Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6]([CH:7]=[O:8])[C@:5]1([CH3:23])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][C:12]([CH3:22])([CH3:21])[C:11]=2[CH:10]=1.CC12C(C)(C)C(C(OC[C@@H]3[C@@H](COC)[C@]3(C)C3C=CC4C(C)(C)CCC(C)(C)C=4C=3)=O)(CC1)OC2=O>>[CH3:1][O:2][CH2:3][C@@H:4]1[C@@H:6]([CH:7]=[O:8])[C@@:5]1([CH3:23])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][C:12]([CH3:22])([CH3:21])[C:11]=2[CH:10]=1
Reactant: COC[C@@H]1[C@H](C=O)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: COC[C@@H]1[C@@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: COC[C@@H]1[C@@H](C=O)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 81 %

Procedure:
Following a procedure similar to that for the preparation of Intermediate 12a but using Intermediate 11a as the starting material afforded the title compound (25 mg, 81% yield) as a colorless oil:
Reaction SMILES: C([NH:14][CH:15]([P:27]([OH:29])[OH:28])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(NC(P(O)O)C(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[NH2:14][CH:15]([P:27]([OH:29])[OH:28])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1
Reactant: COc1ccc(CC(NC(c2ccccc2)c2ccccc2)P(O)O)cc1OC
Agent: CC(C)C(NC(c1ccccc1)c1ccccc1)P(O)O
Product: COc1ccc(CC(N)P(O)O)cc1OC

Procedure:
The procedure described in Example 36B was repeated using DL-1-benzhydrylamino-2-(3,4-dimethoxyphenyl)-ethanephosphonous acid (as obtained in Example 20) instead of DL-1-benzhydrylamino-2-methylpropanephosphonous acid to give DL-1-amino-2-(3,4-dimethoxyphenyl)-ethanephosphonous acid. This was treated with 60% hydrogen bromide at 80° followed by propylene oxide to give DL-1-amino-2-(3,4-dihydroxyphenyl)-ethanephosphonous acid, melting point 237°-238°, identical to that obtained in Example 20.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]34[CH2:22][CH2:21][C:17]([CH2:23][OH:24])([CH2:18][CH:19]3Br)[CH2:16][O:15]4)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.CC(N=NC(C#N)(C)C)(C#N)C.CCCC[SnH](CCCC)CCCC>C1(C)C=CC=CC=1.O1CCCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]34[CH2:22][CH2:21][C:17]([CH2:23][OH:24])([CH2:18][CH2:19]3)[CH2:16][O:15]4)=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Nc1ccc(-c2ccc(C34CCC(CO)(CO3)CC4Br)cc2)nc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2ccc(C34CCC(CO)(CC3)CO4)cc2)nc1
Temperature: 100 °C
Yield: 31.3 %

Procedure:
To a stirred solution of (1-(4-(5-aminopyridin-2-yl)phenyl)-6-bromo-2-oxabicyclo[2.2.2]octan-4-yl)methanol (240 mg, 0.617 mmol) in toluene (8 ml) and tetrahydrofuran (8 ml) at 40° C. in a microwave vial under nitrogen, was added the mixture of AIBN (40.5 mg, 0.247 mmol) and Bu3SnH (0.980 ml, 3.70 mmol) in toluene at 40° C. The reaction mixture was heated at 100° C. for 3 hours. Most of solvent was removed by evaporation under vacuum, and the residue was purified by chromotography (heptanes/acetone 1/2) to afford (1-(4-(5-aminopyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methanol (60 mg, 31%) as yellow solid. LC/MS, [MS+1] 311.1, RT: 0.80; (Condition E).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:14]=[CH:15][C:16]([CH3:38])=[C:17]([NH:19][C:20](=[O:37])[CH2:21][O:22][CH2:23][C:24]([NH:26][C:27]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:28]=2[C:29]([OH:31])=[O:30])=[O:25])[CH:18]=1>>[Cl:36][C:33]1[CH:34]=[CH:35][C:27]([NH:26][C:24](=[O:25])[CH2:23][O:22][CH2:21][C:20]([NH:19][C:17]2[CH:18]=[C:13]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:14]=[CH:15][C:16]=2[CH3:38])=[O:37])=[C:28]([CH:32]=1)[C:29]([OH:31])=[O:30]
Reactant: Cc1ccc(Br)cc1NC(=O)COCC(=O)Nc1ccc(Cl)cc1C(=O)O
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(C)c(NC(=O)COCC(=O)Nc3ccc(Cl)cc3C(=O)O)c2)cc1

