Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[N:3]=1.C(N(CC)CC)C.[Cl:35][CH2:36][CH2:37][CH2:38][S:39](Cl)(=[O:41])=[O:40]>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][S:39]([CH2:38][CH2:37][CH2:36][Cl:35])(=[O:41])=[O:40])[CH2:23][CH2:22]2)[N:3]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N)CC2)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NS(=O)(=O)CCCCl)CC2)nc1N
Reaction time: 0.17 h

Procedure:
To a stirred solution of trans-[4-amino-2-(4-amino-cyclohexylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (565 mg, 1.5 mmol, Example 120) and triethylamine (167 mg, 0.25 mL, 1.69 mmol) in tetrahydrofuran (20 mL) at 0° C., 3-chloropropane sulfonyl chloride (0.20 mL, 1.65 mmol, Aldrich) was added. The mixture was stirred for 10 minutes and the reaction was quenched with water. The mixture was extracted with ethyl acetate and the extracts were combined and dried with sodium sulfate. The solvent was removed and the residue was chromatographed (4% methanol/dichloromethane) to give 600 mg of yellow solid. Yield, 77%. MS (ES) MH+=518.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:11])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][C:23](=O)[CH3:24])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:9][NH:10][CH:23]([CH3:24])[CH2:22][C:16]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=2)[OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COc1ccc(CC(C)=O)cc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CC(C)NCC(O)c2cccc(Cl)c2)cc1OC

Procedure:
In accordance with the above preferred reaction scheme 2-(3-chlorophenyl)-2-hydroxyethylamine 1, and 3,4-dimethoxyphenylacetone 2 are reacted with sodium cyanoborohydride in methanol, giving 3-chloroalpha-(((2-(3,4-dimethoxyphenyl)-1-methylethyl)amino)methyl) benzenemethanol 3 which is reacted with carbonyl diimidazole and triethylamine in tetrahydrofuran, followed by separation of isomers, giving cyclized derivative 4 which is reacted with boron tribromide in dichloromethane, giving (R*,R*)-(±)-5-(3-chlorophenyl)-3-(2-(3,4-dihydroxy phenyl)-1-methylethyl)2-oxazolidinone 5. Compound 5 is then reacted with diethyl dibromomalonate and anhydrous potassium carbonate in acetone, giving (R*,R*)-(±)-5-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid, diethyl ester 6 which is then reacted first with sodium hydroxide in ethanol and then with hydrogen chloride gas in methanol, giving the product (R*,R*)-(±) 5-(2-((2-(3-chlorophenyl)2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid, dimethyl ester 7.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[NH2:45][CH2:46][CH2:47][OH:48]>C(#N)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21]([NH:45][CH2:46][CH2:47][OH:48])=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2]
Reactant: NCCO
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)NCCO)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (80.0 mg, 0.128 mmol; Example 6A) was reacted with 2-aminoethanol (23.4 mg, 0.384 mmol) in acetonitrile (1 ml) to give the target compound (27 mg, 39% of theory).
Reaction SMILES: C([O:8][C:9](=[O:33])[CH2:10][NH:11][C:12](=[O:32])[C@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25](=[O:27])[CH3:26])=[C:20]([O:28][C:29](=[O:31])[CH3:30])[CH:19]=1)[NH:14]C=O)C1C=CC=CC=1.[ClH:34].CO.C(O)(=O)C>CCOCC>[ClH:34].[C:29]([O:28][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[O:24][C:25](=[O:27])[CH3:26])[CH2:17][C@@H:13]([C:12]([NH:11][CH2:10][C:9]([OH:33])=[O:8])=[O:32])[NH2:14])(=[O:31])[CH3:30]
Reactant: CC(=O)Oc1ccc(C[C@H](NC=O)C(=O)NCC(=O)OCc2ccccc2)cc1OC(C)=O
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(C[C@H](N)C(=O)NCC(=O)O)cc1OC(C)=O
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Next, the step of deprotecting the N-formyl-3,4-diacetyloxy-L-phenylalanyl-glycine-benzyl ester was performed. 0.90 g (2.0 millimole) of the aforementioned compound was allowed to react with a 2.2 ml of a 1N methanolic-hydrochloric acid solution (prepared by diluting 2 ml of concentrated hydrochloric acid to 24 ml with methanol) overnight. Initially, a suspension formed and an additional 5 ml of methanol was added to the suspension. After about 0.5 hours, all of the solid had gone into solution. The solution was concentrated in vacuo at room temperature and the nmr spectrum of the residue showed the absence of CH3CO2 and O=CH--N absorptions. The residue was dissolved in 60 ml of anhydrous methanol to which 0.5 ml of glacial acetic acid had been added. The solution was shaken in a Parr shaker under hydrogen atmosphere over 0.1 g of a 10% Pd/C catalyst overnight. The suspension was then filtered to remove the catalyst and concentrated in vacuo at room temperature. The residue was twice diluted with acetone (100 ml) and concentrated. Then, it was dissolved in glacial acetic acid saturated with hydrogen chloride (10 ml) and allowed to react with acetyl chloride (10 ml). A solid formed, but soon went back into solution. After 8 hours at room temperature, the acetic acid solution was then diluted to 125 ml with ether. The ether was then decanted and the gummy dark residue left behind was suspended in ether (100 ml). The suspension was stirred overnight to yield a fine white solid in suspension, which was filtered quickly and dried in a vacuum desiccator to yield 0.59 g (shrinking at 100° C, wet at 114° C, and foaming from 120°-127° C, 78% yield) of 3,4-diacetyloxy-L-phenylalanyl-glycine hydrochloride. The nmr was consistent with the proposed structure of the compound obtained and upon analysis of a sample of this compound, by recrystallization from methanol-ether, the following data was obtained. Analysis Calculated for: C15H19N2O7Cl: C, 48.06; H, 5.11; and N, 7.48. Found: C, 48.22; H, 5.34; and N, 7.72.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:11])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+].[Br:23]Br.O>C(Cl)Cl>[CH2:1]([NH:8][C:9](=[O:10])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:23][C:16]1[CH:15]=[CH:14][NH:13][N:12]=1
Reactant: c1cn[nH]c1
Reactant: BrBr
Agent: O=C(O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Brc1cc[nH]n1
Reaction time: 6 h

