Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:7]=1.C(O)(=O)CC(O)=O.N1CCCCC1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([N:8]2[C:9]3[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[C:6]([CH:5]=[CH:4][C:3]([OH:28])=[O:2])=[CH:7]2)(=[O:18])=[O:19])=[CH:21][CH:22]=1
Reactant: COC(=O)CCc1cn(S(=O)(=O)c2ccc(OC)cc2)c2ccc(OC)cc12
Agent: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)n2cc(C=CC(=O)O)c3cc(OC)ccc32)cc1
Temperature: 80 °C

Procedure:
To a solution of 1-(4-Methoxy benzenesulfonyl)-5-methoxy-1H-indole-3-carbaldehyde 5 (0.51 g, 1.5 mmol) dissolved in pyridine (10 mL), malonic acid (0.53 g, 5.1 mmol) and piperidine, (1 mL) were combined in a reaction vessel. The yellow solution was heated for 3 hours at 80° C. The reaction was allowed to cool to ambient temperature and diluted with 150 mL of ethyl acetate. The organic layer was washed with 1N HCl (6×50 mL) and saturated sodium chloride solution (1×50 mL). After drying over sodium sulfate, the organic layer was filtered through a pad of sodium sulfate and evaporated under reduced pressure to yield product 118 as an off-white solid. (0.521 g, 90%) 1HNMR (CDCl3) δ 7.86 (m, 5H), 7.2 (d, J=2.4 Hz, 1H), 7.0 (dd, J=2.8 Hz, 9.2 Hz, 1H), 6.91 (d, J=8.8 Hz, 2H), 6.46 (d, J=16, 1H), 3.87 (s, 3H, CH3) (M−1=386.2).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[CH:17][N:16]2[CH:24]=1.[CH2:25]([NH2:28])[C:26]#[CH:27]>>[CH2:25]([NH:28][C:21]([C:19]1[CH:18]=[CH:17][N:16]2[CH:24]=[C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])[N:14]=[C:15]2[CH:20]=1)=[O:22])[C:26]#[CH:27]
Reactant: C#CCN
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Product: C#CCNC(=O)c1ccn2cc(-c3c(-c4ccccc4)noc3C)nc2c1
Yield: 63 %

Procedure:
As described for Example 11b, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid (64 mg, 0.2 mmol) was converted, using propargylamine instead of aminomethylcyclopropane, to the title compound (45 mg, 63%) which was obtained as a white solid. MS: m/e=357.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C@@H:69]([NH2:73])([CH2:71][CH3:72])[CH3:70]>C1(C)C=CC=CC=1.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH:73][C@H:69]([CH2:71][CH3:72])[CH3:70])[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=1)=[O:4]
Reactant: CC[C@H](C)N
Reactant: CCOC(=O)c1cc(C(=O)OC)cc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C(=O)OC)cc(N[C@@H](C)CC)n1
Yield: 72 %

