(COc1ccc(Cl)cc1)N=C1N[SH](=O)(c2ccccc2)c2ccccc21

Procedure:
24 g. 3-imino-1-phenyl-3H-1,2-benzisothiazole-1-oxide, 13.2 g. triethylamine and 21 g. 4-chlorophenoxyacetyl chloride are heated under reflux for 1 hour in 1 liter chloroform. After working up the reaction mixture in the usual manner, there is obtained 3-(4-chlorophenoxyacetylimino)-1-phenyl-3H-1,2-benzisothiazole-1-oxide which, after recrystallisation from acetonitrile, is obtained in the form of colourless, felted needles melting at 196°C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([N:7]([CH2:10][CH3:11])CC)=[O:6].[Li]CCCC.C(C1[CH:39]=[CH:38][C:26]([C:27]([NH:29][CH2:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:28])=[CH:25][CH:24]=1)#N>C1COCC1>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:4]2[C:3]=1[CH:15]=[C:10]([C:11]1[CH:39]=[CH:38][C:26]([C:27]([NH:29][CH2:30][CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[O:28])=[CH:25][CH:24]=1)[NH:7][C:5]2=[O:6]
Reactant: CCN(CC)C(=O)c1cccc(Cl)c1C
Reactant: CN1CCC(CNC(=O)c2ccc(C#N)cc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(CNC(=O)c2ccc(-c3cc4c(Cl)cccc4c(=O)[nH]3)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
3-Chloro-N,N-diethyl-2-methyl-benzamide (150 mg, 0.66 mmol) was dissolved in anhydrous THF (2 mL) under N2 and cooled to −78° C. n-BuLi (2.5M in n-hexanes, 558 μL, 1.39 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 30 minutes. 4-Cyano-N-(1-methyl-piperidin-4-ylmethyl)-benzamide (180 mg, 0.66 mmol) in anhydrous THF (2 mL) was added dropwise to the reaction mixture and stirred at −78° C. continued for 1 h. The reaction mixture was poured into ice/water, allowed to warm to RT and extracted with CH2Cl2 (×3) and the organic phase dried (MgSO4). The solution was filtered and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC-MS to afford 4-(5-chloro-1-oxo-1,2-dihydro-isoquinolin-3-yl)-N-(1-methyl-piperidin-4-ylmethyl)-benzamide as a white solid (37 mg, 13%).
Reaction SMILES: C(OC[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:20][N:21]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=3)[CH2:22][C:23]#[CH:24])[CH:16]=2)[N:11]=[CH:10]1)(=O)C(C)(C)C.[N+:34]([C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH2:40][NH2:41])([O-:36])=[O:35]>>[O:19]=[C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:20][N:21]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([NH:41][CH2:40][C:39]4[CH:42]=[CH:43][CH:44]=[C:37]([N+:34]([O-:36])=[O:35])[CH:38]=4)=[O:31])=[CH:27][CH:26]=3)[CH2:22][C:23]#[CH:24])[CH:16]=2)[N:11]=[CH:10][NH:9]1
Reactant: C#CCN(Cc1ccc2ncn(COC(=O)C(C)(C)C)c(=O)c2c1)c1ccc(C(=O)O)cc1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: C#CCN(Cc1ccc2nc[nH]c(=O)c2c1)c1ccc(C(=O)NCc2cccc([N+](=O)[O-])c2)cc1
Yield: 56 %