Procedure:
To a solution of pyrazole benzyl carbamate (115.0 mg, 0.38 mmol), prepared in step A, in 6 mL of CH2Cl2 at room temperature was added solid potassium carbonate in one portion. A solution of bromine was added dropwise to the stirred mixture. After 6 h, 30 mL of H2O was added, and the mixture was extracted with CH2Cl2 (30 mL×3). The combined organic extracts were washed with a 10% Na2S2O3 aqueous solution (20 mL), a saturated NaHCO3 aqueous solution (20 mL) and brine (20 mL), and dried with Na2SO4. Evaporation of solvent gave a slightly yellow oil, which was purified by preparative TLC (CH2Cl2-MeOH=20:1). The silica was extracted with CH2Cl2 and methanol, the extracts were filtered and concentrated under reduced pressure to afford an oil, which was further dried on high vacuum, yielding 134.2 mg (93%) of the bromo-pyrazole benzyl carbamate (MH+=381).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19](O)=[O:20])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[OH2:20].[CH3:36][N:37]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:19](=[O:20])[CH2:18][N:17]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:22])([F:23])[F:1])=[CH:8][CH:7]=1
Reactant: CNCc1ccccc1
Reactant: O=C(O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C(=O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Product: O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.21 g, 0.01 mole) and 1,1'-carbonyldiimidazole (1.62 g, 0.01 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hrs. N-methylbenzylamine (1.33 g, 0.011 mole) was added, and the reaction mixture was allowed to stir at room temperature for 1 hr.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][Cl:17])=[CH:14][CH:13]=1.[I-].[Na+]>COC(O)C>[ClH:17].[CH3:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:6]2[C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[S:3][C:2]2=[NH:1])=[CH:14][CH:13]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: Nc1nc2ccccc2s1
Agent: COC(C)O
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(Cn2c(=N)sc3ccccc32)cc1
Product: Cl
Yield: 35 %

