Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH2:19]Br>>[Cl:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH2:19][N:10]1[C:11]([CH3:15])([CH3:14])[C:12](=[O:13])[N:9]1[CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Reactant: Fc1ccc(CBr)c(Cl)c1
Product: CC1(C)C(=O)N(C2CCCCCCC2)N1Cc1ccc(F)cc1Cl

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one and 2-chloro-4-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless crystalline powder.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])/[C:8]/2=[CH:17]/OC)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]([C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)[C:25](=[O:34])[CH:24]=1.C(N(CC)CC)C>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])/[C:8]/2=[CH:17]\[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]([C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)[C:25](=[O:34])[CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(C(C)(C)C)cc21
Reactant: NCc1ccn(-c2ccoc2)c(=O)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc2c(c1)/C(=C/NCc1ccn(-c3ccoc3)c(=O)c1)C(=O)NC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
A mixture of (4E)-6-tert-butyl-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (50 mg, 0.19 mmol), 4-aminomethyl-1-furan-3-yl-1H-pyridin-2-one hydrochloride (43 mg, 0.19 mmol), and triethylamine (150 μL, 1.1 mmol) in N,N-dimethylformamide (2 mL) is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure, and the residue is triturated with chloroform to provide (4Z)-6-tert-butyl-4-[({[1-(3-furyl)-2-oxo-1,2-dihydropyridin-4-yl]methyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione as a white solid (34 mg, 43%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[O:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: O=Cc1ccccc1F
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Oc1ccc(Cl)nc1
Yield: 93.6 %

Procedure:
A mixture of 6-chloro-pyridin-3-ol (418 mg, 3.2 mmol), 2-fluorobenzaldehyde (522 mg, 4.21 mmol), potassium carbonate (442 mg, 3.2 mmol) and copper powder (201 mg, 3.2 mmol) was heated in DMF (6.4 mL) at 120° C. for 6 hours. The reaction was then cooled, and concentrated to an oil. The residue was purified by flash chromatography (eluting with 20% ethyl acetate/hexane) to give the title compound as a brown solid (700 mg, 93%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:13]([C:24](O)=[O:25])[CH:12]=[N:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[C:56]12([NH2:66])[CH2:65][CH:60]3[CH2:61][CH:62]([CH2:64][CH:58]([CH2:59]3)[CH2:57]1)[CH2:63]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:56]12([NH:66][C:24]([C:13]3[CH:12]=[N:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][CH:6]=4)[C:14]=3[O:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[O:25])[CH2:63][CH:62]3[CH2:61][CH:60]([CH2:59][CH:58]([CH2:64]3)[CH2:57]1)[CH2:65]2
Reactant: CC(C)c1ccc(-n2ncc(C(=O)O)c2OCCN2CCOCC2)cc1
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(-n2ncc(C(=O)NC34CC5CC(CC(C5)C3)C4)c2OCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.4 %

Procedure:
To a stirred solution of 1-(4-isopropylphenyl)-5-(2-[4-morpholinyl]ethoxy)pyrazole-4-carboxylic acid (43 mg, 0.12 mmol) in dimethylformamide (1 mL) under an argon atmosphere, was added 1-hydroxybenzotriazole (16 mg, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (25 mg, 0.13 mmol), triethylamine (60 uL, 0.43 mmol) and 1-adamantanamine hydrochloride (25 mg, 0.13 mmol). The reaction mixture was stirred for 24 h at room temperature, heated to 70° C. for 2 h, and stirred for another 96 h at room temperature. The resulting mixture was treated with aqueous sodium carbonate, extracted with ethyl acetate, washed with water four times and dried over Na2SO4. The extract was concentrated in vacuo. This coupling was repeated on the same scale and the combined residue was purified by chromatography twice over silica gel eluting the first column with 2 to 3% methanol in chloroform, and the second with 30 to 40% ethyl acetate in chloroform to afford the title compound (7% yield, 8.5 mg) as a yellow powder, mp 132-134° C. MS (ES) m/e 493.4 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:18][CH:19]=2)=[N:7][CH:6]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: Brc1cnc(Br)nc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Brc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Yield: 100.4 %