Procedure:
Using the same method as in Example 19-(ii), 4-methoxybenzene boronic acid was reacted with the 2-[((2-[(5-bromo-2-methylphenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester obtained in Example 38-(i) to give 5-chloro-2-[((2-[(4′-methoxy-4-methylbiphenyl-3-yl)amino]-2-oxoethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 84%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7](#[N:10])[CH:8]=[CH2:9]>O>[N:1]1([CH2:9][CH2:8][C:7]#[N:10])[CH2:6][CH2:5][N:4]([CH2:9][CH2:8][C:7]#[N:10])[CH2:3][CH2:2]1
Reactant: C=CC#N
Reactant: C1CNCCN1
Solvent: O
Product: N#CCCN1CCN(CCC#N)CC1
Yield: 96 %

Procedure:
A solution of piperazine (1 g, 11.6 mmol) and acrylonitrile (1.6 g, 30.16 mmol, 2.6 eq) in water (10 cm3) were stirred at room temperature for 5 hours, after which the mixture was extracted with dichloromethane (2×50 cm3). The organic extracts were evaporated under reduced pressure to give the pure doubly cyanoethylated compound 3,3′-(piperazine-1,4-diyl)dipropanenitrile (2.14 g, 94.7%) as a white solid, mp 66-67° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[C:13]([C:19]([O:21][CH3:22])=[O:20])#[C:14][C:15]([O:17][CH3:18])=[O:16].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Cl:12][C:10]1[CH:11]=[C:2]2[C:3]([C:4]([OH:6])=[C:13]([C:19]([O:21][CH3:22])=[O:20])[C:14]([C:15]([O:17][CH3:18])=[O:16])=[N:1]2)=[CH:8][CH:9]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: COC(=O)c1ccc(Cl)cc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Temperature: 25 °C
Yield: 28.8 %

Procedure:
A stirred mixture of methyl 2-amino-4-chlorobenzoate (2.50 g, 13.5 mmol) and dimethyl acetylene dicarboxylate (2.05 g, 14.4 mmol) in tert-butanol (22 ml) was refluxed for 7 hours under a nitrogen atmosphere. After adding additional dimethyl acetylenedicarboxylate (1.16 g, 8.13 mmol) and refluxing another 2.5 hours, the reaction mixture was allowed to cool to room temperature and potassium tert-butoxide (1.56 g, 13.9 mmol) was added in one portion. A precipitate formed and the resulting mixture was refluxed for 1.5 hours. The mixture was cooled to room temperature and filtered to separate the solids, which were washed with tert-butanol and diethyl ether. The solids were dissolved in water and acidified with 1 N sulfuric acid to form a precipitate. The resulting mixture was extracted with DCM and the combined extracts were washed with brine and water, dried over MgSO4, filtered and concentrated to give a green solid. Recrystallization of this material from methanol provided the title compound (1.15 g, 47%) as an off-white solid, mp 232-233° C.; MS (Cl): 296 (M+H). Analysis for C13H10ClNO5: Calc'd: C, 52.81; H, 3.41; N, 4.74; Found: C, 52.75; H, 3.47; N, 4.69.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][OH:29])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:33][CH3:34]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][O:29][CH2:33][CH3:34])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CO)C1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of (R)-1-(4-fluorophenyl)-4a-hydroxymethyl-1,4,4a,5,7,8-hexahydro-1,2,6-triazacyclopenta[b]naphthalene-6-carboxylic acid tert-butyl ester (0.25 g) in tetrahydrofuran (2.5 mL) under argon at room temperature was treated sequentially with sodium hydride (0.072 g, 60% dispersion in mineral oil) and iodoethane (0.15 mL), and the resulting mixture was stirred at 50° C. for 2 hour. The solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, water and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (9:1 by volume), to afford the title compound as an amber gum (0.21 g). LCMS (Method E): 428 (M+H)+, Retention time 4.7 minutes.
Reaction SMILES: [N+](=[C:3]1[CH2:11][CH2:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[C:7]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[CH:6][C:5]=2[C:4]1=[O:31])=[N-].[C:32]([OH:36])([CH3:35])([CH3:34])[CH3:33].C(OCC)C>N1C(C)=CC(C)=CC=1C>[C:32]([O:36][C:4]([C:3]1[C:5]2[C:9]([N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH:7]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH:6]=2)=[CH:10][CH:11]=1)=[O:31])([CH3:35])([CH3:34])[CH3:33]
Reactant: [N-]=[N+]=C1CCc2c(cc(C(=O)OCc3ccccc3)n2Cc2ccc(Cl)c(Cl)c2)C1=O
Reactant: CC(C)(C)O
Solvent: CCOCC
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)(C)OC(=O)C1=CC=C2C1=CC(C(=O)OCc1ccccc1)N2Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 97 %