Procedure:
A mixture of 2-aminobenzothiazole (2.104 g, 13.6 mmol) and 4-methylbenzyl chloride (2.25 mL, 12.5 mmol) was refluxed for 8 hours in methoxyethanol in the presence of a catalytic amount of sodium iodide (220 mg, 1.46 mmol). After cooling a precipitate formed which was filtered and rinsed with ether to give 35% yield: mp 243-248° C.; 1H-NMR (DMSO-d6) 2.26 (s, 3H), 5.65 (s, 2H), 7.20 (dd, 4H), 7.39 (t, 1H), 7.48 (t, 1H), 7.55 (d, 1H), 8.02 (d, 1H); HR-MS (EI) m/z 254.0870 (M+).
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[C:7]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]#[N:32])=[CH:21][CH:20]=2)=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:33]([O-])([O-])([O-])[O:34][CH3:35]>>[C:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:17]2[C:7]3[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][CH:15]=[CH:16][C:6]=3[N:5]=[C:33]2[O:34][CH3:35])=[CH:20][CH:21]=1)#[N:32]
Reactant: CCOC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Reactant: COC([O-])([O-])[O-]
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc2nc(OC)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Acetic acid (0.2 g) was added to a solution of ethyl 3-amino-2-[(2'-cyanobiphenyl-4-yl)methyl]aminobenzoate (1.1 g) in methyl orthocarbonate (5 ml). The mixture was stirred at 80° C. for one hour. The reaction mixture was concentrated, and the concentrate was extracted with ethyl acetate. The organic layer was then washed with an aqueous solution of sodium hydrogen carbonate and water. The solvent was evaporated in vacuo to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals (1.09 g, 90%), m.p. 160°-161° C.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[NH:14]([CH2:16]C(O)=O)[CH3:15].C(=O)=O>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:9])[CH2:15][N:14]([CH3:16])[C:7](=[O:8])[C:6]=2[CH:13]=1
Reactant: CNCC(=O)O
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Agent: O=C=O
Solvent: CS(C)=O
Product: CN1CC(=O)Nc2ccc(Br)cc2C1=O
Temperature: 0 °C

Procedure:
A solution of 39.5 g of 5-bromoisatoic acid anhydride and 14.5 g of sarcosine in 150 ml of dimethyl sulphoxide is heated to 100° C. while stirring. In so doing, a vigorous evolution of carbon dioxide occurs from 70° C. and this has finished after ca 30 minutes. The mixture is stirred at 100° C. for a further 30 minutes and thereafter the mixture is poured into 900 ml of ice-water (temperature 5° C.) and the separated material is filtered off under suction. The crystals are washed with water and subsequently dried at 50° C. over phosphorus pentoxide in a vacuum drying cabinet. There is obtained 7-bromo-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione in the form of light beige crystals. A sample recrystallised from methanol has a melting point of 260°-261° C.
Reaction SMILES: CS([O:5][C@@H:6]1[CH2:10][CH2:9][O:8][CH2:7]1)(=O)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([CH3:24])=[CH:22][C:21](O)=[CH:20][C:19]=2[CH3:26])=[CH:14][C:13]=1[CH2:27][OH:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([CH3:26])=[CH:20][C:21]([O:5][C@H:6]3[CH2:10][CH2:9][O:8][CH2:7]3)=[CH:22][C:23]=2[CH3:24])=[CH:14][C:13]=1[CH2:27][OH:28]
Reactant: CS(=O)(=O)O[C@@H]1CCOC1
Reactant: Cc1cc(O)cc(C)c1-c1ccc(F)c(CO)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(O[C@H]2CCOC2)cc(C)c1-c1ccc(F)c(CO)c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 105.4 %