Procedure:
Dissolve 6-chloropyridine-2,4-dicarboxylic acid 2-ethyl ester 4-methyl ester (2.8 g, 11.5 mmol), palladium (II) acetate (258.0 mg, 1.15 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (716 mg, 1.15 mmol) and cesium carbonate (5.6 g, 17.2 mmol) in toluene (25 mL) in a previously degassed sealed vessel. Flush the mixture with nitrogen gas. Add (S)-(+)-sec-butylamine (1.38 mL, 13.8 mmol) to the solution under nitrogen and heat the sealed mixture overnight at 100° C. Cool the reaction to room temperature. Dilute with diethyl ether and filter through a filtering agent. Concentrate the filtrate and purify (silica gel chromatography, eluting with 0:100 to 10:90 ethyl acetate:hexanes) to give the title compound as an oil (72%).
Reaction SMILES: [NH2:1][CH:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][SH:5].[OH-].[K+].Br[CH2:12][CH2:13][OH:14]>C(O)C>[NH2:1][CH:2]([CH2:3][CH2:4][S:5][CH2:12][CH2:13][OH:14])[C:6]([OH:8])=[O:7]
Reactant: NC(CCS)C(=O)O
Reactant: OCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NC(CCSCCO)C(=O)O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To D,L-homocysteine (6.69 g, 49.4 mmol) was added 2N aqueous potassium hydroxide (32 mL) and the resulting solution was cooled to 0° C. 2-Bromoethanol (4.2 mL, 59.3 mmol) in ethanol (56 mL) was then added dropwise and the reaction mixture was allowed to warm to 25° C. After 18 h the reaction mixture was acidified to pH 5 and concentrated to give 2-(amino)4-[(2-hydroxyethyl)sulfanyl]butanoic acid (WO 9808823 ) as a white paste. To this material was added water (110 mL) and dioxane (110 mL) and triethylanine (20.7 mL, 148 mmol) and to the resulting solution was added 4-(2-butynyloxy)phenylsulfonyl chloride (14.2 g, 54.3 mmol). After 20h the reaction mixture was acidified to pH 1 with 1N aqueous hydrochloric acid and extracted with dichloromethane (3+). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give 2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)4-[(2-hydroxyethyl)sulfanyl]butanoic acid as an oil (20.8 g). Electrospray Mass Spec 385.8 (M−H)−.
Reaction SMILES: [CH:1]1([CH2:11][C:12](O)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.[CH3:15][CH:16]1[NH:21][CH:20]([CH3:22])[CH2:19][N:18]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=2)[CH2:17]1.N1(C2C=CC(S(N)(=O)=O)=CC=2)CCNCC1.ClCCC1C2C(=CC=CC=2)C(C)CO1.C[C@H]1CNC[C@@H](C)N1>>[C@H:1]1([CH2:11][CH2:12][N:21]2[C@@H:16]([CH3:15])[CH2:17][N:18]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=3)[CH2:19][C@H:20]2[CH3:22])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1
Reactant: O=C(O)CC1OCCc2ccccc21
Reactant: CC1CN(c2ccc(C(N)=O)cc2)CC(C)N1
Agent: CC1COC(CCCl)c2ccccc21
Agent: C[C@@H]1CNC[C@H](C)N1
Agent: NS(=O)(=O)c1ccc(N2CCNCC2)cc1
Product: C[C@@H]1CN(c2ccc(C(N)=O)cc2)C[C@H](C)N1CC[C@@H]1OCCc2ccccc21

Procedure:
Following the general procedure of EXAMPLE 48 and making non-critical variations (-)-isochromanylacetic acid (LXI, EXAMPLE 45, 0.346 g) and 4-(3,5-dimethylpiperazin-1-yl)benzamide [(IV), 0.462 g; prepared from 4-fluorobenzamide (III) and cis-2,6-dimethylpiperazine (II, Aldrich) by the procedure of EXAMPLE 47, Step 1] gives the title compound, mp 206°-207°; MS (m/z) 393; IR (mineral oil) 1640, 1607, 1246, 3383, 1402, 1395, 1422, 1112 and 1332 cm-1.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:20]([O-:22])=[O:21])[CH:6]=[CH:7][C:8]=2B2OC(C)(C)C(C)(C)O2)[C:3]1=[O:23].Br[C:25]1[CH:26]=[N:27][N:28]([CH2:30][CH2:31][CH2:32][OH:33])[CH:29]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:33][CH2:32][CH2:31][CH2:30][N:28]1[CH:29]=[C:25]([C:8]2[CH:7]=[CH:6][C:5]([N+:20]([O-:22])=[O:21])=[C:4]3[C:9]=2[CH2:10][N:2]([CH3:1])[C:3]3=[O:23])[CH:26]=[N:27]1
Reactant: OCCCn1cc(Br)cn1
Reactant: CN1Cc2c(B3OC(C)(C)C(C)(C)O3)ccc([N+](=O)[O-])c2C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN1Cc2c(-c3cnn(CCCO)c3)ccc([N+](=O)[O-])c2C1=O

Procedure:
A suspension of 2-methyl-7-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one (Compound 1I, 1.825 g, 5.736 mmol), 3-(4-bromo-1H-pyrazol-1-yl)propan-1-ol (1.45 g, 7.07 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (510 mg, 0.62 mmol), and potassium carbonate (2.4 g, 17.3 mmol) in dioxane (20 mL) and H2O (5 mL) was irradiated in a microwave reactor for 45 min at 100° C. The reaction mixture was poured into water and extracted with CH2Cl2 three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified using a Teledyne ISCO CombiFlash® Rf system (eluting with 0-15% MeOH:CH2Cl2) to isolate the desired compound as 920 mg as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.05 (s, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 4.72 (s, 2H), 4.63 (t, J=5.1 Hz, 1H), 4.25 (t, J=7.1 Hz, 2H), 3.43 (q, J=6.1 Hz, 2H), 3.11 (s, 3H), 1.98 (quin, J=6.6 Hz, 2H). HRMS (ESI): m/z 317.11 [M+H]+. UPLC: tR=0.91 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]1[CH:17]=[C:16]([CH2:18][N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:22][CH:21]([NH:36]C(OCC3C=CC=CC=3)=O)[C:20]2=[O:47])[N:15]=[CH:14]1)([O-:3])=[O:2].[BrH:48]>C(Cl)Cl>[BrH:48].[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]1[CH:17]=[C:16]([CH2:18][N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[N:22][CH:21]([NH2:36])[C:20]2=[O:47])[N:15]=[CH:14]1)([O-:3])=[O:2]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(Cc2cn(-c3ccc([N+](=O)[O-])cc3[N+](=O)[O-])cn2)C1=O)OCc1ccccc1
Agent: Br
Solvent: ClCCl
Product: NC1N=C(c2ccccc2)c2ccccc2N(Cc2cn(-c3ccc([N+](=O)[O-])cc3[N+](=O)[O-])cn2)C1=O
Temperature: 25 °C

