Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.[CH:27](=O)[CH3:28].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([N:8]([CH2:27][CH3:28])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1
Reactant: CC=O
Reactant: COC(=O)c1cc(Br)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
To a stirred solution of tert-butyl 4-((5-bromo-3-(methoxycarbonyl)-2-methylphenyl)amino)piperidine-1-carboxylate (5 g, 11.70 mmol) and acetaldehyde (1.58 g, 35.12 mmol) in dichloroethane (60 mL), acetic acid (4.24 g, 70.66 mmol) was added and reaction stirred at room temperature for 10 min. Then sodium triacetoxyborohydride (7.44 g, 35.09 mmol) was added at 0° C. and reaction stirred at room temperature for 2 h. On completion, the reaction was quenched with aqueous sodium bicarbonate, organic phase was separated and aqueous phase was extracted with dichloromethane. Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to give crude material was purified by column chromatography to afford the desired product (5 g, 93.45%).
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)(=O)C.[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[C:13](=[O:21])[N:10]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(=O)Oc1ccc(C#N)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2ccc(O)cc2)sc2ccccc12
Yield: 15.9 %

Procedure:
A mixture of 4-acetoxybenzonitrile (1.35 g, 8.4 mmol), methyl thiosalicylate (2.12 g, 13 mmol), triethylamine (1.50 g, 15 mmol) and toluene (10 ml) was heated and refluxed under a nitrogen flow for 26 hours. The precipitated crystals were taken by filtration and recrystallized from tetrahydrofuran-ethyl acetate to give the title compound (0.34 g, 16%) as crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][CH2:19][OH:20])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][CH2:19][O:20][S:34]([C:31]3[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=3)(=[O:36])=[O:35])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CCO)cc2C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 800 mg (2.88 mmol) 7-(2-hydroxy-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 7c) in 10 mL DCM is added at 0° C. subsequently 0.34 mL (4.33 mmol) pyridine and 605 mg (3.17 mmol) 4-methyl-benzenesulfonyl chloride in 5.0 mL DCM. The reaction mixture is warmed to RT and is stirred 5 h at RT. Additional 0.34 mL (4.33 mmol) pyridine and 605 mg (3.17 mmol) 4-methyl-benzenesulfonyl chloride in 5.0 mL DCM are added and the mixture is stirred over night. The reaction mixture is poured into ice-water and the organic phase is separated, washed with aqueous KHSO4-solution and aqueous NaHCO3-solution, dried over MgSO4. After evaporation of the solvent, the residue is purified via chromatography (silica gel; cyclohexane/EtOAc 8:2 to 1:1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:20]1([CH2:19][CH2:18][CH2:17][O:1][C:2]2[CH:3]=[C:4]([C:8]3([C:14]#[N:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[CH:5]=[CH:6][CH:7]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: N#CC1(c2cccc(O)c2)CCOCC1
Reactant: ClCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(OCCCN3CCCC3)c2)CCOCC1
Yield: 31.2 %

