Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:9]([F:10])=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:26][NH2:27]>C(O)C>[NH2:5][C:4]1[C:3]2[C:2](=[C:9]([F:10])[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13][CH:12]=3)=[CH:7][CH:6]=2)[NH:27][N:26]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)c(F)c2F)cc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc3c(N)n[nH]c3c2F)cc1
Reaction time: 19 h

Procedure:
A solution of 0.8 g of 2,3-difluoro-4-(4-tert-butoxycarbonylaminophenyl)benzonitrile in 25 mL of absolute ethanol is admixed with 0.35 mL of hydrazine hydrate. The reaction mixture is stirred for 19 hours at the reflux of the solvent and then concentrated under reduced pressure. The solid residue is stirred with 25 mL of distilled water, filtered and washed with 2×5 mL of dichloromethane. After suction treatment, 0.54 g of 3-amino-7-fluoro-6-(4-tert-butoxycarbonylaminophenyl)-1H-indazole is obtained, whose characteristics are as follows:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([CH2:15][NH:16][CH:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[I:30])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=O)(C)(C)C>C(Cl)Cl>[I:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][CH:17]([NH:16][CH3:15])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(Cc1ccccc1I)NCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(Cc1ccccc1I)NC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (25 ml) was added to ethyl 2-(tert-butoxycarbonylmethylamino)-3-(2-iodophenyl)propionate (6.4 g, 15 mmol) in CH2Cl2 (35 ml). The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated on a rotary evaporator, the residue was taken up in ethyl acetate, washed (NaHCO3 sat.), dried and concentrated The residue obtained in this manner (3.9 g, 79%) was reacted further as a crude product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[Cu](C#N)[C:19]#[N:20]>CN(C)C=O>[C:19]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)#[N:20]
Reactant: N#C[Cu]C#N
Reactant: Brc1ccc2[nH]cc(Cc3cccnc3)c2c1
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]cc(Cc3cccnc3)c2c1

Procedure:
A mixture of compound of Description 3 [5-Bromo-3-(pyridin-3-ylmethyl)-1H-indole] (1.1 g; 0.0038 mol) and copper cyanide (0.86 g; 0.0096 mol) in dimethylformamide (35 ml) was treated at 140° C. for 8 hours. The reaction mixture was poured into an ice ammonium hydroxide solution and the product was extracted with ethyl acetate. The organic extract was dried (MgSO4) and evaporated under vacuum. After purification by Flash Chromatography on silica gel using as eluent methylene chloride/methanol (97/3), the desired compound was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:44])[C:6]2=[N:7][CH:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:10]=[C:5]2[N:4]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[CH:24][C:25]=3[F:27])[N:20]=[C:19]([N:29]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)C(=O)OC(C)(C)C)[C:18]=2[CH3:43])[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:44])[C:6]2=[N:7][CH:8]=[C:9]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[CH:10]=[C:5]2[N:4]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[CH:24][C:25]=3[F:27])[N:20]=[C:19]([NH:29][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[C:18]=2[CH3:43])[CH2:3]1
Reactant: Cc1c(N(C(=O)OC(C)(C)C)c2ccccn2)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Nc2ccccn2)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of tert-butyl 4-(3,3-dimethyl-6-morpholino-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methylquinolin-2-yl(pyridin-2-yl)-carbamate (55.4 mg, 0.092 mmol) in DCM (1 mL) at 0° C. was added TFA (283 μL, 3.68 mmol). The solution was stirred at rt for 30 min, then concentrated and partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was then dried over MgSO4 and concentrated under reduced pressure to give 4-(3,3-dimethyl-6-morpholino-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methyl-N-(pyridin-2-yl)quinolin-2-amine as a rust-colored solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.85 (1H, d, J=8.4 Hz), 8.31-8.35 (1H, m), 7.78-7.85 (1H, m), 7.58 (1H, br. s.), 7.54 (1H, d, J=2.3 Hz), 7.39-7.45 (1H, m), 7.01-7.08 (1H, m), 6.73-6.80 (1H, m), 5.68-5.71 (1H, m), 3.81-3.86 (1H, m), 3.72-3.79 (4H, m), 3.58-3.63 (1H, m), 2.97-3.04 (4H, m), 2.34 (3H, s), 1.53 (3H, s), 1.50 (3H, s). Mass Spectrum (ESI) m/e=503.