Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][S:5][C:4]=1[N:12]=[C:13]=[O:14])#[N:2].[CH3:15][NH:16][CH3:17]>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:7]([C:8]([CH3:10])([CH3:11])[CH3:9])=[CH:6][S:5][C:4]=1[NH:12][C:13]([N:16]([CH3:17])[CH3:15])=[O:14])#[N:2]
Reactant: CNC
Reactant: CC(C)(C)c1csc(N=C=O)c1C#N
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Nc1scc(C(C)(C)C)c1C#N
Yield: 80 %

Procedure:
20.6 g (0.1 mole) of 3-cyano-4-tert.-butyl-thien-2-yl isocyanate were added dropwise to a solution of 6.5 g (0.145 mole) of dimethylamine in 200 ml of toluene at room temperature. After the exothermic reaction had subsided, the mixture was concentrated and the residue was recrystallized from a little toluene. 20.1 g of 1-(3-cyano-4-tert.-butyl-thien-2-yl)-3,3-dimethyl-urea of melting point 140° C. were obtained in this manner.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:30].C(O)(=O)C.O>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:30][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)c1ccc(Br)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To the solution of (S)-tert-butyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)pyrrolidine-1-carboxylate (compound 18a, 5.0 g, 12.2 mmol) in xylene (75 ml) were added ammonium acetate (23.4 g, 304 mmol) and acetic acid (5 ml) at room temperature. The reaction mixture was placed in an oil bath and heated to 160° C. with water being azeotroped into a Dean-Stark trap. After 3 hours, the resulting mixture was cooled to room temperature and then extracted with ethyl acetate and distillated water. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give a crude product, which was purified with column chromatography (100% ethyl acetate) to yield the pure product 19a (4.4 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][CH:6]=1.Cl.CN(C)CCCN=C=NCC.[NH2:28][C:29]1[N:34]=[C:33]([N:35]([C:37]2[CH:38]=[N:39][C:40]([F:43])=[CH:41][CH:42]=2)[CH3:36])[N:32]=[C:31]([C:44](=[N:46]O)[NH2:45])[N:30]=1>N1C=CC=CC=1.CCOC(C)=O>[F:43][C:40]1[N:39]=[CH:38][C:37]([N:35]([CH3:36])[C:33]2[N:34]=[C:29]([NH2:28])[N:30]=[C:31]([C:44]3[N:45]=[C:11]([C:8]4[CH:9]=[N:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:15])[F:14])=[CH:6][CH:7]=4)[O:13][N:46]=3)[N:32]=2)=[CH:42][CH:41]=1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)nc1
Reactant: CN(c1ccc(F)nc1)c1nc(N)nc(C(N)=NO)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(c1ccc(F)nc1)c1nc(N)nc(-c2noc(-c3ccc(OCC(F)(F)F)nc3)n2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3 %

Procedure:
6-(2,2,2-Trifluoroethoxy)pyridine-3-carboxylic acid (prepared in an analogous manner to Intermediate 206, 0.216 g, 0.051 mmol) was added to a solution of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.049 g, 0.252 mmol) in pyridine (1 mL) and the mixture was stirred at room temperature for 16 h. Further N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0255 g, 0.1 mmol) was added and the mixture was stirred at 50 C for 4 h. 4-Amino-6-[(6-fluoropyridin-3-yl)(methyl)amino]-N′-hydroxy-1,3,5-triazine-2-carboximidamide (Intermediate 156, 0.05 g, 0.18 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0163 g, 0.09 mmol) were added and the mixture was stirred at 50 C for 16 h and then at 60 C for 5 h. The mixture was dissolved in EtOAc and washed with water, and then saturated aq. ammonium chloride, saturated aq. sodium bicarbonate and then brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC, Method B, to afford the title compound (0.002 g, 3%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][NH:8][CH2:7]1.Cl[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=2)[CH2:7]1
Reactant: Clc1ccc(CN[C@H]2CCNC2)c(Cl)c1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1