Procedure:
104.25 g (0.438 mol) of 2,5-dibromopyrimidine, 100.00 g (0.438 mol) of 4-(phenylmethoxy)benzeneboronic acid, 4.75 g (0.00438 mol) of palladium (10%) on activated carbon, 4.50 g (0.01752 mol) of triphenylphosphine and 93.00 g (0.876 mol) of sodium carbonate are heated in 1000 ml of toluene, 500 ml of ethanol and 300 ml of water for 24 hours at 80° C. The palladium catalyst is subsequently separated off from the reaction mixture at 80° C. by filtration. The aqueous lower phase of the reaction mixture is separated off at 80° C., before the organic phase is freed of the solvents on a rotary evaporator and dried in a high vacuum. The crude product thus obtained is recrystallized from acetonitrile (3000 ml), giving 150.07 g (97% yield, based on 2,5-dibromopyridine) of 5-bromo-2-[4-(phenylmethoxy)phenyl]pyrimidine (purity according to HPLC: 98%). ##STR4## mp.: 153°-155° C.
Reaction SMILES: [OH:1][CH:2]([CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:23])[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=3)=[CH:11][O:12]2)=[CH:7][CH:6]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[C:9](=[O:23])[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:24][NH:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[CH:6][CH:7]=3)[O:12][CH:11]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(-c2coc3cc(OCC(O)CNCc4cccc(C(F)(F)F)c4)ccc3c2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1c(-c2ccc(O)cc2)coc2cc(OCC(O)CNCc3cccc(C(F)(F)F)c3)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred suspension of 7-[2-hydroxy-3-({[3-(trifluoromethyl)phenyl]methyl}-amino)propoxy]-3-(4-methoxyphenyl)chromen-4-one (38 mg, 0.076 mmol) in methylene chloride at ° C. was added boron tribromide (1M, 0.38 ml). The resulting mixture was stirred at room temperature for 4 hours, then the solvent removed under reduced pressure. The residue was purified by preparative thin layer chromatography, eluting with 10% methanol/dichloromethane, to provide 3-(4-hydroxyphenyl)-7-[2-hydroxy-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propoxy]chromen-4-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:12]1[NH:13][CH:14]=[CH:15][C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:12]1[N:13]([S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=2)(=[O:38])=[O:37])[CH:14]=[CH:15][C:16]=1[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:10][CH3:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1[nH]ccc1C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](NC(=O)OC(C)(C)C)c1c(C(=O)OC(C)(C)C)ccn1S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.08 h

Procedure:
(R)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)propyl)-1H-pyrrole-3-carboxylate (505b, 4.58 g, 14.12 mmol) was dissolved in THF (40 mL) under nitrogen and cooled in an ice bath. Sodium tert-butoxide (1M in THF, 14.12 mL, 14.12 mmol) was added and the mixture stirred for 5 min. Toluene-4-sulfonyl chloride (2.69 g, 14.12 mmol) was added to the solution and the mixture was stirred at 0° C. for 30 min. Water (50 mL), and EtOAc (50 mL) were added to the reaction mixture and the organic layer was washed with brine and dried over MgSO4, filtered and concentrated affording crude (R)-tert-butyl 2-(1-aminopropyl)-1-tosyl-1H-pyrrole-3-carboxylate (505c) as an orange viscous oil. m/z (ESI, +ve) 501.2 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.CO.[BH4-].[Na+]>O>[Br:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccnc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1cccnc1Br
Yield: 98.3 %

Procedure:
To a 2 L round bottom flask (fitted with stir bar, under nitrogen and at 0° C.) containing 2-bromo-3-pyridine-carboxaldehyde (22.15 g, 119.08 mmol) and methanol (200 mL), is added sodium borohydride (1.35 g, 35.72 mmol) in three portions. After 1 h at 0° C. water (200 mL) is added and the reaction is concentrated under reduced pressure to remove the methanol. The resulting residue is dissolved in ethyl acetate and washed with water (200 mL). The organic extraction is washed with brine, dried over magnesium sulfate, filtered and concentrated to afford 22 g of (2-bromo-3-pyridyl)methanol as a white solid. MS (m/z): 188 (M+1), 190 (M+3).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH:5]1([C:8]([CH2:10][CH:11]2[CH2:13][CH2:12]2)=O)[CH2:7][CH2:6]1.CO.[BH4-].[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl.O>[CH:5]1([CH:8]([NH:4][CH2:1][CH2:2][CH3:3])[CH2:10][CH:11]2[CH2:13][CH2:12]2)[CH2:7][CH2:6]1
Reactant: CCCN
Reactant: O=C(CC1CC1)C1CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCCNC(CC1CC1)C1CC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Add 6.9 ml of propylamine to 2.2 g of cyclopropylmethyl cyclopropyl ketone in 85 ml of methylene chloride. Add 7 ml of a 1M solution of titanium (IV) chloride in methylene chloride dropwise at room temperature. After 18 hours stirring, add 40 ml of anhydrous methanol. Cool to 0° C. and add 1.0 g of sodium borohydride in small amounts. After overnight stirring at room temperature, add 10 ml of water and evaporate under vacuum. Take up in water and extract with methylene chloride. Extract with 2N hydrochloric acid. Wash with ethyl ether. Neutralise the aqueous phase with concentrated sodium hydroxide solution. Extract with methylene chloride, dry over anhydrous sodium sulphate and evaporate to dryness to obtain a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl-].[O:12]([C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[CH:22]=[N+:23]([CH3:25])[CH3:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O(C1C=C(C=CC=1)C=O)C1C=CC=CC=1.CNC>>[CH3:24][N:23]([CH3:25])[CH:22]([C:4]1[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])[NH:6][CH:5]=1)[C:21]1[CH:26]=[CH:27][CH:28]=[C:19]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:20]=1
Reactant: Cc1cccc2[nH]ccc12
Reactant: C[N+](C)=Cc1cccc(Oc2ccccc2)c1
Agent: CNC
Agent: O=Cc1cccc(Oc2ccccc2)c1
Agent: [Cl-]
Product: Cc1cccc2[nH]cc(C(c3cccc(Oc4ccccc4)c3)N(C)C)c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-methyl-1H-indole and (3-phenoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3-phenoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:15][CH2:14][CH:13]1[CH2:12][NH:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:18](F)=[C:19]([F:34])[CH:20]=[C:21]2[C:26]=1[N:25]([CH:27]1[CH2:29][CH2:28]1)[CH:24]=[C:23]([C:30]([OH:32])=[O:31])[C:22]2=[O:33].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]([O:5][C:6]([NH:8][C:9]12[CH2:15][CH2:14][CH:13]1[CH2:12][N:11]([C:18]1[C:17]([Cl:16])=[C:26]3[C:21]([C:22](=[O:33])[C:23]([C:30]([OH:32])=[O:31])=[CH:24][N:25]3[CH:27]3[CH2:29][CH2:28]3)=[CH:20][C:19]=1[F:34])[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NC12CCC1CNC2
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NC12CCC1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1Cl)C2
Yield: 60.9 %