Procedure:
1,3-Dihydro-1-[1-(2,4-dinitrophenyl)-4-imidazolyl]methyl-3-[(benzyloxycarbonyl)amino]-5-phenyl-2H-1,4-benzodiazepin-2-one (70 mg) was dissolved in 10 ml of methylene chloride. The resulting solution was cooled to 0° C. and saturated with hydrogen bromide gas for 10 minutes. The reaction vessel was sealed and the reaction mixture was allowed to warm to room temperature over 0.5 hours. The vessel was vented and the solvent and excess hydrogen bromide gas were removed under reduced pressure to give 70 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2([CH2:15][F:16])[NH:13][C:12](=S)[CH2:11][O:10][CH2:9]2)[CH:7]=1.[NH3:18].CO>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2([CH2:15][F:16])[CH2:9][O:10][CH2:11][C:12]([NH2:18])=[N:13]2)[CH:7]=1
Reactant: N
Reactant: FCC1(c2cc(Br)ccc2F)COCC(=S)N1
Solvent: CO
Product: NC1=NC(CF)(c2cc(Br)ccc2F)COC1

Procedure:
A solution of 6.14 g (18.05 mmol) 5-(5-bromo-2-fluoro-phenyl)-5-fluoromethyl-morpholine-3-thione in 77 ml 7M NH3/MeOH was stirred at rt for 15 h. The mixture was evaporated and purified chromatographed on silica gel (DCM/1-5% MeOH followed by DCM/MeOH/aqueous NH3 95:4.5:0.5) to give the desired product as yellowish resin.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>>[NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1N
Yield: 89 %

Procedure:
A mixture of 118.8 g of 2-amino-4-nitro-benzoic acid, 1000 ml of methanol and 120 ml of concentrated sulfuric acid is heated at the boiling point for 16 hours. The mixture is concentrated under reduced pressure, the residue is taken up in ethyl acetate and the mixture is washed with saturated NaHCO3 solution. After drying over Na2SO4, the organic phase is concentrated. 114.2 g (89%) of methyl 2-amino-4-nitro-benzoate are thus obtained with a melting point (m.p.) of 156-158° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:15][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>C(Cl)Cl.O.C(OCC)C>[CH:29]([O:28][C:26](=[O:27])[NH:1][CH:2]1[CH2:15][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1)([CH3:31])[CH3:30]
Reactant: CC(C)OC(=O)Cl
Reactant: N#Cc1ccc2[nH]c3c(c2c1)CC(N)C3
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)OC(=O)NC1Cc2[nH]c3ccc(C#N)cc3c2C1
Reaction time: 0.17 h
Yield: 73.8 %

Procedure:
Under nitrogen, mix (±)-2-amino-1,2,3,4-tetrahydro-cyclopenta[b]indole-7-carbonitrile (7.0 g, 35.5 mmol) with diisopropylethylamine (7.4 mL, 42.6 mmol) in CH2Cl2 (70 mL). Add isopropyl chloroformate (1.0 M in toluene, 42.6 mL, 42.6 mmol) and stir overnight at room temperature. Dilute with water (100 mL) and ethyl ether (50 mL), stir for 10 min and collect the solid. After drying, obtain 7.42 g (61%) of the title compound as a tan solid. MS (m/z): 284 (M+1), 282 (M−1).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].[C:16]([OH:21])(=[O:20])[C:17]([CH3:19])=[O:18].P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.[Mg+2].[Cl-].[Cl-]>C(O)C(N)(CO)CO.Cl>[C:1]([NH:4][C@H:5]1[C@H:11]([C@@H:10]([C@@H:9]([CH2:14][OH:15])[OH:8])[OH:13])[O:12][C:17]([OH:18])([C:16](=[O:21])[OH:20])[CH2:19][C@@H:6]1[OH:7])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CC(=O)C(=O)O
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O