Procedure:
Stir a mixture of (S)-(2,4-dichlorobenzyl)-pyrrolidin-3-ylamine (200 mg, 0.82 mmol), 6-chloronicotinonitrile (75 mg, 0.54 mmol) and diisopropylethylamine (140 μl, 0.82 mmol) in DMF (5 mL) at room temperature overnight. Concentrate and chromatograph on silica gel to give the title compound. Form the hydrochloride by essentially the procedure in Example 1 to give 1H NMR (300 MHz, MeOH-d4) δ 8.44 (1H, d, J=1.51 Hz), 7.95 (1H, dd, J=9.23, 2.07 Hz), 7.56-7.68 (2H, m), 7.40 (1H, dd, J=8.38, 2.17 Hz), 6.97 (1H, d, J=9.42 Hz), 4.42 (2H, d, J=3.01 Hz), 4.16-4.25 (1H, m), 4.04-4.13 (1H, m), 3.82-3.96 (2H, m), 3.63-3.77 (1H, m), 2.56-2.69 (1H, m), 2.43 (1H, m), MS (ES): 347 [M+].
Reaction SMILES: Cl.[CH3:2][CH:3]1[S:16][C:7]2[N:8]([CH3:15])[C:9]3[C:14]([C:6]=2[C:5](=[O:17])[CH:4]1[CH2:18]N(C)C)=[CH:13][CH:12]=[CH:11][CH:10]=3.[CH3:22][C:23]1[NH:24][CH:25]=[CH:26][N:27]=1.Cl>O.O1CCCC1>[CH3:2][CH:3]1[S:16][C:7]2[N:8]([CH3:15])[C:9]3[C:14]([C:6]=2[C:5](=[O:17])[CH:4]1[CH2:18][N:24]1[CH:25]=[CH:26][N:27]=[C:23]1[CH3:22])=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: Cc1ncc[nH]1
Reactant: CC1Sc2c(c3ccccc3n2C)C(=O)C1CN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1nccn1CC1C(=O)c2c(n(C)c3ccccc23)SC1C

Procedure:
A solution of 2 g (0.062 mol) of 2,9-dimethyl-3-[(dimethylamino)methyl]-4-oxo-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole hydrochloride and 1.64 g (0.020 mol) of 2-methylimidazole in 30 ml of water is stirred under reflux under a nitrogen atmosphere for 16 hours. After the mixture is cooled, the precipitate formed is drained, washed with water and dried. The powder obtained is dissolved in 30 ml of tetrahydrofuran and the solution is treated with an ethereal solution of hydrochloric acid. The precipitate formed is drained, washed with ether, dried and recrystallized in ethanol. The two cis-trans isomers are obtained in a 50:50 ratio.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: OCc1ccccc1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
To a solution of benzyl alcohol (1.04 mL, 10.0 mmol) in dichloromethane (30 mL) is added rhodium (II) acetate dimer (40 mg) followed by ethyl diazoacetate (1.14 g, 10.0 mmol). The reaction mixture is stirred at RT for 20 min. The reaction mixture is rotary evaporated, and the residue is vacuum distilled at 110° C. to give 1.81 g of the product 390. 1H NMR (CDCl3) δ 7.4-7.26 (m, 5H), 4.65 (s, 2H), 4.23 (q, 2H), 4.10 (s, 2H), 1.30 (t, 3H)
Reaction SMILES: O=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16].[Cl:18][CH2:19][CH2:20][N:21]=[C:22]=[O:23]>>[Cl:18][CH2:19][CH2:20][NH:21][C:22]([N:17]([CH2:13][CH2:14][CH2:15][CH3:16])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@@H:3]1[OH:4])=[O:23]
Reactant: O=C=NCCCl
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCN
Product: CCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Yield: 77.8 %

Procedure:
3.6 g of D-mannose, 1.8 g of n-butylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 5-(1). 5.3 g of 1-(2-chloroethyl)-3-n-butyl-3-D-mannopyranosylurea are thereby obtained as colorless caramel.
Reaction SMILES: [CH2:1]([N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[C:8]([NH2:17])[CH:9]=2)[CH2:2][CH3:3].[C:18]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:35])[CH2:28][CH:29]([CH3:34])[CH2:30][C:31](O)=[O:32])=[CH:22][CH:21]=1)#[N:19].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:18]([C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:35])[CH2:28][CH:29]([CH3:34])[CH2:30][C:31]([NH:17][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([CH2:1][CH2:2][CH3:3])[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]3=2)=[O:32])=[CH:24][CH:25]=1)#[N:19]
Reactant: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)cc1
Reactant: CCCn1c2c(c3cc(N)ccc31)CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c2c(c3cc(NC(=O)CC(C)CC(=O)Nc4ccc(C#N)cc4)ccc31)CCCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 33.2 %

