Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH3:32])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:34][O:35][CH2:36]CC(NN)=O>>[CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH2:32][CH2:34][O:35][CH3:36])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Reactant: COCCC(=O)NN
Product: COCCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 152), but using 3-methoxypropanehydrazide (compound 143.1) in place of acetohydrazide. m/z (ES+) 484 (M+H)+, 967 (2M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 11.50-11.33 (br s, 1H), 7.66-7.44 (m, 3H), 7.33-7.27 (m, 3H), 4.98 (d, 1H), 4.24-4.12 (m, 1H), 3.78 (t, 2H), 3.70 (d, 1H), 3.44 (s, 3H), 3.14-3.03 (m, 3H), 2.90-2.75 (m, 2H), 2.42 and 2.34 (2 singlets, amide rotamers, ArCH3, 3H), 2.17 (d, 2H), 2.08-1.88 (m, 3H), 1.84-1.51 (m, 5H).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:21]([O:23][CH3:24])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=1)=O)C1C=CC=CC=1>[Pd].C(O)C>[CH3:20][C:16]1[N:15]=[C:14]([CH2:13][C@@H:12]([C:21]([O:23][CH3:24])=[O:22])[NH2:11])[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@H](Cc1cccc(C)n1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@@H](N)Cc1cccc(C)n1
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of methyl N-(benzyloxycarbonyl)-3-(6-methylpyridin-2-yl)-L-alaninate (7.25 g, 22.1 mmol) [S. W. Jones, C. F. Palmer, J. M. Paul, P. D. Tiffin, Tetrahedron Lett. 1999, 40, 1211-1214] and 10 percent palladium on carbon (0.690 g) in ethanol (80 ml) is hydrogenated at RT and under atmospheric pressure for 1 h. The reaction mixture is passed through a syringe filter (Millipore, 0.45 μg, hydrophobic PTFE) which is washed with ethanol (2×10 ml). The residue is concentrated on a rotary evaporator (removal of solvent residues by entrainment with toluene, twice) and dried under high vacuum. The product is obtained as an oil (3.89 g, yield 91% of theory).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.CCN(CC)CC.[O:24](C(OC(C)(C)C)=O)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:28]([O:27][C:25]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:5][CH2:6]1)=[O:24])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a stirred solution of 300 mg (1.4 mmol) of 1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (commercially available) in 15 ml of CH2Cl2 were added 34 mg (0.28 mmol, 0.2 eq.) of DMAP, 190 μl (1.4 mmol, 1 eq.) of Et3N and 301 mg (1.4 mmol, 1 eq.) of (BOC)2O. After stirring at RT overnight the reaction mixture was poured on water and extracted with CH2Cl2. Column chromatography (SiO2, EtOAc/Hept. 1:1) afforded 360 mg (82%) of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C(O)(=O)C>[Fe].CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1

Procedure:
A mixture of tert-butyl 4-(4-nitrophenyl)piperazine-1-carboxylate (307 mg, 1 mmol), iron powder (196 mg, 3.5 mmol), acetic acid (0.4 mL, 7 mmol) and methanol (5 mL) is heated at 66 C until no nitro compound left. After it is dried it is treated with ethyl acetate and water, and filtered through a pad of celite. The ethyl acetate layer is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, and then dried to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:14]1([CH2:28][CH2:29][CH2:30][OH:31])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]1=[O:27])[C:11]([OH:13])=O)=[O:6].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1.Cl.[CH2:58]([O:65][NH2:66])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>O.CCOC(C)=O.C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:14]1([CH2:28][CH2:29][CH2:30][OH:31])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]1=[O:27])[C:11]([NH:66][O:65][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:13])=[O:6]
Reactant: NOCc1ccccc1