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18](OC)[CH:17]=[CH:16][C:4]=1[C:5]([NH:7][C@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].[CH3:22][O:23]C1C=CC(OC)=CC=1C(O)=O>>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]([O:23][CH3:22])=[CH:16][C:4]=1[C:5]([NH:7][C@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6]
Reactant: COc1ccc(C(=O)N[C@@H]2CN3CCC2CC3)c(OC)c1
Reactant: COc1ccc(OC)c(C(=O)O)c1
Product: COc1ccc(OC)c(C(=O)N[C@@H]2CN3CCC2CC3)c1

Procedure:
Title compound was synthesized according to the procedure used in the synthesis of Compound 88S using 2,5-dimethoxybenzoic acid in place of 2,4-dimethoxybenzoic acid. 1H NMR (400 MHz, Acetone-D4) δ (ppm): 7.61 (m, J=4 Hz, 1H), 7.11 (s, 1H), 7.07 (m, J=4 Hz, 1H), 4.07 (m, 1H), 4.00 (s, 3H), 3.80 (s, 3H), 3.34 (s, 3H), 2.89-2.82 (m, 4H), 2.62 (m, 1H), 1.98 (m, 1H), 1.84 (m, 1H), 1.84 (m, 2H), 1.52 (m, 1H). C16H22N2O3=290.16 LCMS (M+H): m/z 291
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([CH3:14])([S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[I:15][C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[C:17]=1[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[I:15][C:16]1[CH:21]=[CH:20][N:19]([CH2:2][CH2:3][C:4]([CH3:14])([S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:18](=[O:22])[C:17]=1[CH3:23]
Reactant: CCOC(=O)C(C)(CCBr)S(C)(=O)=O
Reactant: Cc1c(I)cc[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(CCn1ccc(I)c(C)c1=O)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (2.08 g, 7.25 mmol) and 4-iodo-3-methylpyridin-2(1H)-one (1.42 g, 6.04 mmol) in tetrahydrofuran (60.4 mL) was added cesium carbonate (4.06 g, 12.1) at ambient temperature. The resulting mixture was stirred at 50° C. overnight. The mixture was allowed to cool to ambient temperature and filtered through a celite pad. The pad was washed with ethyl acetate and the filtrate was concentrated to a crude residue. The material was purified via filtration through a silica gel pad, eluting with heptanes/ethyl acetate. The desired fractions were isolated, the solvent removed via rotary evaporation affording ethyl 4-(4-iodo-3-methyl-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate as an oil. 1.97 g
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:10]=[C:11]1[O:15][C:13](=[O:14])[CH2:12]1>C1C=CC=CC=1>[O:15]=[C:11]([CH3:10])[CH2:12][C:13]([NH:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:14]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)(C)OC(=O)CN
Solvent: c1ccccc1
Product: CC(=O)CC(=O)NCC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
3.93 g (50 mmol) of t-butyl 2-aminoacetate was dissolved in 65 ml of benzene. To the above mixture, 4.41 g (52.5 mmol) of diketene was added dropwise and the reaction mixture was stirred for one hour. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with water, and dried over anhydrous sodium sulfate. The solvent was distilled away from the reaction mixture under reduced pressure, whereby 9.821 g (91.2%) of the captioned compound was obtained.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]=12)C1C=CC=CC=1.Cl>CO>[Cl:23][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:24])[C:17]=1[CH2:16][C:12]1[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]2=[C:9]([OH:8])[C:14](=[O:15])[N:13]=1
Reactant: CC(C)N1CCn2c(Cc3c(Cl)cccc3Cl)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: Cl
Solvent: CO
Product: CC(C)N1CCn2c(Cc3c(Cl)cccc3Cl)nc(=O)c(O)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