Procedure:
To a solution of the compound obtained in Step 2 (229 mg, 1.00 mmol), 5-(4-cyanophenylamino)-3-methyl-5-oxopentanoic acid (247 mg, 1.00 mmol) and DIEA (0.525 mL, 3.01 mmol) in DMF (6 mL) was added HATU (572 mg, 1.50 mmol), and the mixture was stirred at room temperature for 14 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 75% ethyl acetate/hexane) to give the title compound (151 mg, 0.332 mmol, 33.1%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)=[O:12].[H-].[Na+].[CH3:22]I>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:22])[C:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)=[O:12]
Reactant: COc1ccc(CC(=O)c2ccnc(Cl)c2)c(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)C(=O)c2ccnc(Cl)c2)c(Cl)c1
Temperature: 45 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
To a solution of 2-(2-chloro-4-methoxy-phenyl)-1-(2-chloro-pyridin-4-yl)-ethanone (17.1 g, 0.058 mol) in tetrahydrofuran (550 ml) was added sodium hydride (55%-65% dispersion in mineral oil, 2.43 g, 0.063 mol). The mixture was stirred at 45° C. for 3 h and then placed in an ice bath. A solution of methyl iodide (9.01 g, 0.0635 mol) in tetrahydrofuran (50 ml) was added dropwise. The ice bath was removed and the mixture was stirred at 35° C. for 3 h. The mixture was poured in ice water and extracted twice with AcOEt. The organic phases were washed with brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (silica gel, heptane/AcOEt 4:1) to give the title compound (14.7 g) as yellow viscous oil. MS (m/e, ISP neg. ion)=310.3 [M−H−].
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].[CH3:17]N(C=O)C.[H-].[Na+].CI>>[CH3:1][CH:2]1[CH2:7][N:6]([CH3:17])[CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: CN(C)C=O
Reactant: CC1CNCCN1c1ccncc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CC1CN(C)CCN1c1ccncc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
To 2-methyl-1-(3-nitro-4-pyridyl)piperazine in DMF (1.5 mL of 0.3 M, 0.4500 mmol) at 0° C. was added NaH (18.00 mg, 0.4500 mmol). The reaction was stirred for 10 mins then MeI (60.68 mg, 26.61 μL, 0.4275 mmol) was added. The reaction mixture was stirred for 4 hours at RT and quenched by the addition of water. The crude was loaded onto a MeOH pre-washed SCX column, rinsed with MeOH and the product was released with methanolic ammonia. The ammonia extracts were concentrated under reduced pressure. The residue was purified by column chromatography eluting with 1-15% MeOH:DCM to yield 2,4-dimethyl-1-(3-nitropyridin-4-yl)piperazine. MS (ES+) 237.2.
Reaction SMILES: [NH2:1][C:2]1[C:9](I)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[C:15]([Cu])#[N:16]>CN1C(=O)CCC1>[NH2:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[C:5]([C:6]#[N:7])=[CH:8][C:9]=1[C:15]#[N:16]
Reactant: N#C[Cu]
Reactant: N#Cc1cc(I)c(N)cc1C(F)(F)F
Solvent: CN1CCCC1=O
Product: N#Cc1cc(C#N)c(C(F)(F)F)cc1N

Procedure:
4-Amino-5-iodo-2-trifluoromethyl-benzonitrile (1.5 mmoL), CuCN (1.7 mmoL) in NMP (10 mL) was heated at 150° C. for 4 hrs. The reaction mixture was passed through a pad of Celite. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with water, then brine, dried over anhydrous Na2SO4, filtered and concentrated to yield the title compound as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([NH:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][CH:14]=3)=[CH:4][CH:3]=1.S1C=[CH:28][CH:27]=[CH:26]1.CC(=O)C.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([NH:18][CH:19]3[CH2:20][CH2:21][N:22]([CH:27]([CH3:28])[CH3:26])[CH2:23][CH2:24]3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][CH:14]=3)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3cncnc32)cc1
Reactant: c1ccsc1
Agent: [Pd]
Solvent: CO
Solvent: CC(C)=O
Product: CC(C)N1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Yield: 27.2 %