Procedure:
1.22 g of 1-(t-butoxycarbonylamino)-3-azabicyclo[3.2.0]heptane, 0.96 g of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.58 g of 1,8-diazabicyclo[5.4.0]-7-undecene were added to 20 ml of acetonitrile, followed by heating under reflux for 3.5 hours. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (using a 100:1 mixture of chloroform and methanol as the eluent) and recrystallization (from ethyl acetate-diisopropyl ether) to obtain 0.96 g of 7-[1-(t-butoxycarbonylamino)-3-azabicyclo[3.2.0]hept-3-yl]-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (m.p. 200-202° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([C@@H:20]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22](=[O:27])[CH2:21]1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(=[O:9])=[O:8])[CH3:2].[BH4-].[Na+]>O1CCCC1CCO>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([C@@H:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]([OH:27])[CH2:21]1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(=[O:8])=[O:9])[CH3:2]
Reactant: CCOC(=O)CN([C@@H]1CCCCC(=O)C1)S(=O)(=O)c1ccc2ccccc2c1
Agent: OCCC1CCCO1
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(=O)CN([C@@H]1CCCCC(O)C1)S(=O)(=O)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of (R)—N-naphthalene-2-sulfonyl (3-oxo-cyclohepty)glycine ethyl ester (1.05 g, 2.61 mmol) in tetrahydrofuran-ethanol (20 mL, 1:1) at 0° C. is added sodium borohydride (0.147 g, 3.88 mmol) and the reaction is stirred at 0° C. for 1 hour. The reaction was quenched at 0° C. with citric acid (10% aqueous), and the solvents were removed in vacuo. The residue was dissolved in water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by column chromatography (50% hexanes-ethyl acetate) to afford the title compound as a white solid (0.90 g, 85% yield). LCMS (m/z): 406.14 (M+1), 404.13 (M−1).
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[S:48]1[C:52]([CH2:53][NH2:54])=[CH:51][C:50]2[CH:55]=[CH:56][CH:57]=[CH:58][C:49]1=2>>[S:48]1[C:52]([CH2:53][NH:54][C:41]([C:39]2[S:40][C:36]([N:33]3[CH2:34][CH2:35][N:31]([CH2:30][C:29]4[CH:46]=[CH:47][C:26]([F:25])=[CH:27][CH:28]=4)[C:32]3=[O:45])=[CH:37][C:38]=2[CH3:44])=[O:43])=[CH:51][C:50]2[CH:55]=[CH:56][CH:57]=[CH:58][C:49]1=2
Reactant: NCc1cc2ccccc2s1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cc2ccccc2s1
Yield: 78 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with benzo[b]thiophen-2-ylmethanamine, the title compound was obtained as a colorless solid in 78% yield: 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J=7.6 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.36-7.22 (m, 5H), 7.08-6.99 (m, 2 H), 6.14 (t, J=5.4 Hz, 1H), 6.10 (s, 1H), 4.82 (d, J=5.4 Hz, 2H), 4.42 (s, 2H), 3.83-3.74 (m, 2H), 3.47-3.38 (m, 2H), 2.51 (s, 3H); MS (ES+) m/z 480.2 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]1[N:15]=[C:13]([C:12]2[CH:16]=[CH:17][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)[O:14][CH:5]=1
Reactant: O=C(CCl)CCl
Reactant: COc1ccc(C(N)=O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc(CCl)co2)cc1
Temperature: 120 °C
Yield: 87.1 %

