Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[C:19]1([CH2:25][C:26](=[NH:30])OCC)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[ClH:17].[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26](=[NH:30])[CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Reactant: CCOC(=N)Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1c(F)cccc1Cl
Yield: 37.7 %

Procedure:
A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (5.05 g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by flash chromatography (chloroform/methanol) and recrystallisation from ethanol/ether to obtain the product (1.53 g), m.p. 115°-123° C.
Reaction SMILES: FC1C([O:8][C:9](=O)[C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)=C(F)C(F)=C(F)C=1F.CCN(C(C)C)C(C)C.[NH2:46][CH2:47][C:48]([NH:50][C@H:51]([C:59]([NH:61][C@H:62]([C:67]([OH:69])=[O:68])[CH2:63][CH:64]([CH3:66])[CH3:65])=[O:60])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:49]>CN(C=O)C>[NH:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([NH:46][CH2:47][C:48]([NH:50][C@H:51]([C:59]([NH:61][C@H:62]([C:67]([OH:69])=[O:68])[CH2:63][CH:64]([CH3:65])[CH3:66])=[O:60])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:49])=[O:8]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CN)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H]1CCCN1)C(=O)O
Reaction time: 3 h

Procedure:
Fmoc-L-proline pentafluorophenyl ester (50 mg, 0.1 mmol) is dissolved in anhydrous DMF (1 mL) containing DIEA (17 μL, 0.1 mmol). About 0.5-1.0 mL of this solution is added to Gly-L-Phe-L-Leu ELAMS™ in a test tube and the tube vortexed for about 3 hours. The ELAMS™ are pelleted and washed with DMF (4×) and methylene chloride (2×). Deprotection can be effected by treatment with a solution of 20% piperidine in DMF for 30 min. The ELAMS™ are then washed with DMF (2×), ethanol (2×) and methylene chloride (2×) and dried at 60° C. for 4 hours. The identifier tag for each ELAMS™ is detected and recorded.
Reaction SMILES: N1(CCCC(C2C=CC3OC4C(=CC(C(=O)CCCN5CCCCC5)=CC=4)CC=3C=2)=[O:11])CCCCC1.[N:37]1([CH2:43][CH2:44][CH2:45][CH2:46][C:47]([C:49]2[CH:62]=[CH:61][C:60]3[O:59][C:58]4[C:53](=[CH:54][C:55]([C:63](=[O:74])[CH2:64][CH2:65][CH2:66][CH2:67][N:68]5[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]5)=[CH:56][CH:57]=4)[CH2:52][C:51]=3[CH:50]=2)=[O:48])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C>[N:37]1([CH2:43][CH2:44][CH2:45][CH2:46][C:47]([C:49]2[CH:62]=[CH:61][C:60]3[O:59][C:58]4[C:53](=[CH:54][C:55]([C:63](=[O:74])[CH2:64][CH2:65][CH2:66][CH2:67][N:68]5[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73]5)=[CH:56][CH:57]=4)[C:52](=[O:11])[C:51]=3[CH:50]=2)=[O:48])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CCCCC3)ccc1O2
Reactant: O=C(CCCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCCN3CCCCC3)ccc1O2
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CCCCN1CCCCC1)c1ccc2oc3ccc(C(=O)CCCCN4CCCCC4)cc3c(=O)c2c1

Procedure:
Following the procedure of Example 42, only substituting for 2,7-bis(4-piperidinobutyryl)xanthene, 25.8 g (0.05 mole) 2,7-bis(5-piperidinovaleryl)xanthene and using 600 ml of glacial acetic acid and 19.7 g (0.066 mole) sodium dichromate, the solid obtained is recrystallized from a benzene-heptane mixture to give the title compound, M.P. 109°-110° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([NH:20]/[C:21](/[NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[N:22]\[C:23](=[O:34])[C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[NH:17][N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:36]([NH:35]/[C:21](/[NH:20][C:18]1[NH:17][N:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH:19]=1)=[N:22]/[C:23](=[O:34])[C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)N/C(=N/C(=O)c1ccc(C(F)(F)F)cc1)Nc1cc(-c2ccc(OCc3ccccc3)cc2)n[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)N/C(=N/C(=O)c1ccc(C(F)(F)F)cc1)Nc1cc(-c2ccc(O)cc2)n[nH]1
Yield: 68.1 %