Procedure:
Benzyl 5-diazo-1-(3,4-dichlorobenzyl)-4-oxo-4,5,6,7-tetrahydroindole-2-carboxylate (0.3 g) and t-butanol (1 mL) were heated at 180° C. in collidine (10 mL) for 30 minutes, cooled to room temperature, and poured into diethyl ether. The organic layer was washed with 2M HCl (100 mL), dried (MgSO4), and concentrated in vacuo to afford the title compound as an orange oil (0.32 g, 97%), NMR d(CDCl3) 1.45 (9H, s), 2.45-2.80 (4H, m), 3.78 (1H, dd), 5.20 (2H, d), 5.40 (2H, d), 6.80 (1H, dd), 6.95 (1H, s), 7.10 (1H, s), 7.30 (6H, m); M/z (+) 502, 500 (M+).
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@H:5]([NH2:11])[CH2:4]2.[Br:12][C:13]1[S:17][C:16]([C:18](O)=[O:19])=[CH:15][CH:14]=1.O.ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@H:5]([NH:11][C:18]([C:16]1[S:17][C:13]([Br:12])=[CH:14][CH:15]=1)=[O:19])[CH2:4]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: O=C(O)c1ccc(Br)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CN2CCC1CC2)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of (S)-N-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride (1.9 g), 5-bromothiophene-2-carboxylic acid (1.97 g), 1-hydroxybenzotriazole hydrate (1.28 g), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (3.06 g), and N,N-diisopropylethylamine (8.3 mL) in N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. The solution was evaporated, and the residue was partitioned between aqueous sodium hydroxide and chloroform. The chloroform layer was dried (Mg2SO4), filtered, and evaporated. The residue was purified by flash chromatography on silica gel and eluted with 5%-20% 3.5M methanolic ammonia/chloroform mixtures. Evaporation of solvent gave white solid (3 g); MS (ES+) 315, 317 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@@H:5]1[O:10][CH2:9][C@@H:8]([CH3:11])[N:7](CC2C=CC=CC=2)[CH2:6]1)[CH3:3]>CCO.[Pd]>[CH3:3][N:2]([CH2:4][C@H:5]1[O:10][CH2:9][C@@H:8]([CH3:11])[NH:7][CH2:6]1)[CH3:1]
Reactant: C[C@@H]1CO[C@@H](CN(C)C)CN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CO[C@H](CN(C)C)CN1
Temperature: 130 °C