Procedure:
4-(3-Hydroxy-phenyl)-tetrahydro-2H-pyran-4-carbonitrile (1.03 g, 5.10 mmol), 1-(3-chloro-propyl)-pyrrolidine (600 mg, 4.08 mmol), DMF (6.8 ml) and K2CO3 (2.82 g, 20.4 mmol) were reacted together according to general procedure E. The organic phase was washed with 2M NaOH (3×50 ml), brine (3×50 ml), dried over MgSO4, fitered and concentrated in vacuo at 35° C. The crude mixture was slurried in TBME:heptane (1:20, 10 ml). The solid was filtered, washed with heptane (10 ml) and dried on the filter for 2 hours to give the title compound (0.4 g, 31%). 1H NMR (400 MHz, CDCl3) δ 7.32 (t, 1H), 7.07-6.99 (m, 2H), 6.87 (dd, 1H), 4.11-4.04 (m, 2H), 4.05 (t, 2H), 3.90 (td, 2H), 2.63 (t, 2H), 2.57-2.49 (m, 4H), 2.18-1.97 (m, 6H), 1.84-1.75 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][N:12]=[C:11]([CH3:14])[C:10]=1[CH2:15][OH:16].[F:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:21]=[C:22]([F:25])[C:23]=1O.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[F:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:21]=[C:22]([F:25])[C:23]=1[O:16][CH2:15][C:10]1[C:11]([CH3:14])=[N:12][S:13][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[F:1]
Reactant: Cc1ccc(-c2snc(C)c2CO)c(F)c1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1cc(F)c(OCc2c(C)nsc2-c2ccc(C)cc2F)c(F)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [5-(2-fluoro-4-methylphenyl)-3-methyl-1,2-thiazol-4-yl]methanol (100 mg, 0.42 mmol, 1.00 equiv), ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (146 mg, 0.63 mmol, 1.50 equiv), ADDP (221.6 mg, 0.89 mmol, 2.10 equiv), Bu3P (128 mg, 0.63 mmol, 1.5 equiv), toluene (10 mL). The resulting solution was stirred overnight at 60° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 150 mg (79%) of ethyl 3-(3,5-difluoro-4-[[5-(2-fluoro-4-methylphenyl)-3-methyl-1,2-thiazol-4-yl]methoxy]phenyl) propanoate as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][S:8]/[C:9](/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10]\[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[CH2:22]1CCN2C(=NCCC2)CC1.IC>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8]/[C:9](/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10]\[C:11]([O:13][CH3:22])=[O:12])=[CH:20][CH:21]=1
Reactant: COc1ccc(CS/C(=C\C(=O)O)c2ccccc2)cc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: CC#N
Product: COC(=O)/C=C(\SCc1ccc(OC)cc1)c1ccccc1
Reaction time: 0.25 h
Yield: 79.2 %

Procedure:
Z-3-(4'-Methoxybenzylthio)-3-phenyl-2-propenoic acid (5.46 g, 18.2 mmol) was suspended in 22 mL of dry acetonitrile. Addition of DBU (3.30 mL, 22.1 mmol) gave a clear yellow solution. The mixture was stirred in an ice bath and iodomethane (1.32, 21.2 mmol) was then added over 5 minutes. After an additional 15 minutes, the ice bath was removed and the solution was stirred for 1.25 hours. The reaction was poured into 100 mL of ethyl acetate and washed with 75 mL of water, 2×25 mL of 2N aqueous hydrochloric acid, 2×25 mL of saturated aqueous sodium bicarbonate, and 25 mL of saturated aqueous sodium chloride. The ethyl acetate solution was dried over sodium sulfate, decanted, and evaporated to give 4.53 g of crude methyl Z-3 (4'-methoxybenzylthio)-3-phenyl-2-propenoate as pale yellow crystals.
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:10][CH2:9][CH:8]([OH:11])[C:7]2[CH:12]=[CH:13][O:14][C:6]=2[CH2:5]1)#[N:2].[Br:15][C:16]1[C:17]([Cl:23])=[C:18](F)[CH:19]=[CH:20][CH:21]=1>>[ClH:23].[Br:15][C:16]1[C:17]([Cl:23])=[C:18]([O:11][CH:8]2[CH2:9][CH2:10][N:4]([CH2:3][C:1]#[N:2])[CH2:5][C:6]3[O:14][CH:13]=[CH:12][C:7]2=3)[CH:19]=[CH:20][CH:21]=1
Reactant: N#CCN1CCC(O)c2ccoc2C1
Reactant: Fc1cccc(Br)c1Cl
Product: Cl
Product: N#CCN1CCC(Oc2cccc(Br)c2Cl)c2ccoc2C1