Procedure:
(Z)—N-(((3-(4-(Benzyloxy)phenyl)-1H-pyrazol-5-yl)amino)(tert-butylamino)methylene)-4-(trifluoromethyl)benzamide (150 mg) was dissolved in methanol (10 mL) and the solution was degassed with nitrogen. To the solution was added 10% palladium on carbon (30 mg, 0.1 equiv). The mixture was subjected to hydrogen gas at 60 psi pressure in a Parr shaker. The reaction was checked periodically for completion. Upon completion, the reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo to provide the crude product, which was purified by silica chromatography (9:1 to 55:45 hexanes:EtOAc) to provide the title compound (85 mg, 68% yield).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=3)[S:19][C:13]=2[CH2:12]1)=O)C1C=CC=CC=1.B(Br)(Br)Br>C(O)C>[N:17]1[C:14]2[CH2:15][CH2:16][NH:11][CH2:12][C:13]=2[S:19][C:18]=1[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1
Reactant: COc1ccc(-c2nc3c(s2)CN(C(=O)OCc2ccccc2)CC3)cc1
Agent: BrB(Br)Br
Solvent: CCO
Product: Oc1ccc(-c2nc3c(s2)CNCC3)cc1
Temperature: -78 °C
Reaction time: 16 h

Procedure:
Compound 504 (18.0 g, 47.3 mmol) was dissolved in ethanol (300 ml). To the cooled (−78° C.) solution was added boron tribromide (5 eg, 236 mmol) dropwise. After one hour cooling was removed and the mixture was stirred 16 hrs at room temperature. The reaction was quenched with MeOH, the mixture was concentrated in vacuo to give compound 505 as an oil which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:9]([OH:19])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:46]([C:49]1[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=1)([O-:48])=[O:47].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(C)C=CC=CC=1>C1COCC1.C(OCC)(=O)C.O>[N+:46]([C:49]1[CH:50]=[CH:51][C:52]([C:53]([O:19][C@@H:9]([C@@H:8]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:7][C:6](=[O:26])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][O:11][Si:12]([CH3:13])([CH3:14])[C:15]([CH3:16])([CH3:17])[CH3:18])=[O:54])=[CH:56][CH:57]=1)([O-:48])=[O:47]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@H](c1ccccc1)[C@@H](O)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](c1ccccc1)[C@@H](CO[Si](C)(C)C(C)(C)C)OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.5 %

Procedure:
To a solution of 700 mg of tert-butyl[(1R,2R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxy-1-phenylpropyl]carbamate in 35 ml of THF was added 1.2 g of triphenylphosphine, 766 mg of 4-nitrobenzoic acid, and 2.4 ml of a 1.9 M diisopropyl azodicarboxylate/toluene solution under ice-cooling, followed by stirring at room temperature for 5 hours. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 638 mg of (6S,7R)-2,2,3,3,11,11-hexamethyl-9-oxo-7-phenyl-4,10-dioxa-8-aza-3-siladodecan-6-yl 4-nitrobenzoate.
Reaction SMILES: [CH3:1][C:2]1[C:21]([N+:22]([O-])=O)=[CH:20][C:19]([N+:25]([O-])=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]>C(OCC)(=O)C.[Pd]>[NH2:22][C:21]1[C:2]([CH3:1])=[C:3]([CH:18]=[C:19]([NH2:25])[CH:20]=1)[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: Cc1c(C(=O)NCC23CC4CC(CC(C4)C2)C3)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1c(N)cc(N)cc1C(=O)NCC12CC3CC(CC(C3)C1)C2
Yield: 35.8 %