Procedure:
(2S,5R)-2-[Dimethylamino(methyl)]-5-methyl-4-benzylmorpholine (28 g, 113 mmol, 1 equivalent), was dissolved in EtOH (1 M), and the solution was transferred to a stainless steel high pressure vessel equipped with a pressure gauge. 10% Pd/C was added (2.8 g, 10 wt. %), and the vessel charged with H2. The reaction mixture was stirred at 130° C. and 200 psi of H2 overnight. The reaction mixture was cooled to room temperature, filtered and evaporated. The desired amine was obtained in quantitative yield as a yellow oil. GC/MS: 128 (10%, M+−2×CH3), 58 (100%, NHCH2CHO), Rt 8.16 minutes.
Reaction SMILES: [NH2:1][C:2]1[N:35]=[C:5]2[N:6]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)[C:7]([CH3:24])=[C:8]([C:22]#[N:23])[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=3[S:18]([CH3:21])(=[O:20])=[O:19])[N:4]2[N:3]=1.C1COCC1.Cl[C:42]([O:44][CH3:45])=[O:43]>N1C=CC=CC=1>[C:22]([C:8]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=2[S:18]([CH3:21])(=[O:20])=[O:19])[N:4]2[N:3]=[C:2]([NH:1][C:42](=[O:43])[O:44][CH3:45])[N:35]=[C:5]2[N:6]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=2)[C:7]=1[CH3:24])#[N:23]
Reactant: COC(=O)Cl
Reactant: CC1=C(C#N)C(c2ccc(C#N)cc2S(C)(=O)=O)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)Nc1nc2n(n1)C(c1ccc(C#N)cc1S(C)(=O)=O)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
Under an atmosphere of argon protective gas, 2-amino-7-[4-cyano-2-(methylsulfonyl)phenyl]-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (7 mg, 13.6 μmol) was dissolved in a mixture of abs. THF (0.6 ml) and abs. pyridine (11 μl). At room temperature, abs. pyridine (5×11 μl) and methyl chloroformate (5×6.4 mg, 5×68.1 μmol; 25 eq.) were added in a plurality of portions. The mixture was then heated as 80° C. for 12 h. Once HPLC analysis showed substantial conversion, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (5.4 mg, 69% of theory).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>C1COCC1.C(Cl)Cl>[C:1]([C:4]1[S:8][C:7]([NH:9][C:17](=[O:19])[CH3:18])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1sc(N)nc1C
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(C)c(C(C)=O)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
5-Acetyl-2-amino-4-methylthiazole (P5) (12.35 g, 79 mmol) is suspended in THF/DCM 3:2 mixture (150 mL). The mixture was cooled down to 0° C. and pyridine (16 mL) is added, followed by the dropwise addition of acetyl chloride (8.43 mL, 119 mmol, 1.5 eq). The mixture was stirred 2 hours at 0° C. As the acetylation is complete, the reaction is quenched with addition of water (70 mL) and diluted with EtOAc (100 mL). The two phases are separated and the organic phase is washed with one portion of 10% citric acid solution. Organic layer is dried over MgSO4, filtrated and evaporated. The resulting crude mass is purified by crystallization in EtOAc/Cyclohexane mixture, to obtain N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)acetamide (P6) as a colorless powder (13.13 g, 83.6% yield). 1H NMR (DMSO-d6) δ: 2.17 (s, 3H), 2.47 (s, 3H), 2.56 (s, 3H), 12.44 (br s, 1H). M− (ESI): 197.3; M+ (ESI): 199.3. HPLC, Rt: 1.7 min (purity: 99.7%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[CH:6][C:5]([F:11])=[C:4]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:3]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[F:11][C:5]1[CH:6]=[C:7]([C:8](=[O:10])[CH3:9])[CH:2]=[N:3][C:4]=1[O:12][CH2:13][C:14]([F:15])([F:16])[F:17]
Reactant: CC(=O)c1cc(F)c(OCC(F)(F)F)nc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)c1cnc(OCC(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A mixture of 1-(2-chloro-5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.23 g, 0.86 mmol, Step-3) and triethylamine (0.17 mL, 1.20 mmol) in ethanol (9 mL) is stirred at room temperature for 1 hour. Then 10% palladium on carbon (0.03 g, 0.28 mmol) is added to the mixture. The mixture is stirred at room temperature under a balloon of hydrogen gas for 5 hours. After filtration through a pad of celite, the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (5:1) to give 0.15 g (76% yield) of the title compound as colorless oil.
Reaction SMILES: Br[C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.C[O:22][B:23](OC)[O:24]C.[Li]CCCC>C1COCC1>[CH:16]1([N:13]2[C:5]3[N:6]=[C:7]([NH:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=3[CH:3]=[C:2]([B:23]([OH:24])[OH:22])[C:14]2=[O:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CNc1nc(C)c2cc(Br)c(=O)n(C3CCCC3)c2n1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNc1nc(C)c2cc(B(O)O)c(=O)n(C3CCCC3)c2n1
Yield: 17.7 %