Procedure:
To a solution of 1,3 dichloroacetone (0.504 g, 3.90 mmol) in toluene (5 ml) was added 4-methoxy benzamide (0.30 g, 1.90 mmol). The reaction mixture was heated at 120° C. for 1 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified over silica gel (230-400 M, 15% EtOAc-Hexane) to get the desired product (0.37 g, 83%).
Reaction SMILES: [H-].[Na+].[C:3]1([C@@H:9]2[O:14][C@@H:13]([CH2:15][OH:16])[CH2:12][CH2:11][O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:3]1([C@@H:9]2[O:14][C@@H:13]([CH2:15][O:16][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[CH2:12][CH2:11][O:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OC[C@H]1CCO[C@H](c2ccccc2)O1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOC[C@H]1CCO[C@H](c2ccccc2)O1
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
To a suspension of NaH (3 g, 60% in mineral oil) in 30 mL of dry THF was added a solution of (R)-2-phenyl-(S)-4-hydroxymethyl-1,3-dioxane (1.47 g, 7.6 mmol) in 10 mL of THF at 0° C. After 30 min, hexadecyl bromide (3 mL, 9.88 mmol) and tetrabutylammonium iodide (0.28 g, 0.76 mmol) were added. After the mixture was stirred overnight, the reaction was quenched by addition of 5 mL of MeOH. The solvent was removed under reduced pressure, and ether and water were added. The product was extracted with ether. The organic layer was dried over Na2SO4 and concentrated. The product was purified by column chromatography on silica gel, eluting with EtOAc-PE (5%) to afford 1.55 g (50%) of 6 as a white solid; mp 51-54° C. MS: m/z 441 (M++Na+), (calcd. for C27H45O3, 418.662). 1H NMR (300 MHz, CDCl3): δ7.51-7.31 (m, 5H, Ph), 5.54 (s, PhCH—), 4.32-4.27 (m, —CHO), 4.10-3.94 (m, 2H, —CH2O—), 3.65-3.59 (m, 4H, —CH2O), 1.89-1.83 (m, 2H, —CH2—), 1.62-1.54 (m, 2H), 1.25 (s, 26H), 0.88 (t, 3H, CH3). 13C-NMR (CDCl3, 75 MHz): δ139.28, 129.32, 128.77, 126.79, 101.88, 77.09, 74.44, 72.61, 67.61, 32.74, 30.51, 30.30, 30.18, 29.18, 26.93, 23.51, 14.94.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH:25]C(=O)[O-])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:29]2[CH2:32][CH2:31][CH2:30]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>Cl.C(OCC)(=O)C>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([NH2:25])[CH2:23][CH2:24]3)[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:29]2[CH2:32][CH2:31][CH2:30]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CC[C@H]3CC[C@H](NC(=O)[O-])CC3)CC2)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Tert-butyl N-[trans-[4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]carbamate (11.20 g, 22.41 mmol) was dissolved in HCl/ethyl acetate (150 mL). The resulting solution was stirred at about 25° C. for 16 h. Solvent was removed under reduced pressure to provide the title compound (8.9 g, 21.16 mmol, 94% yield) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9](Br)[N:8]([C@@H:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:37]([Cu])#[N:38].N#N>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9]([C:37]#[N:38])[N:8]([C@@H:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2c(Br)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reactant: N#C[Cu]
Agent: N#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 160 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
A solution of (R)-tert-butyl 3-(4-amino-6-bromo-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (9) (200 mg, 0.36 mmol) and CuCN (110 mg, 1.08 mmol) in DMF (10 mL) was purged with N2 for three times. The resulting mixture was stirred at 160° C. overnight. After cooling to r.t., the reaction mixture was concentrated to obtain the crude product which was purified by flash chromatography (silica gel, 0 to 100% ethyl acetate in petroleum ether) to afford (R)-tert-butyl 3-(4-amino-6-cyano-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (101) (117 mg, 65% yield) as a yellow solid. LC-MS (ESI): m/z (M+1) 497.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[CH2:14]O.S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[Cl:18][CH2:14][C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: OCc1cnoc1-c1cc(Cl)ccc1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: ClCc1cnoc1-c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
To a solution of 5-(2,5-dichlorophenyl)-4-isoxazolylmethanol (3.80 g) in toluene (60 ml) was added dropwise thionyl chloride (2.78 g) at 0° C. and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 4-chloromethyl-5-(2,5-dichlorophenyl)isoxazole (2.15 g, yield 53%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:9, volume ratio). NMR (CDCl3) δ: 4.45 (2H, s), 7.4–7.55 (3H, m), 8.48 (1H, s).