Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:33])[NH:11][C@@H:12]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:14]=1)[CH2:2]2.Cl.O1CCOC1CCCOC(C1CCNCC1)=O.[CH:52]([C:54]1[CH:62]=[CH:61][C:57]([C:58](O)=[O:59])=[CH:56][CH:55]=1)=[O:53].C1([C@H](NC(O[C@@H]2C3CCN(CC3)C2)=O)C2C=C(C=CC=2)OCC2C=CC(C(O)=O)=CC=2)C=CC=CC=1>>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([O:9][C:10](=[O:33])[NH:11][C@H:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:58](=[O:59])[C:57]4[CH:61]=[CH:62][C:54]([CH:52]=[O:53])=[CH:55][CH:56]=4)[CH2:25][CH2:26]3)[CH:14]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:2]2
Reactant: O=C(N[C@@H](c1ccccc1)c1cccc(OCC2CCNCC2)c1)O[C@H]1CN2CCC1CC2
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1)O[C@H]1CN2CCC1CC2
Agent: O=C(OCCCC1OCCO1)C1CCNCC1
Product: O=Cc1ccc(C(=O)N2CCC(COc3cccc([C@@H](NC(=O)O[C@H]4CN5CCC4CC5)c4ccccc4)c3)CC2)cc1

Procedure:
The title compound was prepared as described in Example 1 Step 11 with (R)-quinuclidin-3-yl((S)-phenyl(3-(piperidin-4-ylmethoxy)phenyl)methyl)carbamate and 4-formyl benzoic acid 3-(1,3-dioxolan-2-yl)propyl piperidine-4-carboxylate hydrochloride and 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoic acid respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][C:17]#[N:18])[CH2:12][CH:13]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: N#CCCCN1CC=C(c2ccc(Cl)cc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: NCCCCN1CC=C(c2ccc(Cl)cc2)CC1
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a stirred solution of 4-[4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]butyronitrile (13.0 g) in dry tetrahydrofuran (130 ml) was added 1M solution of lithium aluminum hydride in tetrahydrofuran (60 ml), and the mixture was stirred for 1 hour. After saturated aqueous ammonium chloride solution (10 ml) was added with stirring, the organic layer was separated by decantation, dried over magnesium sulfate and evaporated to dryness to give an oil of 4-[4-[4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]butylamine (7.18 g).
Reaction SMILES: FC1C=CC(CNC)=CC=1.[CH2:11]([CH:19]1[CH2:23][CH2:22][NH:21][CH2:20]1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][NH:30][C:31]([C:33]2[S:37][C:36]([C:38]3[CH:43]=[N:42][CH:41]=[C:40](I)[N:39]=3)=[N:35][C:34]=2[CH3:45])=[O:32])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][NH:30][C:31]([C:33]2[S:37][C:36]([C:38]3[CH:43]=[N:42][CH:41]=[C:40]([N:21]4[CH2:22][CH2:23][CH:19]([CH2:11][CH2:12][C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)[CH2:20]4)[N:39]=3)=[N:35][C:34]=2[CH3:45])=[O:32])=[CH:27][CH:26]=1
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccc(F)cc1
Reactant: c1ccc(CCC2CCNC2)cc1
Agent: CNCc1ccc(F)cc1
Product: Cc1nc(-c2cncc(N3CCC(CCc4ccccc4)C3)n2)sc1C(=O)NCc1ccc(F)cc1
Yield: 75 %

Procedure:
Following the procedure described in Example 14, making variations as required to replace 4-fluoro-N-methyl-benzylamine with 3-phenethyl-pyrrolidine to react with 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide, the title compound was obtained in 75% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.50 (s, 1H), 7.89 (s, 1H), 7.31-7.38 (m, 2H), 7.24-7.30 (m, 2H), 7.14-7.23 (m, 3H), 7.00-7.09 (m, 2H), 6.18 (bs, 1H), 4.55 (d, J=4.0 Hz, 2H), 3.70-3.78 (m, 1H), 3.62-3.69 (m, 1H), 3.39-3.48 (m, 1H), 3.06-3.13 (m, 1H), 2.70 (s, 3H), 2.68-2.75 (m, 2H), 2.27-2.38 (m, 1H), 2.15-2.26 (m, 1H), 1.64-1.86 (m, 3H); MS (ES+) m/z 502.3 (M+1), Rt=138 min.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1COCC1>[N:11]1([CH2:10][CH2:9][CH2:8][NH:7][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C=C1CC(=O)O1
Reactant: NCCCN1CCCCC1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCCCN1CCCCC1
Reaction time: 1.5 h