Procedure:
To a stirred and cooled (−78° C.) solution of 6-bromo-8-cyclopentyl-4-methyl-2-(methylamino)-pyrido[2,3-d]pyrimidin-7(8H)-one (1.00 g, 2.94 mmol) and trimethylborate (1.40 mL, 12.6 mmol) in THF (60 mL) was added BuLi (9.5 mL, 1.6 M, 15.2 mmol). After stirring for 20 min, the mixture was quenched with small amount of 2 N HCl and water, extracted with EtOAc (3 times), dried and evaporated. The crude mixture was purified by silica gel chromatography to give the title compound (157.2 mg, 18%).
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2[CH3:18])[C@H:5]([OH:19])[C@@H:4]1[OH:20].[CH3:21][NH:22][CH3:23]>CO>[CH3:21][N:22]([CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2[CH3:18])[C@H:5]([OH:19])[C@@H:4]1[OH:20])[CH3:23]
Reactant: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Reactant: CNC
Solvent: CO
Product: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CN(C)C)[C@@H](O)[C@H]1O

Procedure:
A mixture of 3a (150 mg, 0.50 mmol) and a 2M solution of dimethylamine in methanol (10 mL) in a steel bomb was heated for 2 days at 90° C. The reaction mixture was concentrated to dryness and purified by column chromatography (elution with 4:1:0.15 chloroform:methanol:NH4OH). The desired fractions were combined, concentrated and dried in vacuo: yield 38 mg (25%); MS m/z 309 (M+H)+; 1HNMR (DMSO-d6) δ 8.08 (s, 1H, H-2), 7.11 (bs, 2H, 6-NH2), 5.74 (d, 1H, H-1′, J1′,2′=5.5 Hz), 5.31 (d, 1H, OH-2′, J2′-2′OH=5.9 Hz), 5.18 (d, 1H, OH-3′, J3′-3′OH=5.4 Hz), 5.03 (ddd, 1H, H-2′, J1′,2′=5.5 Hz, J2′,3′=4.6 Hz, J2′-2′OH=5.9 Hz), 4.15 (ddd, 1H, H-3′, J2′,3′=4.6 Hz, J3′,4′=5.5 Hz, J3′-3′OH=5.4 Hz), 3.91-3.96 (m, 1H, H-4′), 2.55-2.61 (m, 1H, 5′-CH2), 2.53 (s, 3H, 8-CH3), 2.42-2.48 (m, 1H, 5′-CH2), 2.14 (bs, 6H, N—(CH3)2); UV λmax, nm, pH 1, 258.5 (∈ 15,300), pH 7, 259.3 (∈ 15,300), pH 13, 260.1 (∈ 15,500). Anal. (C13H20N6O3.0.35CHCl3.0.5C2H5OH) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=O)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([NH2:26])[C:22]([NH2:25])=[CH:23][CH:24]=1>O=P(Cl)(Cl)Cl.O>[Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12]3[NH:26][C:21]4[CH:20]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:24]=[CH:23][C:22]=4[N:25]=3)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: FC(F)(F)c1ccc2nc(-c3ccc(-c4ncccc4Cl)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.3 %