9-Benzyloxy-6-(2,6-dichlorobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (65) (0.04 g, 84.7 μmol, Eq: 1.00) was suspended in methanol (0.5 ml) and HCl conc (600 mg, 0.5 ml, 16.5 mmol, Eq: 194) was added. The resulting mixture was stirred at room temperature overnight. The organic solvent was mostly removed. Aqueous NaHCO3 was added slowly. The water was removed under reduced pressure. The residue was taken up in ethanol and stirred at room temperature overnight. The suspension was filtered and the filtrate was concentrated to dryness. The remaining solid was purified by reverse phase flash chromatography (13 g C18, water/acetonitrile 0-100% acetonitrile). Product containing fractions were combined and lyophilized to of ford 6-(2,6-dichlorobenzyl)-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (66) (0.01 g, 30.6% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14](O)=O)[N:11]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([O:26]C)=[O:25])=[CH:20][CH:19]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=1[SH:77].SC[C@H]([C@@H](CS)O)O.O.[OH-].[Li+].Cl>CN(C)C=O.C(OCC)(=O)C.O.C(O)(=O)C>[S:77]1[C:72]2[CH:73]=[CH:74][CH:75]=[CH:76][C:71]=2[N:70]=[C:14]1[C:12]1[N:11]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([OH:26])=[O:25])=[CH:22][CH:23]=2)[N:10]=[C:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[CH:13]=1
Reactant: Nc1ccccc1S
Reactant: COC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2C(=O)O)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: O[C@H](CS)[C@H](O)CS
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 3-(3,5-dichlorophenyl)-1-[4-(methoxycarbonyl)benzyl]-1H-pyrazole-5-carboxylic acid (20 mg, 0.049 mmol), and PyBOP (36 mg, 0.069 mmol) in 1 mL of N,N-dimethylformamide was added N,N-diisopropylethylamine (15 μL, 0.088 mmol). After stirring at ambient temperature for 10 min, 2-aminothiophenol (7 μL, 0.059 mmol) was added, and stirring continued for 1 h. The resultant mixture was added drop-wise to 10 mL of glacial acetic acid containing dithiothreitol (15 mg, 0.097 mmol), and the mixture heated at 110° C. for 1 h. The acetic acid was removed in vacuo, the residue suspended in ethyl acetate and the organic layer washed successively with two portions of aqueous saturated sodium bicarbonate solution and one portion of brine. The organic layer was dried over magnesium sulfate, concentrated in vacuo, and the residue suspended in 2 mL of dioxane and 1 mL of water. Lithium hydroxide monohydrate (42 mg, 1.02 mmol) was added and the mixture heated at 50° C. for 2 h. The mixture was diluted with ethyl acetate and water and acidified with 1N hydrochloric acid solution. The organic layer was washed with one portion of brine, dried over magnesium sulfate, and concentrated in vacuo to provide the title compound which was used without purification. HPLC/MS: m/z=479.91 (M+1).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[C:10]2[N:16]=[C:17](S(C)(=O)=O)[N:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[C:9]=2[C:8]1=[O:31].[C:41]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:43])[CH3:42]>>[C:41]([N:44]1[CH2:49][CH2:48][N:47]([CH:12]2[N:11]([CH3:15])[C:10]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:26])[C:9]=3[C:8](=[O:31])[N:7]([CH2:6][C:5]3[CH:4]=[C:3]([C:2]([F:39])([F:40])[F:1])[CH:34]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:32]=3)[CH2:14][CH2:13]2)[CH2:46][CH2:45]1)(=[O:43])[CH3:42]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2C
Product: CC(=O)N1CCN(C2CCN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C(=O)c3c(-c4ccccc4C)ncnc3N2C)CC1
Yield: 82.6 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-10-methyl-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 21; 88.0 mg) was reacted with 1-acetylpiperazine (23.1 mg) to obtain 9-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-10-methyl-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine (78.6 mg, 83%).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:31])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Cl>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:31])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(Cc1cccc(Oc2ccccc2)c1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(Oc2ccccc2)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