Procedure:
A solution of 2-methyl-3,5-dinitro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 65) (2.66 g) in ethyl acetate (200 ml) was hydrogenated over palladium on carbon (10%, 0.5 g) for 72 hours. The reaction mixture was then filtered through celite® and the residue washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure to give a solid (0.8 g). This was purified by column chromatography over silica eluting with dichloromethane: ethanol (9:1). The product was further purified by treatment with charcoal in boiling ethanol followed by filtration and concentration to remove coloured impurities to give the title compound as a near colourless solid (0.58 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([N:13]1[CH2:20][CH:19]3[CH:15]([CH2:16][NH:17][CH2:18]3)[CH2:14]1)[CH:6]=[N:5]2.[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)=[C:27]([CH:31]=1)[C:28](O)=[O:29]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([N:13]1[CH2:14][CH:15]3[CH2:16][N:17]([C:28]([C:27]4[CH:31]=[C:23]([O:22][CH3:21])[CH:24]=[CH:25][C:26]=4[N:32]4[N:36]=[CH:35][CH:34]=[N:33]4)=[O:29])[CH2:18][CH:19]3[CH2:20]1)[CH:6]=[N:5]2
Reactant: Fc1cc2ncc(N3CC4CNCC4C3)nc2cc1F
Reactant: COc1ccc(-n2nccn2)c(C(=O)O)c1
Product: COc1ccc(-n2nccn2)c(C(=O)N2CC3CN(c4cnc5cc(F)c(F)cc5n4)CC3C2)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 44 and 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI): mass calculated for C24H21F2N7O2, 477.2; m/z found 478.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.25 (s, 1H), 7.84 (t, J=7.6, 1H), 7.64 (dt, J=19.7, 10.8, 3H), 7.42 (dd, J=11.4, 8.0, 1H), 7.03 (dd, J=9.0, 2.8, 1H), 6.92 (d, J=2.8, 1H), 3.97-3.84 (m, 5H), 3.64 (dd, J=18.2, 14.6, 5H), 3.12 (dd, J=19.8, 8.6, 3H).
Reaction SMILES: CO.[CH3:3][C:4]1([CH3:31])[CH2:8][C:7]2[C:9]([CH3:30])=[C:10]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1.[BH4-].[Na+]>O>[CH3:31][C:4]1([CH3:3])[CH2:8][C:7]2[C:9]([CH3:30])=[C:10]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:22]=[CH:23][C:24]([CH:27]([OH:29])[CH3:28])=[CH:25][CH:26]=4)[CH2:17][CH2:16]3)[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1
Reactant: CC(=O)c1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(C)c(N2CCN(c3ccc(C(C)O)cc3)CC2)c(C)c2c1OC(C)(C)C2
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To the methanol (1.0 mL) solution of 1-{4-[4-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazin-1-yl]phenyl}ethanone (39 mg, 0.10 mmol) synthesized in Example 95, sodium borohydride (11 mg, 0.30 mmol) was added under ice cooling. The mixture was stirred for 2 hours. The reaction solution was added with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure. The resulting residue was crystallized from hexane to obtain the title compound 24 mg (yield 60%). Melting point was 133 to 136° C. (hexane-ethyl acetate).
Reaction SMILES: Br[CH2:2][CH2:3][CH3:4].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:2][CH2:3][CH3:4])[CH:10]=[CH:9]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCn1ccc2cc(Br)ccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
1-Bromopropane (1.25 g, 10.2 mmol) was added to a solution of 5-bromo indole (2 g, 10.2 mmol) in DMF (30 mL) followed by cesium carbonate (6.63 g, 20.4 mmol), and the mixture was stirred at 100° C. for 2 h. Insoluble solids were filtered off, and filtrate was concentrated. Residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using 5% ethyl acetate in hexane as eluent to afford title compound (1.8 g, 74%) as oil. 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J=1.6 Hz, 1H), 7.28 (m, 1H), 7.20 (m, 1H), 7.09 (d, J=3.2 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 4.05 (t, J=7.2 Hz, 2H), 1.87 (m, 2H), 0.9 (t, J=7.2 Hz, 3H); ESI-MS m/z=238 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2)#[CH:2].[CH3:13][N:14]([CH2:16][C:17]1[N:18]([C:22]2[CH:23]=[C:24]([NH:32][C:33](=[O:42])[C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[C:36](I)[CH:35]=3)[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=2)[CH:19]=[CH:20][N:21]=1)[CH3:15]>>[CH3:15][N:14]([CH2:16][C:17]1[N:18]([C:22]2[CH:23]=[C:24]([NH:32][C:33](=[O:42])[C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[C:38]([CH2:2][CH2:1][C:3]4[CH:4]=[N:5][CH:6]=[C:7]5[C:12]=4[N:11]=[CH:10][CH:9]=[CH:8]5)[CH:39]=3)[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=2)[CH:19]=[CH:20][N:21]=1)[CH3:13]
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cncc2cccnc12
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1CCc1cncc2cccnc12