Procedure:
A mixture of 4.9 parts of 9-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-9H-purin-8-amine, 1 part of a solution of thiophene in methanol 4%, 120 parts off methanol and 8 parts of 2-propanone was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1.5 parts (27.2%) of 9-[(4-fluorophenyl)methyl]-N-[1-(1-methylethyl)-4-piperidinyl]-9H-purin-8-amine; mp. 185.6° C. (compound 138).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH3:30]>CN(C=O)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH:26][CH3:30])(=[O:24])=[O:25])=[CH:19][CH:18]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc(-c2nn(C3CCCC3)c3ccnc(OC)c23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (50.0 mg) obtained in Step A of Example 92 in DMF (3 ml) was added sodium hydride (60% dispersion in mineral oil, 5.91 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added iodomethane (0.0126 ml), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (10.9 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[OH:17][CH:18]([CH2:28][N:29]([CH3:31])[CH3:30])[CH2:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[Br:1][C:2]1[C:3]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][C:5]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([O:20][CH2:19][CH:18]([OH:17])[CH2:28][N:29]([CH3:30])[CH3:31])=[CH:22][CH:23]=2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Sc2ccccc2)n1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Agent: Cl
Product: CN(C)CC(O)COc1ccc(Nc2ncc(Br)c(Sc3ccccc3)n2)cc1

Procedure:
Using an analogous method to that described in Example 1, but starting from 5-bromo-2-chloro-4-(phenylthio)pyrimidine (Method 6) and 4-[2-hydroxy-3-(N,N-dimethylamino) propoxy]aniline hydrochloride (Method 8), the product was obtained. NMR: 2.2 (s, 6H), 2.3 (m, 2H), 3.7 (m, 1H), 3.9 (m, 2H), 4.7 (d, 1H), 6.5 (d, 2H), 7.0 (d, 2H), 7.6 (5H), 8.3 (s, 1H), 9.5 (s, 1H); MS (MH+): 475, 477.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CCCCCC.CN([CH:26]=[O:27])C.Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([CH:6]=1)[CH:26]=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(F)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(F)c(C=O)c1
Temperature: -45 °C
Reaction time: 5 h

Procedure:
A solution of 1-tert-butyl-4-fluoro-benzene (4.54 g, 30 mmol) in THF (100 mL) cooled at −78° C. was treated dropwise with a 2.5M solution of nBuLi in hexane (24 mL, 59 mmol). The reaction mixture was stirred for 5 h at −45° C. then DMF (3.5 mL, 44 mmol) was added at −75° C. and the reaction mixture was stirred for 0.5 h at −75° C. The reaction mixture was poured onto 1N aq. HCl and extracted with Et2O. Combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The title compound was obtained after chromatographic purification (Combi Flash, 40 g silica gel, hexane to hexane-EtOAc 10:1) as a light yellow oil: TLC (hexane-EtOAc 10:1) Rf=0.48, HPLC RtA=2.10 min; 1H NMR (400 MHz, CDCl3): δ10.36 (s, 1H), 7.85 (dd, 1H), 7.62 (m, 1H), 7.08 (dd, 1H), 1.32 (s, 9H).
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=O>C(O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:1]=[C:2]([CH2:3][N:4]3[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]3)[S:14][CH:16]=2)=[CH:20][CH:21]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnn(CC(N)=S)c1
Solvent: CCO
Product: CCOC(=O)c1cnn(Cc2nc(-c3ccc(Cl)cc3)cs2)c1
Yield: 81.1 %