Reactant: O=C(NCCC(C(=O)O)C1(CCCO)CCN(CCc2ccccc2)C1=O)c1ccc(F)c(F)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCCC(C(=O)NOCc1ccccc1)C1(CCCO)CCN(CCc2ccccc2)C1=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A cold (0° C.) solution of α-[2-[(3,4-difluorobenzoyl)amino]ethyl]-3-(3-hydroxypropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetic acid (586 mg, 1.20 mmol) in 2:1 CH2Cl2 /DMF (7.5 mL) is treated with HOBT (195 mg, 1.44 mmol), EDC (276 mg, 1.44 mmol), and 4-methylmorpholine (158 μL, 1.44 mmol). The ice bath is removed, and after 1 hour, O-benzylhydroxylamine HCl (287 mg, 1.80 mmol) and a second portion of 4-methylmorpholine (198 μL, 1.80 mmol) are added. The solution is stirred overnight at room temperature under N2. The solution is diluted with H2O (25 mL) and extracted into CH2Cl2 (3×50 mL). The extracts are combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to provide an oil. The residual oil is reconstituted in EtOAc (50 mL) and washed with 1N HCl (10 mL), 1N NaOH (10 mL), H2O (10 mL), and brine (10 mL). The organic layer is dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 603 mg of a white foam. The material is purified by silica gel chromatography (25 g SG; EtOAc) to provide 433 mg (62%) of the title compound as a white, amorphous solid:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[O:11][CH:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][C:30]=1[CH3:38])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:1]([N:8]1[CH2:13][C:12]2([CH2:18][CH2:17][N:16]([C:33]([C:32]3[CH:36]=[CH:37][C:29]([O:28][CH:25]([CH3:26])[CH3:27])=[C:30]([CH3:38])[CH:31]=3)=[O:34])[CH2:15][CH2:14]2)[O:11][CH:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Reactant: c1ccc(CN2CC(c3ccccc3)OC3(CCNCC3)C2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(c2ccccc2)O3)ccc1OC(C)C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
A mixture of 4-benzyl-2-phenyl-1-oxa-4,9-diazaspiro[5.5]undecane (222 mg, 0.69 mmol), 4-isopropoxy-3-methyl-benzoic acid (140 mg, 0.72 mmol) and HATU (262 mg, 0.69 mmol) was stirred in a mixture of DCM (1 mL) and DMF (1 mL) for 5 minutes. Triethylamine (192 μL, 1.38 mmol) was added and the reaction mixture was stirred for 16 hours, then concentrated in vacuo, diluted with sat. aq. NaHCO3, extracted with ethyl acetate (3×2 mL), dried over MgSO4, filtered and concentrated in vacuo and purified by silica gel column chromatography using 0-60% EtOAc/DCM as eluent to give (10-benzyl-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone (343 mg, 100%) as a yellow oil. ESI-MS m/z calc. 406.5. Found 407.7 (M+1)+; Retention time: 1.13 minutes (3 min run).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]([NH:7][C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[N:11][N:12]=1)[CH3:6])C.[Li+].[OH-].Cl>C1COCC1.O.CCOC(C)=O>[F:27][C:21]1[CH:22]=[C:23]([I:26])[CH:24]=[CH:25][C:20]=1[NH:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[C:10]1[O:9][C:8]([NH:7][CH:5]([CH3:6])[C:4]([OH:28])=[O:3])=[N:12][N:11]=1
Reactant: CCOC(=O)C(C)Nc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(Nc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A mixture of 2-{5-[3-(2-Fluoro-4-iodo-phenylamino)-pyridin-4-yl]-[1,3,4]oxadiazol-2-ylamino}-propionic acid ethyl ester (45 mg, 0.09 mmol, 1.0 eq) and LiOH (5 mg, 0.18 mmol, 2 eq) in THF-H2O (1:1) (0.5 mL) was stirred at RT for 2 hr. The pH was adjusted to pH 5 with 1N HCl and the mixture was diluted with EtOAc, washed with brine, and dried over anhydrous MgSO4. Filtration and solvent removal resulted in a residue that was washed with ether to give rise to the desired product (41 mg). LC/MS (Method A) [5.04 min; 470(M+1)]
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH3:16][O:17][CH2:18][CH2:19][N:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[C:28]([NH2:31])[CH:29]=[CH:30][C:23]=2[CH2:22][CH2:21]1.Cl[C:33]1[N:38]=[C:37]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[S:46]([CH:49]([CH3:51])[CH3:50])(=[O:48])=[O:47])[C:36]([Cl:52])=[CH:35][N:34]=1.C(=O)([O-])[O-]>C(O)(C)C>[Cl:52][C:36]1[C:37]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[S:46]([CH:49]([CH3:51])[CH3:50])(=[O:48])=[O:47])=[N:38][C:33]([NH:31][C:28]2[CH:29]=[CH:30][C:23]3[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][O:17][CH3:16])[CH2:26][CH2:25][C:24]=3[CH:27]=2)=[N:34][CH:35]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)cc2CC1