Procedure:
The title compound can be synthesized from 8-ethynyl-1,6-naphthyridine and N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 1. 8-ethynyl-1,6-naphthyridine is prepared from 8-bromo-1,6-naphthyridine and ethynyltrimethylsilane according to the 2 steps procedure described in Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]45[CH2:26][CH2:25][C:22]([CH2:27][C:28]([O:30]C)=[O:29])([CH2:23][CH2:24]4)[CH2:21][CH2:20][CH2:19]5)=[CH:14][CH:13]=3)[C:8]([CH3:33])([CH3:32])[O:7][C:6]=2[N:5]=[CH:4][N:3]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([C:18]45[CH2:26][CH2:25][C:22]([CH2:27][C:28]([OH:30])=[O:29])([CH2:23][CH2:24]4)[CH2:21][CH2:20][CH2:19]5)=[CH:16][CH:17]=3)[C:8]([CH3:33])([CH3:32])[O:7][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)CC12CCCC(c3ccc(C4=Nc5c(N)ncnc5OC4(C)C)cc3)(CC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Oc2ncnc(N)c2N=C1c1ccc(C23CCCC(CC(=O)O)(CC2)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a solution of methyl {5-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]bicyclo[3.2.2]non-1-yl}acetate (Intermediate 25; 55 mg, 0.12 mmol) in MeOH (5 mL) was added 2M NaOH (0.3 mL) and the reaction mixture was allowed to stir at ambient temperature overnight, then at 50° C. for 8 hrs and ambient temperature overnight. The solvent was removed under reduced pressure and the residue was acidified to pH 2 with 2M HCl, the filtrate extracted into EtOAc (2×50 mL), the organic extracts combined, dried (MgSO4) and concentrated to leave a yellow gum. The product was purified by reverse phase preparative HPLC, loading the sample in DMSO/MeCN/H2O (7:2:1) and eluting with 5-95 water-MeCN with 0.2% TFA in each phase, to provide the title compound (31 mg, 0.0714 mmol, 59%) as a pale yellow solid, 1H NMR δ 1.34-1.56 (14H, m), 1.63 (6H, s), 1.95 (2H, s), 7.15 (2H, d), 7.63-7.66 (2H, m), 8.02 (1H, s); MS m/e MH+ 435
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J19) (311 mg, 1.0 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (297 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (400 mg, 75%).
Reaction SMILES: [ClH:1].Cl.C([N:10]1[CH2:14][CH2:13][C:12]([CH2:16][NH:17][CH:18]2[CH2:20][CH2:19]2)([OH:15])[CH2:11]1)C1C=CC=CC=1>CO.[Pd]>[ClH:1].[ClH:1].[CH:18]1([NH:17][CH2:16][C:12]2([OH:15])[CH2:13][CH2:14][NH:10][CH2:11]2)[CH2:20][CH2:19]1
Reactant: OC1(CNC2CC2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: OC1(CNC2CC2)CCNC1