Procedure:
Diketene (2.40 mL, 31.1 mmol, 1.50 equiv) was added at 0° C. to a stirred solution of 1-(3-aminopropyl)piperidine (2.95 g, 20.7 mmol, 1.0 equiv, Bates, R. J.; Cymerman-Craig, J.; Moyie, M.; Yong, R. J. J. Chem. Soc. 1956, 388) in anhydrous THF (40 mL) under argon, and stirring was continued at room temperature for 1.5 hours. The mixture was concentrated to give 4.8 g (100%) of light brown oil, which was characterized spectroscopically and used for the next reaction without purification.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:29])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH2:27][CH3:28])[N:6]=2.[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:31]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:27]([C:19]1[N:18]([C:7]2[N:6]=[C:5]3[C:10]([N:11]=[C:3]([CH2:2][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[CH2:31]4)[N:4]3[CH3:29])=[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:8]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=1)[CH3:28]
Reactant: C1CN(C2CNC2)CCO1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCl)n(C)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.4 %

Procedure:
To a solution of 8-chloromethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (107 mg, 0.26 mmol) and 4-azetidin-3-ylmorpholine (44 mg, 0.31 mmol) in DMF (3 mL) was added K2CO3 (106 mg, 0.77 mmol). The resulting mixture was allowed to stir at room temperature for 16 h. The reaction mixture was dissolved in EtOAc, washed with H2O (×4) then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-5%). The resulting residue was further purified by Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH, followed by reverse phase HPLC (Phenomenex Luna C18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 95:5 to 2:98) to afford 309 as a white solid (14 mg, 11%). LCMS (Method G): RT 5.74 min, [M+H]+ 518.3. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.98 (m, 1 H); 7.77-7.73 (m, 1 H); 7.27-7.23 (m, 2 H); 4.35 (m, 4 H); 3.89-3.82 (m, 6 H); 3.83 (s, 3 H); 3.72 (m, 4 H); 3.56 (m, 2 H); 3.34 (q, J=7.5 Hz, 2 H); 3.15-3.03 (m, 3 H); 2.34 (m, 4 H) and 1.44 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]([F:20])=[C:18]2[C:13]([C:14]([CH3:21])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[C:22]([O:24]C)=[O:23].[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]([F:20])=[C:18]2[C:13]([C:14]([CH3:21])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[C:22]([OH:24])=[O:23]
Reactant: COC(=O)c1cc2c(C)ncnc2c(F)c1Nc1ccc(I)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncnc2c(F)c(Nc3ccc(I)cc3F)c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To a solution of methyl 7-(2-fluoro-4-iodophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylate (205 mg, 0.48 mmol) in a mixture of THF (10 ml) and H2O (5 ml) was added a solution of LiOH (57 mg, 2.4 mmol) in H2O (2.4 ml). After stirring at room temperature for 4 h, the reaction was concentrated, acidified with 1 M. HCl solution, and extracted with EtOAc (2×20 ml). The organic solution was dried over MgSO4 and concentrated to give 190 mg (96%) the title compound as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl[CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[CH:33]([S:34]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:36])=[O:35])=[CH2:32]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CS(=O)(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Reaction time: 15 h

Procedure:
To ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (60 mg, 0.21 mmol) was added DCM (1.1 mL) and DIPEA (45 μL, 0.26 mmol) at 0° C. Then 2-chloroethanesulfonyl chloride (68 mg, 0.42 mmol) was added and the reaction was stirred vigorously for 15 hours before being quenched by pouring into a separatory funnel containing aqueous sodium hydrogen carbonate (20%). The aqueous layer was then extracted with ethyl acetate (×3) and the organic layers were combined, dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was then purified using a silica column, eluting with DCM with a 10-80% of a 2% methanol/EtOAc modifying co-solvents. The product was collected and concentrated in vacuo to afford the desired product as a yellow solid. LRMS (ESI) calc'd for C17H17N4O4S [M+H]+: 373, found 373. 1H NMR (600 MHz, CDCl3) δ 10.74 (bs, 1H), 9.04 (s, 1H), 8.12 (s, 1H), 7.38-7.54 (m, 5H), 6.61 (dd, 1H, J=17.4, 10.8 Hz), 6.33 (d, 1H, J=16.2 Hz), 5.96 (d, 1H, J=10.2 Hz), 4.04 (q, 2H, J=7.2 Hz), 1.01 (t, 3H, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)C(Br)c1ccc(F)cc1