To a solution of zinc chloride (7.08 g, 51.9 mmol) in diethyl ether (100 ml) was added sodium borohydride (3.93 g, 103.9 mmol) and the mixture was stirred at room temperature for 30 min. The insoluble material was filtered off. To the filtrate was added a solution of ethyl 3-(4-fluorophenyl)-3-oxo-2-((3-(phenyloxy)phenyl)methyl)propionate (10.2 g, 26.0 mmol) in diethyl ether (50 ml) and the mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid was added to the reaction solution under ice-cooling for quenching, water (200 ml) was further added, and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(phenyloxy)phenyl)methyl)propionate (5.26 g, 51%) as a colorless oil.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:3]([CH3:5])[CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:35][O:36][C:37](=[O:48])[C:38]([C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([Cl:47])[CH:41]=1)=O>O1CCCC1>[CH3:35][O:36][C:37](=[O:48])[C:38]([C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([Cl:47])[CH:41]=1)=[CH:2][CH:3]([CH3:5])[CH3:4]
Reactant: COC(=O)C(=O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(=CC(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A suspension of isobutyl triphenylphosphonium bromide (2.02 g, 4.96 mmol) in dry tetrahydrofuran (5.4 mL) was cooled to 0° C. and then treated dropwise with a 1.0M solution of sodium bis(trimethylsilyl)amide (5 mL, 4.96 mmol). The bright orange reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was then treated with a solution of (3,4-dichloro-phenyl)-oxo-acetic acid methyl ester (0.77 g, 3.30 mmol) in tetrahydrofuran (3 mL). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was quenched with water (10 mL) and then concentrated in vacuo to remove tetrahydroftiran. The residue was further diluted with water (50 mL) and then extracted with ethyl acetate (2×75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 97/3 hexanes/ethyl acetate) afforded the 2-(3,4-dichloro-phenyl)-4-methyl-pent-2-enoic acid methyl ester (749 mg, 83%) as a yellow viscous oil containing a 3.5:1 mixture of (E):(Z) isomers. The isomeric mixture was used without further separation and characterization.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][F:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[F:18][CH2:17][CH2:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCCF)CC1
Solvent: O=C(O)C(F)(F)F
Product: FCCCCN1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-tert-butoxycarbonyl-4-(4-fluoro-n-butyl)piperazine (3.50 g, 10.74 mmol) in trifluoroacetic acid (20 mL) was stirred at room temperature for 1 h. The reaction mixture was evaporated to dryness under vacuum and the resulting residue was triturated from Et2O to afford the titled compound (2.61 g, 87%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C1(C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C(Cl)Cl.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:21]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=3)=[CH:4][CH:3]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: C1CNCCN1
Reactant: Nc1ncc(-c2ccc(Br)cc2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc(-c2ccc(N3CCNCC3)cc2)cn1

Procedure:
A mixture of 5-(4-bromo-phenyl)-pyrimidin-2-ylamine (100 mg, 0.401 mmol), palladium acetate (20 mg, 0.089 mmol), cesium carbonate (200 mg, 0.62 mmol), piperazine (100 mg, 1.16 mmol) and 2-di-t-butylphosphino)-biphenyl (50 mg, 0.167 mmol) was stirred in dioxane:water (10 ml, v/v 5:1) at reflux temperature for 4 hours. The reaction was cooled, diluted with MeCl2 (100 ml) and H2O (50 ml). The organic layer was separated, dried (MgSO4), filtered and solvent evaporated. The residue was purified by chromatography eluting with 100% EtOAc then with 10% v/v MeOH/EtOAc/NH4OH yielding product 82 as a white solid. (70 mg. 68%) ESMS (MH, 256).