Procedure:
Using the procedure described in Example 10, p-[N-(3,4-dihydro-3-pivaloyloxymethyl-4-oxoquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzoic acid was reacted with 3-nitrobenzylamine to give p-[N-(3,4-dihydro-4-oxoquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]-N-(3-nitrobenzyl)benzamide (containing 1 equivalent of water, 56%), m.p. 197°-199° C.
Reaction SMILES: [C:1]([CH2:9][C:10]([CH3:12])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Br[CH2:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=1)[O:23][Si:24]([CH3:30])([CH3:29])[C:25]([CH3:28])([CH3:27])[CH3:26].[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH3:30][Si:24]([CH3:29])([C:25]([CH3:27])([CH3:26])[CH3:28])[O:23][C:22]1[CH:21]=[C:20]([CH2:19][CH2:12][C:10](=[O:11])[CH2:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CBr)c1
Reactant: CC(=O)CC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CCC(=O)CC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
Sodium hydride (2.13 g of a 50% dispersion in mineral oil, 44 mmol) was washed twice with hexanes, covered with dry THF (150 mL) and 1-benzoylacetone (6.00 g, 37 mmol) added portionwise. The mixture was stirred at room temperature under an atmosphere of nitrogen for 10 minutes to give a slurry which was cooled to -20° C. n-Butyllithium (2.60 g, 40 mmol) in hexane (16.3 mL) was added dropwise to provide a solution which was stirred for 20 minutes prior to the dropwise addition of [3-(bromomethyl)phenoxy]dimethyl(1,1-dimethylethyl)silane (11.17 g, 37 mmol). After 15 minutes, the mixture was poured onto saturated ammonium chloride solution and extracted with CH2Cl2. The combined extracts were dried over sodium sulfate, concentrated in vacuo and the residual oil chromatographed on a column of silica gel. Elution with a mixture of hexanes and diethyl ether (9:1) gave 5-[3-[dimethyl(1,1-dimethylethyl)siloxy]phenyl]-1-phenyl- 1,3-pentanedione (9.00 g, 63%).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:36])=[C:7]2[C:12](=[C:13]([C:15]3[C:16]([CH3:21])=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10](=[O:29])[C:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:8]2)=[O:4].[NH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].C[O-].[Na+]>>[CH2:22]([N:11]1[C:12]2[C:7](=[C:6]([OH:36])[C:5]([C:3]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:4])=[N:14][C:13]=2[C:15]2[C:16]([CH3:21])=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:10]1=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2C)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: Cc1ncccc1-c1nc(C(=O)NCCC(=O)O)c(O)c2cc(-c3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 63.4 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-8-(2-methyl-pyridin-3-yl)-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (28 mg, 0.059 mmol), β-alanine (628 mg, 7.0 mmol) and NaOMe solution (10.5 mL, 5.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 20 mg of the title compound. MS: (+) m/z 535.51 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH2:23][CH2:22][C@H:21]([NH:24][C:25]([C:27]4[NH:28][C:29]([CH3:34])=[C:30]([Cl:33])[C:31]=4[Cl:32])=[O:26])[C@H:20]([O:35][CH3:36])[CH2:19]3)[S:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:6][CH:7]=1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O>[Cl:32][C:31]1[C:30]([Cl:33])=[C:29]([CH3:34])[NH:28][C:27]=1[C:25]([NH:24][C@H:21]1[CH2:22][CH2:23][N:18]([C:10]2[S:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([C:5]3[CH:4]=[N:3][C:2]([N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)=[CH:7][N:6]=3)[N:9]=2)[CH2:19][C@H:20]1[O:35][CH3:36])=[O:26]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1-c1cnc(Cl)cn1
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1-c1cnc(N2CCN(C)CC2)cn1
Temperature: 85 °C
Yield: 82.8 %

Procedure:
Ethyl 4-(5-chloropyrazin-2-yl)-2-[(3R,4S)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate (Example 59, 100 mg, 0.1748 mM) was added to a solution of 1-methylpiperazine (87.93 mg, 0.874 mM) and N,N-diisopropylethylamine (67.12 mg, 0.5244 mM) in N-methyl 2-pyrrolidinone (1.5 mL) and the resulting reaction mixture was stirred for over night at 80-90° C. After completion of the reaction, the reaction mixture was poured into water (40 mL), and the obtained solid was filtered and dried to afford ethyl 2-[(3R,4S)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-[5-(4-methylpiperazin-1-yl)pyrazin-2-yl]-1,3-thiazole-5-carboxylate 92 mg (82%) as off-white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[H-].[Na+].O=[CH:13][CH2:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[C:24]([O:26][CH3:27])=[O:25])[CH:17]=[CH:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[C@H:2]([NH:1][CH2:13][CH2:14][N:15]1[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[C:24]([O:26][CH3:27])=[O:25])[CH:17]=[CH:16]1)[CH2:3]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: COC(=O)c1cccc2ccn(CC=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cccc2ccn(CCN[C@@H]3CN4CCC3CC4)c12
Reaction time: 1 h
Yield: 72 %