Procedure:
A solution of 4-fluorophenylacetic acid (9.7 g), N-bromosuccinimide (11.2 g) and azobisisobutyronitrile (AIBN, 0.2 g) in carbontetrachloride (100 ml) was reluxed for 2 hours. After cooling it was filtered through Celite® and the filtrate was evaporated to give an oily residue of α-bromo-4-fluorophenylacetic acid, which was used for next step without purification.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[CH3:20][C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[C:23]([NH2:32])[CH:22]=1>CN(C=O)C>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:32][C:23]2[CH:22]=[C:21]([CH3:20])[N:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:24]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Cc1cc(N)nn1-c1ccccc1
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(Nc2cc(C)n(-c3ccccc3)n2)=C(c2ccccc2)S1(=O)=O
Temperature: 140 °C
Yield: 61.8 %

Procedure:
2-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (110 mg, 0.330 mmol) was dissolved in dry DMF (0.5 mL) under nitrogen atmosphere. 5-Methyl-1-phenyl-1H-pyrazol-3-amine (172 mg, 0.991 mmol) was added and the reaction mixture was heated in a microwave reactor for 25 mins at 140° C. The crude product was purified by preparative HPLC affording the title compound (89 mg, 58.6%). 1H NMR (500 MHz, CD3CN): δ 0.99 (t, 3H), 1.42-1.51 (m, 2H), 1.76-1.84 (m, 2H), 2.14 (s, 3H), 3.73 (t, 2H), 5.87 (s, 1H), 6.87-6.90 (m, 2H), 7.27-7.38 (m, 8H), 7.74 (bs, 1H).
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4].[CH2:23]([CH2:25][NH2:26])[OH:24]>C1(C)C=CC=CC=1>[OH:24][CH2:23][CH2:25][NH:26][C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4]
Reactant: NCCO
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)OC)s1
Solvent: Cc1ccccc1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NCCO)s1
Yield: 18.2 %

Procedure:
To a stirred solution of 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (70 mg, 0.22 mmol) in toluene (0.5 mL) was added ethanolamine (16 mg, 0.26 mmol) and TBD (18 mg, 0.12 mmol). After 20 h the reaction mixture was concentrated in vacuo then purified by chromatography (silica, 0 to 10% methanol in dichloromethane) to give the title compound (14 mg, 18%) as a white solid. MS: m/e=350.3 [M+H]+.
Reaction SMILES: C(OC([N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)(OCC)C)C.C([Li])CCC.[Cl:19][C:20]1[CH:34]=[CH:33][C:23]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1.Cl>CCOCC.CCCCCC>[Cl:19][C:20]1[CH:34]=[CH:33][C:23]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)([C:13]2[NH:12][CH:11]=[N:10][N:9]=2)[OH:25])=[CH:22][CH:21]=1
Reactant: CCOC(C)(OCC)n1cncn1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1nnc[nH]1
Yield: 72 %

Procedure:
A solution of 9.25 g of 1-(1,1-diethoxyethyl)-1,2,4-triazole in 150 ml of ether was treated first with 38.5 ml of 1.3M n-butyllithium in hexane and then with 12.6 g of 4,4'-dichlorobenzophenone in the same manner as Exaample 1. The mixture was added to ice and hydrochloric acid producing a white suspension which was recovered by filtration. The solid was recrystallized from 600 ml of methanol/200 ml of water to provide 11.52 g of the desired title product, m.p. 233°-234° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH2:15][C:16]([OH:18])=O)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[N:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[C:32]([N:29]1[CH2:28][CH2:27][N:26]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:16](=[O:18])[CH2:15][C:11]3[CH:12]=[C:13]([CH3:14])[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=4)=[N:9][CH:10]=3)=[N:25][CH:24]=2)[CH2:31][CH2:30]1)(=[O:34])[CH3:33]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: Cc1cc(CC(=O)O)cnc1-c1ccnc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(-c4ccnc(F)c4)c(C)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a reaction vial was added 2-(2′-fluoro-3-methyl-2,4′-bipyridin-5-yl)acetic acid 193-2 (60 mg, 0.17 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (50 mg, 0.22 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (115 mg, 0.3 mmol) and DIEA (104 μL, 0.58 mmol) in DMF (1 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction was diluted with DMSO and then purified by reverse-phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(2′-fluoro-3-methyl-2,4′-bipyridin-5-yl)acetamide 193 as white solid. MS m/z 449.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.58 (s, 1H), 8.42 (d, 1H, J=1.6 Hz), 8.28 (d, 1H, J=5.2 Hz), 7.98 (d, 1H, J=2.8 Hz), 7.87 (d, 1H, J=9.2 Hz), 7.67 (d, 1H, J=1.6 Hz), 7.50-7.48 (m, 1H), 7.37 (dd, 1H, J1=9.2 Hz, J2=3.2 Hz), 7.30 (s, 1H), 3.71 (s, 2H), 3.50 (b, 4H), 3.09 (t, 2H, J=5.2 Hz), 3.02 (t, 2H, J=5.2 Hz), 2.30 (s, 3H), 1.97 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][NH2:20])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cccc(-c2cccc(OCCNC(=O)OC(C)(C)C)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(-c2cccc(OCCN)c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.5 %