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[C@H:20]([C:21]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([C:30]4[CH:31]=[C:32]5[C:37](=[CH:38][CH:39]=4)[CH:36]=[C:35]([C:40]4[N:41]=[C:42]([C@@H:46]6[CH2:51][C@@H:50]7[C@@H:48]([CH2:49]7)[N:47]6C(OC(C)(C)C)=O)[NH:43][C:44]=4[Cl:45])[CH:34]=[CH:33]5)=[CH:29][C:23]=3[N:22]=2)[CH2:19][C@@H:18]2[C@H:16]1[CH2:17]2)=O)(C)(C)C>C(Cl)Cl>[C@@H:16]12[CH2:17][C@@H:18]1[CH2:19][C@@H:20]([C:21]1[NH:25][C:24]3[CH:26]=[CH:27][C:28]([C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[C:35]([C:40]6[NH:41][C:42]([C@@H:46]7[CH2:51][C@@H:50]8[C@@H:48]([CH2:49]8)[NH:47]7)=[N:43][C:44]=6[Cl:45])[CH:36]=5)[CH:31]=4)=[CH:29][C:23]=3[N:22]=1)[NH:15]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc(-c2ccc3cc(-c4ccc5[nH]c([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)nc5c4)ccc3c2)c(Cl)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1nc([C@@H]2C[C@H]3C[C@H]3N2)[nH]c1-c1ccc2cc(-c3ccc4[nH]c([C@@H]5C[C@H]6C[C@H]6N5)nc4c3)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
TFA (2 mL, 26.0 mmol) was added to a solution of a TFA salt of tert-butyl (1R,3S,5R)-3-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-naphthyl)-5-chloro-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (131 mg, 0.140 mmol) in DCM (10 mL) and the mixture was stirred for 3 h at rt. The volatiles were removed under vacuum and the residue was taken into MeOH and filtered through a Strata XC MCX cartridge. The cartridge was washed with methanol and the compound was release from the cartridge by eluting with a solution of 2M of ammonia/methanol. The ammonia/methanol filtrate was evaporated under reduced pressure to yield 2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-5-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-4-chloro-1H-imidazol-5-yl)-2-naphthyl)-1H-benzimidazole (55 mg, 0.11 mmol) as tan solid. LC-MS retention time 1.375 min; m/z 507.33 (1:1) (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire C18 4.6×30 mm 5 μm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10% water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 8.26 (s, 1H), 8.19 (s, 1H), 8.00-8.09 (m, 3H), 7.92 (ddd, J=12.1, 8.6, 1.8 Hz, 2H), 7.85 (dd, J=8.6, 1.5 Hz, 1H), 7.81 (d, J=8.6 Hz, 1H), 4.96 (dd, J=11.0, 7.6 Hz, 1H), 4.64 (app t, J=9.3 Hz, 1H), 3.53-3.59 (m, 1H), 3.44-3.50 (m, 1H), 2.82 (dd, J=13.0, 7.5 Hz, 1H), 2.61-2.74 (m, 3H), 2.03-2.15 (m, 2H), 1.24-1.30 (m, 1H), 1.18-1.24 (m, 1H), 0.96-1.09 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:13][CH2:14]O>>[CH2:13]([O:11][C:10](=[O:12])[CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1)[CH3:14]
Reactant: CCO
Reactant: Nc1cccc(CCC(=O)O)c1
Product: CCOC(=O)CCc1cccc(N)c1

Procedure:
3-(3-Aminophenyl)propionic acid (250 mg, 1.52 mmol) was esterified with EtOH using Method A to give the title compound.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.P(Cl)(Cl)(Cl)=O.N.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[CH2:17]([NH:21][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CSc1nc(C)cc(O)n1
Reactant: CCCCN
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCNc1cc(C)nc(SC)n1

Procedure:
4-Hydroxy-6-methyl-2-methylthiopyrimidine (10.0 g, 64.13 mmol), prepared by the procedure described in Example 158A, was dissolved in ~45 mL (483 mmol, 7 equivalents) of phosphorus oxychloride under nitrogen and heated at reflux for 6.5 hours. The phosphorus oxychloride was distilled off and the remaining residue was dissolved in ether and poured onto ice. The aqueous phase was extracted several times with ether. The combined ether extracts were dried over magnesium sulfate and the 4-chloro-6-methyl-2-methylthiopyrimidine crystallized from the ether to afford 6.91 g (62%) as pale orange needles. 1H NMR (CDCl3, 300 MHz) δ 2.45 (s, 3H), 2.58 (s, 3H), 6.77 (s, 1H). MS (DCl/NH3) m/e 175 (M+H)+. The chloro-compound was reacted with n-butylamine by the procedure described in Example 158C to give 4-butylamino-6-methyl-2-methylthiopyrimidine.