Procedure:
The crude (R)-tetrahydrofuran-3-yl methanesulfonate 1b (83 mg, 0.50 mmol), 4′-fluoro-3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-ol 18c (110 mg, 0.45 mmol) and cesium carbonate (293 mg, 0.90 mmol) were dissolved in 2 mL of N,N-dimethylformamide. The reaction mixture was heated to 90° C. and stirred for 12 hours. The resulting mixture was concentrated under reduced pressure, mixed with 10 mL of water and extracted with ethyl acetate (10 mL×3). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (S)-(4-fluoro-2′,6′-dimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 18d (150 mg) as a colorless slime, which was directly used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].Br[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[N:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Reactant: CC(C)=CCBr
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(CC=C(C)C)c1=O
Yield: 87.6 %

Procedure:
Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 1-bromo-3-methyl-2-butene as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 87.6%.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:15]=1[NH2:16].[NH2-].[Li+].Cl>C(#N)C>[F:11][C:9]1[C:8]([F:12])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([I:21])=[CH:20][C:14]=2[F:13])[CH:10]=1
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: Nc1ccc(I)cc1F
Agent: Cl
Agent: [Li+]
Agent: [NH2-]
Solvent: CC#N
Product: O=C(O)c1cc(F)c(F)cc1Nc1ccc(I)cc1F
Temperature: 60 °C
Yield: 43.5 %

Procedure:
2,4,5-Trifluorobenzoic acid (643 mg, 3.65 mmol) and 2-fluoro-4-iodoaniline (1.0 g, 4.22 mmol) were taken into acetonitrile (30 mL) followed by addition of lithium amide (290 mg, 12.7 mmol) and the mixture was heated to 60° C. under a nitrogen atmosphere for one hour. On cooling to room temperature the mixture was added to 1 N aqueous hydrochloric acid (100 mL) and the precipitate formed was collected by filtration and washed once with water then hexanes and dried in vacuo to give 4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (624 mg, 43% yield) as a tan solid. 1H-NMR (400 MHz, D6-DMSO): 13.65 (br s, 1H), 9.63 (s, 1H), 7.84 (tr, 1H), 7.71 (d, 1H), 7.52 (d, 1H), 7.32 (tr, 1H), 7.03-6.98 (dd, 1H).
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][C:35]=1[F:46])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CS(OCCCC1CCCC1)(=O)=O>>[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][N:43]([CH2:23][CH2:24][CH2:25][CH:20]3[CH2:19][CH2:18][CH2:22][CH2:21]3)[CH2:42][CH2:41]2)=[CH:36][C:35]=1[F:46])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Fc1cc(N2CCNCC2)ccc1OCc1ccccc1
Reactant: BrCCc1ccccc1
Agent: COc1ccc(N2CCNCC2)cc1
Agent: CS(=O)(=O)OCCCC1CCCC1
Agent: Cl
Product: Fc1cc(N2CCN(CCCC3CCCC3)CC2)ccc1OCc1ccccc1

Procedure:
Production Example 1 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride and (2-bromoethyl)-benzene were replaced with 1-(4-benzyloxy-3-fluorophenyl)piperazine (368 mg) and 3-cyclopentylpropyl methanesulfonate (319 mg), respectively, to provide crude 1-(4-benzyloxy-3-fluorophenyl)-4-(3-cyclopentylpropyl)piperazine (505 mg).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[S:19][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:6]=2[CH:5]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1>>[F:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][N:16]1[CH2:15][CH2:14][CH:13]([NH:12][C:11]2[C:6]3[CH:5]=[C:4]([Cl:3])[S:19][C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:18][CH2:17]1
Reactant: Fc1cccc(CBr)c1
Reactant: Clc1cc2c(NC3CCNCC3)ncnc2s1
Agent: Cl
Product: Fc1cccc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1