Procedure:
The methyl-3′-[2-[[(tert-butoxy)carbonyl]amino]ethoxy]-[1,1′-biphenyl]-3-carboxylate (659 mg) was dissolved in methylene chloride (25 mL) and trifluoroacetic acid (2.5 mL) was added. The mixture was stirred at room temperature for 6 h, additional trifluoroacetic acid (1.0 mL) was added and the mixture was stirred overnight. The mixture was concentrated and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to give the crude product. This residue was partitioned between 1:1 hexane: ethyl acetate and 1 N aqueous HCl. The aqueous layer was separated, washed with 1:1 hexane: ethyl acetate and made basic by addition of solid sodium bicarbonate. The mixture was extracted twice with ethyl acetate, and the combined organic extracts were dried over sodium sulfate, filtered and concentrated to afford the title compound (474 mg) as a colorless oil. Electrospray MS (positive ion): (M+H) 272.0.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)(O)O.[NH2:25][NH:26][C:27]([NH2:29])=[NH:28].C1(C)C=CC=CC=1.C(=O)=O>O>[C:1]([NH2:25])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:25][NH:26][C:27]([NH2:29])=[NH:28]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: N=C(N)NN
Agent: O=C(O)O
Agent: O=C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCC(N)=O
Temperature: 140 °C