Procedure:
A solution prepared by dissolving 22 g of N-acetylglucosamine and 11 g of pyruvic acid in 50 mM of Tris-HCl buffer (pH 7.5) containing 5 mM ATP and 5 mM MgCl2. To the solution was added 15 mg of protein having renin binding activities obtained in example 3 and 500 unit of N-acetylneuraminic acid lyase, and the total volume of the solution was adjusted to 0.5 liter. The mixture was reacted at 30° C. for 48 hours. After the reaction, 12.4 g of N-acetylneuraminic acid was produced in the reaction mixture. Reaction product was isolated by ion-exchange chromatography with Dowex 11 (DOW CHEMICAL CO.). After concentration, 10.3 g of N-acetylneuraminic acid was obtained by lyophilization.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)/[C:3]=1[CH2:20][CH2:21][N:22]([OH:26])C(N)=O.ClC1C=C(C=CC=1)C(OO)=[O:32]>ClCCl>[NH:22]([CH2:21][CH2:20][C:3]1/[C:4](=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:19])=[O:32])=[CH:16][CH:17]=2)/[C:5]2[C:10]([C:2]=1[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=2)[OH:26]
Reactant: CSc1ccc(/C=C2/C(CCN(O)C(N)=O)=C(C)c3ccccc32)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1=C(CCNO)/C(=C/c2ccc(S(C)=O)cc2)c2ccccc21

Procedure:
To a solution of the hydroxylamine from Example 16, Step 6 (130 mg, 0.40 mmol) in dichloromethane (5 mL) at 0° C. was added in one portion 850% m-chloroperoxy benzoic acid (90 mg, 0.44 mmol, 1.1 eq.). After 45 minutes the reaction mixture was diluted with dichloromethane and washed successively with 1N aqueous sodium hydroxide, water, brine, dried over MgSO4 and evaporated to dryness. The residue was chromatographed on silica gel eluting with a 30:1 mixture of dichloromethane:methanol to yield the title compound as yellow oil.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([OH:28])=O)=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8](=[O:30])[C@H:7]2[CH2:31][CH3:32])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH:64]1([CH2:67][N:68]2[CH2:73][CH2:72][N:71]([CH2:74][C@@H:75]([O:78][CH3:79])[CH2:76][NH2:77])[CH2:70][CH2:69]2)[CH2:66][CH2:65]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([NH:77][CH2:76][C@H:75]([O:78][CH3:79])[CH2:74][N:71]5[CH2:70][CH2:69][N:68]([CH2:67][CH:64]6[CH2:65][CH2:66]6)[CH2:73][CH2:72]5)=[O:28])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8](=[O:30])[C@H:7]2[CH2:31][CH3:32])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C1CCCC1
Reactant: CO[C@@H](CN)CN1CCN(CC2CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC[C@@H](CN4CCN(CC5CC5)CC4)OC)c4c3OCC4)nc2N1C1CCCC1
Reaction time: 2 h
Yield: 47.6 %