Procedure:
To a stirred suspension of (S)-(−)-3-aminoquinuclidine (1.4 g, 7.0 mmol) in methylene chloride (50 mL) was added sodium hydride (562 mg, 14.0 mmol) in portions and the mixture was stirred for 1 h. Acetic acid (0.6 mL) was added dropwise, followed by methyl 1-(2-oxoethyl)-1H-indole-7-carboxylate (1.3 g, 5.9 mmol) from Step B above and the reaction was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (4.2 g, 19.6 mmol) was then added in one portion and stirring was continued overnight at room temperature. The solvent was removed under reduced pressure and the crude material was purified by column chromatography (silica gel, 90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) to afford (S)-methyl 1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indole-7-carboxylate (1.39 g, 66%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 7.79 (dd, J=4.5, 1.0 Hz, 1H), 7.69 (dd, J=4.3 Hz 1H), 7.18 (d, J=1.8 Hz, 1H), 7.10 (t, J=7.5 Hz, 1H), 6.57 (d, J=1.8 Hz, 1H), 4.51 (t, J=6.5 Hz, 2H), 3.96 (s, 3H), 3.46 (s, 1H), 3.07-3.03 (m, 1H), 2.90-2.85 (m, 1H), 2.82-2.70 (m, 5H), 2.63-2.60 (m, 1H), 2.29-2.25 (m, 1H), 1.68-1.59 (m, 3H), 1.40-1.39 (m, 1H), 1.25-1.22 (m, 1H); MS (ESI+) m/z 328 (M+H).
Reaction SMILES: C1(C[O:8][C:9]2[C:14]([O:15]CC3C=CC=CC=3)=[CH:13][N:12]=[C:11]([C:23]([NH:25][N:26]3[CH2:31][CH2:30][N:29]([S:32]([NH:35][C:36]([N:38]4[CH2:41][C@H:40]([NH:42]C(=O)OCC5C=CC=CC=5)[C:39]4=[O:53])=[O:37])(=[O:34])=[O:33])[C:28](=[O:54])[C:27]3=[O:55])=[O:24])[CH:10]=2)C=CC=CC=1>CN(C)C=O.[Pd]>[NH2:42][C@H:40]1[CH2:41][N:38]([C:36]([NH:35][S:32]([N:29]2[CH2:30][CH2:31][N:26]([NH:25][C:23]([C:11]3[NH:12][CH:13]=[C:14]([OH:15])[C:9](=[O:8])[CH:10]=3)=[O:24])[C:27](=[O:55])[C:28]2=[O:54])(=[O:33])=[O:34])=[O:37])[C:39]1=[O:53]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)N2CCN(NC(=O)c3cc(OCc4ccccc4)c(OCc4ccccc4)cn3)C(=O)C2=O)C1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: N[C@H]1CN(C(=O)NS(=O)(=O)N2CCN(NC(=O)c3cc(=O)c(O)c[nH]3)C(=O)C2=O)C1=O
Reaction time: 0.75 h

Procedure:
To a solution of (S)-[1-[[[[4-[[[4,5-bis(phenylmethoxy)-2-pyridinyl]carbonyl]amino]-2,3-dioxo-1-piperazinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (1.54 g, 2 mmol) in 30 ml of dimethylformamide was added 0.77 g of palladium on charcoal, and the mixture was hydrogenolyzed for 45 minutes. The catalyst was removed by filtration over Hyflo and the resulting solution was used for the next step without isolation of the title compound.
Reaction SMILES: [C:1]([CH2:4][C:5]1[O:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1)([OH:3])=[O:2].[CH3:13]O>>[CH3:13][O:2][C:1]([CH2:4][C:5]1[O:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1)=[O:3]
Reactant: CO
Reactant: O=C(O)Cc1ccc(C(=O)O)o1
Product: COC(=O)Cc1ccc(C(=O)O)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Intermediate 22 (220 mg, 1.29 mmol) in methanol (8 mL) is added Amberlyst-15 resin (50 mg) and the mixture is stirred at room temperature for 18 hrs. The resin is filtered and the solvent is removed under reduced pressure to give the product which is used as is in subsequent reactions. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.75 (s, 3H), 3.82 (s, 2H), 6.45 (d, J=3.54 Hz, 1H), 7.29 (d, J=3.54 Hz, 1H), 10.17 (s, broad, 1H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=O.Cl>ClCCl.[H-].C([Al+]CC(C)C)C(C)C>[CH2:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][CH2:9][CH:5]1[CH:3]=[O:2])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: O=CC1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
To a solution of 12.00 g of (±)-N-benzyloxycarbonyl-2-pyrrolidine carboxylic acid methyl ester in 50 ml of dry dichloromethane, 50 ml of diisobutylaluminum hydride (1M toluene solution) was added dropwise under an argon atmosphere at −70° C. or lower, followed by stirring for 2 hours. To the reaction solution, 230 ml of 1N hydrochloric acid was added dropwise, and then the mixture was heated to room temperature and extracted with diethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4.72 g of the desired compound as a colorless oily substance.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([OH:16])=O)[O:11][N:10]=2)=[C:5]([F:17])[CH:4]=1)#[N:2].[CH:18]1([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[O:32][N:31]=[C:30]([CH:33]([CH3:35])[CH3:34])[N:29]=3)[CH2:24][CH2:23]2)[CH2:20][CH2:19]1>>[CH:18]1([N:21]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[O:32][N:31]=[C:30]([CH:33]([CH3:35])[CH3:34])[N:29]=3)[CH2:24][CH2:23]2)[C:14]([C:12]2[O:11][N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[F:17])[CH:13]=2)=[O:16])[CH2:19][CH2:20]1
Reactant: N#Cc1ccc(-c2cc(C(=O)O)on2)c(F)c1
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Product: CC(C)c1noc(N2CCC(N(C(=O)c3cc(-c4ccc(C#N)cc4F)no3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from 3-(4-cyano-2-fluoro-phenyl)-isoxazole-5-carboxylic acid and cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine following a procedure analogous to that described in Example 18. LC (method 18): tR=1.23 min; Mass spectrum (ESI+): m/z=465 [M+H]+.