Procedure:
A 5 liter, 3-neck flask was charged with 847.5 grams (3 moles) oleic acid, 3 moles of aminoguanidine bicarbonate, 300 mls of toluene and 15 drops of a silicone anti-foam agent. The reaction mixture was heated to reflux under a nitrogen blanket. Vigorous foaming was noted as carbon dioxide gas evolved. When the foaming subsided, water evolution began. A total of about 57 ml of water was collected from the reaction by means of a Dean-Stark trap. The temperature of the reaction mixture was raised to about 140° C. to facilitate the removal of toluene. The reaction product, believed to be primarily aminoguanidine oleamide, was filtered and placed under nitrogen for storage.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[NH:12][C:13]([C@H:15]1[N:23]([C:24](=[O:43])[C@@H:25]([NH:29][C:30](=[O:42])[C@@H:31]([N:33](C)[C:34](=O)OC(C)(C)C)[CH3:32])[CH:26]([CH3:28])[CH3:27])[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[CH2:16]1)=[O:14].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:3]=1[NH:12][C:13]([C@H:15]1[N:23]([C:24](=[O:43])[C@@H:25]([NH:29][C:30](=[O:42])[C@@H:31]([NH:33][CH3:34])[CH3:32])[CH:26]([CH3:27])[CH3:28])[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[CH2:16]1)=[O:14]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1c(F)cccc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1c(F)cccc1C(F)(F)F)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
In a 50 mL round-bottomed flask, tert-butyl (S)-1-((S)-1-((S)-2-(2-fluoro-6-(trifluoromethyl)phenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (20 mg, 32.8 μmol Eq: 1.00) was combined with DCM (1.5 mL) to give a colorless solution. TFA (500 μL, 6.49 mmol, Eq: 198) was added and the reaction mixture was stirred at rt for 30 min. The crude reaction mixture was concentrated in vacuo. The residue was taken up in DCM, washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated in vacuo to give (S)—N-(2-fluoro-6-(trifluoromethyl)phenyl)-1-((S)-3-methyl-2-((S)-2-(methylamino)propanamido)butanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide as a white solid (10 mg), m/z=510.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[CH:8][CH:7]=1)=[O:5].Cl[C:18]([O:20][CH3:21])=[O:19].C(OCC)C>C(Cl)Cl>[CH3:1][N:2]([CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:14])[F:15])=[CH:8][CH:7]=1)=[O:5])[C:18]([O:20][CH3:21])=[O:19]
Reactant: CN(C)CC(=O)c1ccc(OC(F)F)cc1
Reactant: COC(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)N(C)CC(=O)c1ccc(OC(F)F)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To 16.8 g (73 mmole) of 2-dimethylamino-4'-difluoromethoxyacetophenone in 100 ml of methylene chloride cooled to 0° C. was added 7.6 g (81 mmole) of methyl chloroformate. After the addition was complete the reaction mixture was allowed to warm to 20° C. and stirred overnight. Concentration in vacuo, partitioning between diethyl ether and 1M aqueous hydrochloric acid, washing with brine, drying over anhydrous magnesium sulfate, and reconcentration in vacuo gave a crude oil. Chromatography of this oil on silica gel using diethyl ether in hexanes gave 12 g of 2-(N-methyl-N-(methoxycarbonyl)amino)-4'-difluoromethoxyacetophenone an oil, bp 150°-190° C. at 0.7 torr.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][NH2:5].[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CC(O)C>[Cl:12][C:13]1[N:18]=[C:17]([NH:5][CH2:4][C:3]2[C:2]([F:1])=[CH:9][C:8]([F:10])=[CH:7][C:6]=2[F:11])[CH:16]=[CH:15][N:14]=1
Reactant: NCc1c(F)cc(F)cc1F
Reactant: Clc1ccnc(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc(F)c(CNc2ccnc(Cl)n2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4,6-trifluorobenzylamine (5 g, 31 mmol) was added dropwise to a stirred suspension of 2,4-dichloropyrimidine (4.6 g, 31 mmol) and DIPEA (5.4 mL, 62 mmol) in IPA (100 mL) at 0° C. then the reaction mixture was warmed to room temperature and stirred overnight. The precipitate was collected and washed with diethyl ether to afford the first crop of 2-chloro-N-(2,4,6-trifluorobenzyl)pyrimidin-4-amine IV-1. The filtrate was concentrated and purified by column chromatography (0-30% v/v ethyl acetate/petrol) to afford a second crop (total yield 5.3 g, 62%). LC-MS (Method F), RT=2.27 min. (ES+) 274.
Reaction SMILES: [C:1]([CH:4]([CH2:14][CH2:15][CH2:16][CH:17]([OH:27])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>CCOCC>[C:1]([CH:4]([CH2:14][CH2:15][CH2:16][CH:17]([O:27][C:28](=[O:30])[CH3:29])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(=O)OC(CCCC(CCCCCCC(=O)O)C(C)=O)COc1ccc(F)cc1

Procedure:
A mixture of 8-acetyl-12-hydroxy-13-(4-fluorophenoxy)tridecanoic acid (9.5 g., 0.025 mole) and acetic anhydride (6.1 g., 0.06 mole) is heated at 60° for 18 hours. The mixture is then cooled and dissolved in 80 ml. of ether. The solution is extracted with an ice-cold solution of 8 g. of sodium hydroxide in 150 ml. of water. The basic solution is separated and acidified with concentrated hydrochloric acid. The oily acid that separates is taken up in ether, washed with water and dried over sodium sulfate. The ether is evaporated to leave the crude product as a viscous yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@H:4]([CH2:21][C:22]([O:24]C)=[O:23])[NH:5][C:6](=[O:20])[CH:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][S:9]C(=O)C.[S-2].[Na+].[Na+]>>[CH2:13]([CH:7]([CH2:8][SH:9])[C:6]([NH:5][C@H:4]([C:3]([OH:26])=[O:2])[CH2:21][C:22]([OH:24])=[O:23])=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C[C@H](NC(=O)C(CSC(C)=O)Cc1ccccc1)C(=O)OC
Agent: [Na+]
Agent: [S-2]
Product: O=C(O)C[C@H](NC(=O)C(CS)Cc1ccccc1)C(=O)O

Procedure:
Prepared by Method C of Example 19 but utilising N-(S-acetyl-2'-benzyl-3'-mercaptopropionyl)aspartic acid dimethyl ester and stirring with sodium sulphide for 3 hours. This afforded the title compound as a clear oil, an approximately equimolar mixture of diastereoisomers.