Reaction time: 1 h
Yield: 62.6 %

Procedure:
10-Camphorsulfonic acid (49 mg, 0.21 mmol) was added to 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (44 mg, 0.20 mmol) and (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (66 mg, 0.19 mmol) in Isopropyl alcohol (2 mL). The mixture was irradiated in a CEM microwave (140° C., 30 min) MP-Carbonate (2.69 mmol/g loading; 0.16 g, 0.43 mmol) was added and the mixture stirred for 1 h, then filtered, washing with 2 mL iPrOH. Brine was added, but the only ppt was NaCl. The aq. layer was extracted with EtOAc, and combined with the iPrOH, dried and conc. in vacuo. The residue was taken up in DCM with a few drops of MeOH and chromatographed (ISCO, 2×12 g, 0-10% MeOH:DCM) to afford 5-Chloro-N*2*-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-N*4*-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine as a colorless oil (63 mg, 62%). LCMS 530 (M+H), 1H-NMR (CDCl3): 9.58 (s, 1H), 8.57 (d, 1H, J=8.4 Hz), 8.13 (s, 1H), 7.91 (d, 1H, J=7.9 Hz), 7.59 (dd, 1H, J=7.8, 8.1 Hz), 7.24 (m, 3H), 7.02 (d, 1H, J=7.9 Hz), 6.94 (s, 1H), 3.55 (m, 2H), 3.38 (s, 3H), 3.24 (sept, 1H, J=6.8 Hz), 2.88 (m, 4H), 2.73 (m, 6H), 1.31 (d, 6H, J=6.8 Hz).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.Cl.CN.C(Cl)CCl.C1C=CC2N(O)N=[N:28][C:26]=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH:28][CH3:26])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CNC(=O)c1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
To a mixture of 4,5-difluoro-2-nitrobenzoic acid (1.872 g, 9.22 mmol), methylamine hydrogen chloride (0.75 g, 1.2 eq), EDC (2.12 g, 1.2 eq), HOBt (1.5 g, 1.2 eq) in DMF (20 mL) was added DIEA (5.0 mL, 3.0 eq). The mixture was stirred at room temperature for 15 min. It was concentrated and the crude was dissolved in EtOAc. It was washed with a saturated NaHCO3. The solvent was removed and the crude was purified by silica gel chromatography (20%˜80% EtOAc/Hex) to obtain the desired product 4,5-difluoro-N-methyl-2-nitrobenzamide (1.33 g, isolated yield 67%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13][C:14]([OH:16])=O.[C:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13][C:14]([N:27]1[CH2:26][CH2:25][N:24]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:29][CH2:28]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cc1Br
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2ccc(-n3cnnn3)cc2Br)CC1

Procedure:
A solution of [2-bromo-4-(1H-tetrazol-1-yl)phenyl]acetic acid (500 mg, 1.77 mmol), Boc-piperazine (329 mg, 1.77 mmol), EDC (418 mg, 2.12 mmol), HOBt (286 mg, 2.12 mmol) and TEA (530 mg, 5.31 mmol) in 20 mL of DCM was stirred at room temperature overnight. The solvent was removed under reduce pressure and the crude was purified via prep-TLC to afford tert-butyl 4-{[2-bromo-4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazine-1-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:8][CH:9]=1
Reactant: CCOC(=O)c1cccc(-c2ccc([N+](=O)[O-])cn2)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cccc(-c2ccc(N)cn2)c1
Reaction time: 16 h
Yield: 96.9 %

Procedure:
To a solution of ethyl 3-(5-nitropyridin-2-yl)benzoate (8.0 g, 29.40 mmol) in ethanol (150 mL) was added 5% Pd/C (800 mg). The reaction mixture was stirred under H2 balloon pressure for 16 h. The reaction mixture was filtered and concentrated to give 6.9 g (97%, yield) of ethyl 3-(5-aminopyridin-2-yl)benzoate as a tan solid.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[NH:10]1[CH2:11][CH2:12][CH:7]([N:1]2[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]2)[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC=CCC2)CC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1=CCN(C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 4-(5,6-dihydropyridin-1 (2H)-yl)piperidine-1-carboxylate (800 mg, 3 mmol) was dissolved in dichloromethane (54 ml). To this was added trifluoroacetic acid (7.9 ml) and triethyl silane (1.2 ml). The mixture was stirred at room temperature for 3 h. Solvent was removed from the mixture en vacuo. The residue was dissolved in saturated sodium bicarbonate (50 ml) and stirred for 30 min. Sodium hydroxide (50 ml, 50% in water) was added to the solution which was then extracted with dichloromethane (3×100 ml). The organic extract was dried over sodium sulfate and the solvent evaporated to give 370 mg (74%) as a colorless oil. 1H-NMR (CDCl3, 400 MHz) δ 5.74-5.70 (m, 1H), 5.68-5.64 (m, 1H), 3.14-3.07 (m, 4H), 2.64-2.53 (m, 4H), 2.43-2.37 (m, 1H), 2.15 (m, 2H), 1.85-1.82 (m, 2H), 1.73 (s, 1H), 1.47-1.38 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([C:9](I)=[N:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[CH2:21]([Sn:25]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])Cl)[CH2:22][CH2:23][CH3:24]>C1COCC1>[C:1]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([Sn:25]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:21][CH2:22][CH2:23][CH3:24])=[N:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1nc(I)c2ccc(C(C)(C)C)cc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(C(C)(C)C)ccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-tert-butyl-3-iodo-1-methyl-1H-indazole (150 mg, 0.45 mmol) in THF (3 mL) at 0° C. was slowly added isopropylmagnesium chloride (2.0 M in THF, 0.27 mL, 0.54 mmol). The bright yellow heterogeneous reaction mixture was stirred at 0° C. for 1 h then tributylchlorostannane (0.15 mL, 0.54 mmol) was added dropwise. Stirring was continued at 0° C. for 20 min then at room temperature for 3 h. The reaction mixture was quenched with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated to afford 6-tert-butyl-1-methyl-3-tributylstannanyl-1H-indazole as a viscous yellow oil which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([NH:14][C:15]([C@@H:17]3[NH:21][C@@H:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C@:19]4([C:34]5[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=5)[NH:28][C:27]4=[O:36])[C@H:18]3[C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=3[F:44])=[O:16])=[CH:13][C:7]=2[CH:6]=1)=[O:4].Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:35][C:31]1[CH:30]=[C:29]2[NH:28][C:27](=[O:36])[C@:19]3([C@@H:18]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=4[F:44])[C@H:17]([C:15]([NH:14][C:12]4[CH:11]=[CH:10][C:8]5[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=5[CH:13]=4)=[O:16])[NH:21][C@H:20]3[CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:34]2=[CH:33][CH:32]=1
Reactant: COC(=O)c1cc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@@]4(C(=O)Nc5cc(Cl)ccc54)[C@H]3c3cccc(Cl)c3F)ccc2s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc3sc(C(=O)O)cc3c2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a solution of rac-5-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-benzo[b]thiophene-2-carboxylic acid methyl ester (42 mg, 0.065 mmol) in THF (3 mL) was added LiOH monohydrate (11 mg, 0.26 mmol) in water (2 mL) and the reaction mixture was allowed to stir at rt overnight. The mixture was then treated with 1N HCl to slightly acidic, diluted with ethyl acetate (80 mL), washed with water (2×15 mL), dried with Na2SO4 and concentrated to give rac-5-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-benzo[b]thiophene-2-carboxylic acid as a white solid (41 mg, 100%). MS (ES+) m/z [(M+H)+]: 640
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH3:20][O:21][C:22]1[CH:38]=[CH:37][C:25]([C:26]2[CH:27]=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:29]=[C:30]([NH2:32])[CH:31]=2)=[CH:24][CH:23]=1>CCCCCC.CCOC(C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:32][C:30]3[CH:31]=[C:26]([C:25]4[CH:37]=[CH:38][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[CH:27]=[C:28]([C:33]([F:34])([F:35])[F:36])[CH:29]=3)=[O:19])=[CH:14][CH:15]=2)[CH:2]=1