Procedure:
7.9 g (24.7 mmol) of 1-benzyl-3-cyclopropylaminomethyl-3-hydroxypyrrolidine dihydrochloride in 100 ml of methanol are hydrogenated on 2 g of palladium/active carbon (10%) at 50° C. and 100 bar. The product is filtered off with suction and concentrated, and the residue is triturated with butanol. The crystalline salt is filtered off with suction, washed with acetone and dried.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[NH2:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:28][C:29]([NH:31][C@@H:32]([CH3:36])[C:33](O)=[O:34])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[NH:20][C:33](=[O:34])[C@@H:32]([NH:31][C:29]([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[CH3:36])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(Nc2cc(F)ccc2N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc(F)cc1NC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(2-amino-5-fluorophenylamino)azetidine-1-carboxylic acid tert-butyl ester (15.5 mmol), (S)-2-benzyloxycarbonylaminopropionic acid (3.81 g, 17.1 mmol), HOAt (2.32 g, 17.1 mmol), 4-methylmorpholine (3.75 mL, 34.1 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.27 g, 17.1 mmol) in DCM (53 mL) was stirred at RT for 2 h. The reaction mixture was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with EtOAc (×3) and the combined organic fractions were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo to afford the title compound as a yellow oil (quantitative). LCMS (Method B): RT 3.63 min [M+H]+ 487.3.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])=[CH:6][C:5]=1[C:16]([F:19])([F:18])[F:17])([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])=[CH:6][C:5]=1[C:16]([F:17])([F:18])[F:19]
Reactant: CC(C)C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)C(=O)Nc1ccc(N)c(C(F)(F)F)c1

Procedure:
Hydrogenate, at approximately 3 atmospheres, a mixture of 8.3 g. of 4'-nitro-3'-trifluoromethylisobutyranilide in 100 ml. of ethanol containing 0.5 g. of 5% palladium on charcoal. Filter and remove the solvent, obtaining 4'-amino-3'-trifluoromethylisobutyranilide, m.p. 114.5°-116° C.
Reaction SMILES: CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.[Cl:17][C:18]1[C:23]([C:24]#N)=[CH:22][CH:21]=[CH:20][N:19]=1.Cl.[O:27]1CCCC1>>[Cl:17][C:18]1[C:23]([CH:24]=[O:27])=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: N#Cc1cccnc1Cl
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Product: O=Cc1cccnc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
200 ml of a 1.02M hexane solution of diisobutylaluminum hydride were added to a solution of 16.7 g of 2-chloro-3-cyanopyridine in 200 ml of tetrahydrofuran at a temperature of -30° to 20° C. over a period of 30 minutes, after which the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, hydrochloric acid was added to the reaction mixture at 0° C, and then the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium carbonate and with a saturated aqueous solution of sodium chloride, in that order, and then dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 6:1 to 5:1 by volume as the eluent, to give 7.0 g of the title compound having Rf=0.50 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:12][NH:11][CH2:10]1)(C(C)(C)C)(C)C.[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=2)[CH2:15][CH2:14]1.CC([O-])(C)C.[Na+].O1CCOCC1>O>[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N:11]3[CH2:10][CH:9]([OH:8])[CH2:12]3)=[CH:20][CH:19]=2)[CH2:14][CH2:15]1
Reactant: CC(C)(C)[Si](C)(C)OC1CNC1
Reactant: Ic1ccc(OCC2CC2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OC1CN(c2ccc(OCC3CC3)cc2)C1
Temperature: 75 °C
Reaction time: 2.5 h

Procedure:
6.50 g (26.0 mmol) 3-(tert-butyldimethylsilyloxy)azetidine, 7.13 g (26.0 mmol) of 1-(cyclopropylmethoxy)-4-iodobenzene (WO2012/028676), 10.0 g (104 mmol) NaOtBu and 1.54 g (2.08 mmol) chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2-(2-aminoethyl)-phenyl)-palladium (II) are added to 65 mL dioxane and stirred at 75° C. for 2.5 h under inert gas atmosphere. Water is added and the resulting mixture is extracted with EtOAc. The org. layers are combined, dried over MgSO4, filtered and the solvent is removed in vacuo. The resulting crude product is purified by HPLC (ACN/H2O/NH3).