Procedure:
7-[[(7R)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 1q (115 mg, 0.26 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (85 mg, 0.26 mmol) were dissolved in 30 mL of anhydrous dichloromethane followed by the addition of diisopropylethylamine (0.1 mL, 0.58 mmol) and the crude compound (2S)-3-[4-(cyclopropylmethyl)piperazin-1-yl]-2-methoxy-propan-1-amine 35d (60 mg, 0.26 mmol) successively. The reaction solution was stirred for 2 hours. The resulting solution was added with 30 mL of saturated sodium carbonate solution and extracted with dichloromethane (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-[(2S)-3-[4-(cyclopropylmethyl)piperazin-1-yl]-2-methoxy-propyl]-2,3-dihydrobenzofuran-4-carboxamide 35 (80 mg, yield: 47.0%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([NH:11]CC2C=CC(OC)=CC=2)[CH:8]=[N:9][CH:10]=1)[CH3:3]>C(O)(C(F)(F)F)=O>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[N:9][CH:10]=1)[CH3:1]
Reactant: COc1ccc(CNc2cncc(CN(C)C)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)Cc1cncc(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
5-((dimethylamino)methyl)-N-(4-methoxybenzyl)pyridin-3-amine (LVI) (0.15 g, 0.56 mmol) was dissolved in TFA (2.0 mL) and stirred at room temperature for 1 h. The TFA was removed, and the residue was treated with 7N ammonia in MeOH/chloroform mixture (7/93) to neutralize the TFA and concentrated again to a residue. The residue was purified by flash silica gel chromatography utilizing a 4 g Thomson normal-phase silica gel cartridge (100% CHCl3→3:97 MeOH[7N NH3]:CHCl3) to afford 5-((dimethylamino)methyl)pyridin-3-amine (LVII) (0.044 g, 0.29 mmol, 52% yield) as a brown oil. ESIMS found for C8H13N3 m/z 152 (M+H).
Reaction SMILES: [CH2:1]([C@H:8]([CH2:12][CH:13]=[CH2:14])[C:9](O)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[CH3:16][NH:17][CH3:18].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH3:16][N:17]([CH3:18])[C:9](=[O:10])[C@H:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:12][CH:13]=[CH2:14]
Reactant: C=CC[C@@H](CCCCCCC)C(=O)O
Reactant: CNC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC[C@@H](CCCCCCC)C(=O)N(C)C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
To a mixture of 5.00 g (0.025 mol) of the product of Example 5 and 2.27 g (0.028 mol) of dimethylamine hydrochloride in DMF at 0° C. was added 4.2 mL (0.028 mol) of diethyl cyanophosphonate followed by 7.38 mL (0.053 mol) of triethylamine. The reaction mixture was stirred at 0 degrees for 1 h and then at room temperature for 3 h. The resulting pale yellow suspension was diluted with 750 mL of EtOAc/Hex (2:1) and this solution was then washed with 5% aqueous HCl solution, water, saturated sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:4) to provide 5.68 g (100%) of the title compound as a colorless oil. CI Mass Spec: 226.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13](/[CH:15]=[CH:16]\[C:17]3[C:18]([CH3:24])=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2]>[Pd].C1COCC1>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][CH2:16][C:17]3[C:18]([CH3:24])=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc2cc(/C=C\c3ccc(C)nc3C)ccc12
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1csc2cc(CCc3ccc(C)nc3C)ccc12
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
A mixture of ethyl(6-((Z)-2-(2,6-dimethylpyridin-3-yl)vinyl)-1-benzothiophen-3-yl)acetate (110 mg), 10% Pd—C (50% wet, 50 mg) and THF (5 mL) was hydrogenated under atmospheric pressure for 30 min. The catalyst was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (90 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH2:18])=[CH:16][C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:2].[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>C(#N)C>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([Cl:26])[CH:28]=3)=[CH:16][C:15]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CCN(c2ncc(-c3ccccc3)cc2N)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CC#N
Product: CCOC(=O)CC1CCN(c2ncc(-c3ccccc3)cc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 0.10 g (0.29 mmol) of (3′-amino-5′-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester in acetonitrile (5 mL) is added 0.041 mL (0.32 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred at room temperature for 2 hours then concentrated under reduced pressure. A saturated aqueous solution of ammonium chloride is added and the mixture is extracted with ethyl acetate. The combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 0.115 g (81%) of [3′-(3-chloro-benzoylamino)-5′-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester as a colorless foam.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+](CC)([O-])=O.FC1C=CC=C[C:17]=1[CH:18]=[O:19].[N+](CCC)([O-])=O>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:18](=[O:19])[CH3:17]
Reactant: O=Cc1ccccc1Cl
Reactant: O=Cc1ccccc1F
Solvent: CC[N+](=O)[O-]
Solvent: CCC[N+](=O)[O-]
Product: CC(=O)Cc1ccccc1Cl
Yield: 27 %

Procedure:
Following a procedure similar to that described in Preparation 9, except that equivalent amounts of 2-chlorobenzaldehyde and nitroethane were used in place of the 2-fluorobenzaldehyde and nitropropane, the title compound was obtained as a brown oil in a yield of 27%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:27][OH:28]>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH2:19])=[N:27][OH:28])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#CCCCCC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(CCCCC1CCN(Cc2ccccc2)CC1)=NO
Yield: 62.8 %

Procedure:
A mixture of 1-benzyl-4-(4-cyanobutyl)piperidine (2.20 g), potassium carbonate (3.56 g) and hydroxylamine hydrochloride (2.39 g) was heated under reflux for 20 hours. After cooling, the mixture was filtered and evaporated in vacuo. The residue was dissolved in ether, filtered and recrystallized to afford 5-(1-benzylpiperidin-4-yl)-1-hydroxyiminopentylamine (1.56 g).