Reactant: COc1ccc(-c2cc(N)cc(C(F)(F)F)c2)cc1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3)cc(C(F)(F)F)c2)cc1

Procedure:
The title compound is prepared as described in Example 1 but using (4-imidazo[4,5-b]pyridin-3-yl-phenyl)acetic acid (Step 7.1) and 4′-methoxy-5-trifluoromethyl-biphen-3-ylamine. Title compound: ES-MS: 502.9 [M+H]+; tR=5.00 min (System 1); Rf=0.21 (Hexane/EtOAc, 1:4).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:18]([OH:20])=O)[N:15]([CH3:17])[CH:16]=2)=[O:10])=[CH:4][C:3]=1[F:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][NH2:53])[CH:47]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:21][C:3]1[CH:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:18]([NH:53][CH2:52][C:48]3[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=3)=[O:20])[N:15]([CH3:17])[CH:16]=2)=[O:10])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: NCc1cccnc1
Reactant: Cc1ccc(NC(=O)Nc2cn(C)c(C(=O)O)n2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)Nc2cn(C)c(C(=O)NCc3cccnc3)n2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
60 mg (0.2 mmol) of 4-({[(4-methyl-3-fluorophenyl)amino]carbonyl}amino)-1-methyl-1H-imidazole-2-carboxylic acid (Example 18A) are dissolved in 4 ml of DMF and, after addition of 150 mg (0.39 mmol) of HATU and 36 mg (0.3 mmol) of DMAP, stirred at room temperature for 15 minutes. 43 mg (0.39 mmol) of (pyridin-3-ylmethyl)amine are added dropwise to this solution, and the mixture is stirred overnight. The reaction mixture is purified by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.[CH3:18][O-:19].[Na+]>CO>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:19][CH3:18])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: O=[N+]([O-])c1c(Cl)cc(N2CCOCC2)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(N2CCOCC2)cc(Cl)c1[N+](=O)[O-]
Temperature: 65 °C
Yield: 44.8 %

Procedure:
To a solution of 4-(4,6-dichloro-5-nitropyridin-2-yl)-morpholine (2.02 g) in methanol (15 ml) was added sodium methoxide (0.98 g) and the mixture was heated for 16 hours at 65° C. After cooling to ambient temperature the reaction mixture was concentrated in vacuo. The crude product was subjected to flash chromatography (SiO2, heptane/ethylacetate 3:1) to furnish 0.89 g (45% yield) of 4-(4-chloro-6-methoxy-5-nitropyridin-2-yl)-morpholine (fast eluting band) and 0.38 g (19%) of 4-(6-chloro-4-methoxy-5-nitropyridin-2-yl)-morpholine (late eluting band), both as yellow solids.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([CH2:13][O:14][C:15]2[CH:26]=[CH:25][C:18]([O:19][CH2:20][C:21]([O:23]C)=[O:22])=[C:17]([CH3:27])[CH:16]=2)=[N:10][CH:9]=1.[Li+].[OH-].Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([CH2:13][O:14][C:15]2[CH:26]=[CH:25][C:18]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[C:17]([CH3:27])[CH:16]=2)=[N:10][CH:9]=1
Reactant: COC(=O)COc1ccc(OCc2ncc(-c3ccccc3Cl)s2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(OCc2ncc(-c3ccccc3Cl)s2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The solution of methyl 2-(4-((5-(2-chlorophenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetate from Step A is treated with a solution of 1 M LiOH in H2O (1 mL), and the mixture is stirred for 12 h at rt. The mixture is acidified with 1 M HCl (10 mL) and extracted with EtOAc (20 mL). The organic layer is dried (MgSO4), filtered, concentrated and purified on reverse phase HPLC(H2O/MeCN gradient) to afford the title compound E1 as a white solid: 1H-NMR (400 MHz, CDCl3) δ=7.96 (s, 1H), 7.50 (m, 2H), 7.30 (m, 2H), 6.89 (d, J=2.4 Hz, 1H), 6.77 (dd, J=2.4, 8.8 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 5.33 (s, 2H), 4.64 (s, 2H), 2.29 (s, 3H). MS calcd. for C19H17ClNO4S (M+H+) 390.0. found 390.0.