Procedure:
To a solution of the compound (500 mg) obtained in Example 1b in ethanol (5 mL) was added 2-bromo-1-[4-chlorophenyl]ethanone (546 mg), and the mixture was heated under reflux for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ether to give the title compound (660 mg) as a colorless solid.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].CCN(CC)CC.[C:25](Cl)(=[O:28])[CH:26]=[CH2:27]>C(Cl)Cl>[CH2:1]([N:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([F:15])([F:16])[F:17])=[CH:8][CH:7]=1)[C:25](=[O:28])[CH:26]=[CH2:27])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CC(=O)Cl
Reactant: C=CCCNc1ccc(OCC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCN(C(=O)C=C)c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To the mixture of but-3-enyl-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-amine (1.56 g, 6 mmol) and NEt3 (1.7 g, 17 mmol) in 30 mL of DCM, acryloyl chloride (0.65 g, 7 mmol) was added slowly into at 0° C. The mixture was stirred at ambient temperature overnight. And then the solution was washed with water (2×15 mL) and brine (2×20 mL), dried with anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica-gel column chromatography (eluting with petroleum ether/ethyl acetate=20:1) to obtain the title compound (1.6 g, 89%) as colorless oil. LC-MS: 300.1 [M+1]+.
Reaction SMILES: Br[C:2]1[N:19]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]2)[C:5]2[C:6]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=3)=[N:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=1.Cl.[F:29][CH2:30][C@@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1.[F-].[K+].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.CS(C)=O>[Cl:18][C:16]1[CH:17]=[C:12]([C:6]2[C:5]3[N:19]([CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]4)[C:2]([N:32]4[CH2:33][CH2:34][CH2:35][C@H:31]4[CH2:30][F:29])=[N:3][C:4]=3[CH:9]=[C:8]([C:10]#[N:11])[N:7]=2)[CH:13]=[N:14][CH:15]=1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: FC[C@@H]1CCCN1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3CF)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C

Procedure:
To a vial was added 2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1, 382.2 mg, 0.86 mmol), (S)-2-(fluoromethyl)pyrrolidine hydrochloride (240 mg, 1.72 mmol), potassium fluoride (250 mg, 4.30 mmol), DMSO (2.6 mL), and N,N-diisopropylethylamine (0.75 mL, 4.30 mmol). The vial was sealed and heated to 100° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C25H28ClFN6 [M+H]+ 467. found 467.
Reaction SMILES: [CH2:1]([N:4]([CH2:17][C:18]([OH:20])=O)[NH:5][C:6](=[O:16])[NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[CH:2]=[CH2:3].[NH2:21][C@@H:22]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:49][CH:48]=1)[C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)=[O:24]>>[CH2:1]([N:4]([CH2:17][C:18]([NH:21][C@@H:22]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:49][CH:48]=1)[C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:39][CH2:40][CH3:41])[O:42][CH2:43][CH3:44])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)=[O:24])=[O:20])[NH:5][C:6]([NH:7][C@@H:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:9])=[O:16])[CH:2]=[CH2:3]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: C=CCN(CC(=O)O)NC(=O)N[C@H](C)c1ccccc1
Product: C=CCN(CC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2cccnc12)[C@@H](C)C(OCC)OCC)NC(=O)N[C@H](C)c1ccccc1
Yield: 85.1 %

Procedure:
According to the procedure described in the synthesis method of Compound II-1, (R)-2-(1-allyl-2-(1-phenylethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-4) 133 mg (0.48 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxy-propan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) 203 mg (0.4 mmol) and purified on silica gel column chromatography (n-hexane:Ethyl acetate=90:10 to 80:20) to obtain the title compound 261 mg (85%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:14]([C:16]1[CH:33]=[CH:32][C:19]2[NH:20][C:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([O-])=[O:28])=[CH:25][CH:24]=3)=[N:22][C:18]=2[CH:17]=1)#[N:15]>>[C:14]([C:16]1[CH:33]=[CH:32][C:19]2[NH:20][C:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH:11][C:10]4[CH:12]=[CH:13][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:8][CH:9]=4)=[O:28])=[CH:25][CH:24]=3)=[N:22][C:18]=2[CH:17]=1)#[N:15]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: N#Cc1ccc2[nH]c(-c3ccc(C(=O)[O-])cc3)nc2c1
Product: N#Cc1ccc2[nH]c(-c3ccc(C(=O)Nc4ccc(N5CCOCC5)cc4)cc3)nc2c1

Procedure:
Compound 450 was prepared from 4-morpholinoaniline and 4-(5-cyano-1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C25H21N5O2: 424.18; found: 423.95.