Procedure:
The title compound was prepared (58 mg, 53%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine dihydrochloride (100 mg, 0.29 mmol) and 1-(bromomethyl)-3-fluorobenzene (55 mg, 0.29 mmol) by following the general procedure described for Preparation 12. 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.28 (dd, 1H), 7.09 (d, 1H), 7.08 (d, 1H), 6.98 (s, 1H), 6.95 (dt, 1H), 4.85 (d, 1H), 4.19 (m, 1H), 3.49 (s, 2H), 2.87 (d, 2H), 2.23 (dt, 2H), 2.09 (d, 2H), 1.60 (m, 2H); MS (ESI) m/z: Calculated for C18H19ClFN4S, 377.1; Observed: 377.2 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][Cl:19]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[O:9][CH2:17][CH2:18][Cl:19]
Reactant: Oc1c(Br)cccc1Br
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCOc1c(Br)cccc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution comprising 2,6-dibromophenol (3.90 g, 15.00 mmol), potassium carbonate (2.48 g, 17.94 mmol) and DMF (40 ml) was added with 1-bromo-2-chloro ethane (4.30 g, 29.98 mmol) and stirred at room temperature for 16 hours. The reaction solution was concentrated and liquid separation was carried out with ethyl acetate-water. The organic layer was washed with saturated sodium chloride water and dried with anhydrous sodium sulfate. The residue obtained by concentration was purified by silica gel column chromatography (n-hexane) to obtain the target compound (4.75 g, quant.) as a colorless oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16](C(OC(C)(C)C)=O)[CH3:17])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][CH3:17])=[CH:13][CH:14]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN(C)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3.66 g (10 mmol) of the above prepared 2-{4-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phenoxy}-2-methyl-propionic acid ethyl ester in 50 ml dichloromethane was treated at 0° C. with 3.98 ml TFA and stirred at room temperature for 16 h. The reaction was evaporated and treated with ice water, neutralized with NaHCO3 (pH=8) and extracted dichloromethane (two times). The organic phases were washed with water, dried (MgSO4), and evaporated to give 2.77 g of crude product. Purification by flash chromatography on SiO2 with CH2Cl2/MeOH (95:5) yielded 1.95 g of the title compound as brown-yellow oil.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][CH:14]([F:48])[C:15]1[N:16]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1>C(OCC)(=O)C>[F:48][CH:14]([F:13])[C:15]1[N:16]([C:40]2[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:3][C:4](=[O:7])[O:5][N:38]=3)=[CH:29][CH:30]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1
Reactant: CCCc1nc(C(F)F)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C(F)F)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
A mixture of hydroxylammonium chloride (0.19 g), sodium hydrogen carbonate (0.27 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-{[2-(difluoromethyl)-1-(4-methoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.16 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.08 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.07 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.11 g, 60%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([NH:15][NH:16]C(OC(C)(C)C)=O)([CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([OH:13])[CH:7]=1.Br[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28](=[O:29])[O:27]1>CC(C)=O>[CH3:1][O:2][C:3](=[O:24])[C:4]([NH:15][NH2:16])([CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:28](=[O:29])[O:27]2)[CH:7]=1
Reactant: COC(=O)C(C)(Cc1ccc(O)c(O)c1)NNC(=O)OC(C)(C)C
Reactant: O=C1OC(Br)c2ccccc21
Solvent: CC(C)=O
Product: COC(=O)C(C)(Cc1ccc(O)c(OC2OC(=O)c3ccccc32)c1)NN
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.2 %

Procedure:
A mixture of compound 108 (380 mg, 1.1 mmol), bromophthalide (213 mg, 1 mmol) and CsHCO3 (325 mg, 1 mmol) in acetone was stirred at room temperature for 16 h. After removing the solvent under reduced pressure, the residue was partitioned between 10% citric acid and ethyl acetate. The organic phase was separated and dried over MgSO4. After removing the solvent under reduced pressure, the resulting residue was treated with 50% trifluoroacetic acid in dichloromethane at room temperature for 30 min. After removing the solvent, the resulting residue was purified by reverse phase preparative HPLC to afford two separated stereoisomers 113 (123 mg) and 114 (120 mg), respectively. Compound 113: 1H NMR (CD3OD, 400 MHz): 1.43 (s, 3H), 2.98 (dd, 2H), 3.80 (s, 3H), 6.62–7.20 (m, 4H), 7.66–7.95 (m, 4H). MS (ESI) m/z 373.25 (M+H+) and Compound 114:1H NMR (CD3OD, 400 MHz): 1.44 (s, 3H), 2.99 (dd, 2H), 3.84 (s, 3H), 6.80–7.18 (m, 4H), 7.69–7.93 (m, 4H). MS (ESI) m/z 373.25 (M+H+).