Procedure:
To a solution of 0.64 g (2.75 mmol) 4-(3-chloropyridin-2-yl)benzoic acid in 20 mL POCl3 was added 0.44 g (2.5 mmol) 4-trifluoromethylbenzene-1,2-diamine, followed by stirring for 3 hours in a heat flux condition. The solution was cooled to room temperature and dissolved in distilled water. After the adjustment of pH to 8-10 with ammonia, extraction was conducted using ethyl acetate. The organic layer was dried over magnesium sulfate and vacuum concentrated. The residue thus obtained was separated using column chromatography (developing solvent: chloroform/methanol=30/1) to produce 0.61 g of 2-[4-(3-chloropyridin-2-yl)phenyl]-6-trifluoromethyl-1H-benzoimidazole (yield 65%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][CH2:24][N:25]1[CH2:31][CH2:30][C:29]2[CH:32]=[CH:33][C:34]([N+:36]([O-:38])=[O:37])=[CH:35][C:28]=2[CH2:27][CH2:26]1)=[N+]=[N-].O>O1CCCC1>[NH2:20][CH2:23][CH2:24][N:25]1[CH2:31][CH2:30][C:29]2[CH:32]=[CH:33][C:34]([N+:36]([O-:38])=[O:37])=[CH:35][C:28]=2[CH2:27][CH2:26]1
Reactant: [N-]=[N+]=NCCN1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCN1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triphenylphosphine (0.71 g) was added to a solution of 3-(2-azidoethyl)-7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (0.68 g) in dry tetrahydrofuran under a nitrogen atmosphere and the reaction mixture was then stirred at room temperature for 18 hours and heated at 50° for 5 hours. After cooling, water was added and the mixture was stirred at room temperature for 3 days. The solvent was then evaporated in vacuo and the residue was diluted with 2M hydrochloric acid and washed three times with ethyl acetate. The aqueous layer was made alkaline (pH=12) with 5M sodium hydroxide and extracted three times with ethyl acetate. The latter organic extracts were combined and dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as an oil, yield 0.56 g, which was used without further purification.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[C:38](=[N:40]O)[NH2:39]>>[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[C:38]1[N:40]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:12]2)[O:28][N:39]=1
Reactant: NC(=NO)c1ccc(F)cc1F
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(-c4ccc(F)cc4F)no3)C2)CC1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 46.2 mg (0.269 mmol) of 2,4-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 63.9 mg (47% of theory).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Br:9][C:10]1[C:11]([CH3:19])=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14]>S(=O)(=O)(O)O>[Br:9][C:10]1[C:11]([CH3:19])=[C:12]([CH:16]=[C:17]([I:1])[CH:18]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1c(Br)cccc1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1c(Br)cc(I)cc1C(=O)O
Temperature: 7.5 °C
Reaction time: 3 h

Procedure:
N-Iodosuccinimide (5.8 g) is added in portions to an ice-cold solution of sulphuric acid (20 mL). The resulting mixture is stirred for 40 min before 3-bromo-2-methyl-benzoic acid (5.0 g) dissolved in sulphuric acid (20 mL) is added at such a rate that the solution temperature maintained below 5° C. The mixture is stirred at 5-10° C. for another 3 h before warming to room temperature over night. Then, the mixture is poured on crushed ice (300 g) and the resultant solution is extracted with ethyl acetate. The combined extracts are washed in succession with aqueous 10% Na2S2O3 solution (2×), water (3×), and brine (1×). After drying (MgSO4) the organic layer, the solvent is evaporated under reduced pressure to give a solid. The solid is triturated with 70° C.-warm water, separated from the water by filtration and dried. After the solid is triturated with little ether, filtered and dried, the product is obtained as a white solid.