Procedure:
The same method as in Example 3 was conducted using 7-cyanomethyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 41) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][CH:29]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:30][C:31](O)=[O:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.C[N:39](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[F:1][C:2]1[C:3]([NH:28][CH:29]([C:34]([CH3:35])([CH3:37])[CH3:36])[CH2:30][C:31]([NH2:39])=[O:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC(CC(=O)O)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C(CC(N)=O)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of racemic 3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-4,4-dimethylpentanoic acid, 163a, (0.50 g, 0.94 mmol) in 15 mL of THF was added HBTU (0.36 g, 0.95 mmol). The reaction was stirred for 15 minutes and then ammonia gas was bubbled through for 5 minutes. The reaction was allowed to stir for 12 hours and then concentrated to dryness. The residue was redissolved in 20 mL of MeOH and treated with 3 mL of 2N LiOH. The reaction was warmed to 60° C. for 3 hours and then concentrated to dryness. The residue was purified by silica gel chromatography (EtOAc) to afford 250 mg of desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=1.78 minutes (M+H) 375.45.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=CC=CC=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:12][C:13]([NH:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23]C)=[O:21])=[CH:18][CH:17]=1)=[O:14]>Cl>[C:2]1([CH:11]=[CH:12][C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:25][CH:26]=2)=[O:14])[CH:1]=[CH:10][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C=Cc2ccc3ccccc3c2)cc1
Agent: Cl
Product: COC(=O)c1ccc(NC(=O)C=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This was obtained as a white solid from cinnamoyl chloride (1.1 g, 6.62 mmol) and ethyl 4-aminobenzoate (1.10 g, 6.62 mmol) in a similar manner as described for preparation of 42. The reaction mixture was stirred at room temperature overnight and the mixture was poured in HCl (aq, 2N, 20 ml). The product was extracted with DCM (2×20 ml), dried over Na2SO4 and the solvent removed under reduced pressure. The crude amide 41 was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH3:2].Br[CH2:18][CH2:19][CH2:20][P:21]([O:26][CH2:27][CH3:28])(=[O:25])[O:22][CH2:23][CH3:24]>>[CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:18][CH2:19][CH2:20][P:21](=[O:25])([O:26][CH2:27][CH3:28])[O:22][CH2:23][CH3:24])[C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH3:2]
Reactant: CCOCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CCOP(=O)(CCCBr)OCC
Product: CCOCn1cnc2c1c(=O)n(CCCP(=O)(OCC)OCC)c(=O)n2C

Procedure:
The title substance was prepared from 0.048 mol of 7-ethoxymethyl-3-methylxanthine and 0.058 mol of diethyl 3-bromopropanephosphonate analogously to Example 32 and chromatographed on silica gel (eluent: ethyl acetate/methanol 10:1).
Reaction SMILES: ClC1C2C(=CC(OC)=C(OC)C=2)N=C[N:3]=1.[CH3:16][O:17][C:18]1[C:26]([O:27][CH3:28])=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([N+:29]([O-:31])=[O:30])[CH:19]=1.S(Cl)(Cl)=O.N>>[CH3:16][O:17][C:18]1[C:26]([O:27][CH3:28])=[CH:25][C:21]([C:22]([NH2:3])=[O:23])=[C:20]([N+:29]([O-:31])=[O:30])[CH:19]=1
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: N
Solvent: O=S(Cl)Cl
Product: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OC

Procedure:
The common synthetic intermediate 4-chloro-6,7-dimethoxyquinazoline 5 used for synthesizing all the tested compounds by following literature procedures (Scheme 1). 4,5-dimethoxy-2-nitrobenzoic acid 1 was treated with thionyl chloride, and then reacted with ammonia to give 4,5-dimethoxy-2-nitrobenzamide 2 (Nomoto et al., 1990, Chem. Pharm. Bull 38: 1591-1595). The nitro group in compound 2 was reduced with sodium borohydride in the presence of copper sulfate (31) to give 4,5-dimethoxy-2-aminobenzamide 3, which was cyclized by refluxing with formic acid to give 6,7-dimethoxyquinazoline-4(3H)-one 4. The quinazolinone 4 was refluxed with phosphorus oxytrichloride to provide the key starting material 5 with good yield.
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20][CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2F)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].O>CN(C)C=O>[C:24]([N:21]1[CH2:22][CH2:23][CH:18]([C:9]2[C:10]3[C:15](=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:19][CH2:20]1)(=[O:26])[CH3:25]
Reactant: CC(=O)N1CCC(C(=NNc2ccccc2)c2ccc(F)cc2F)CC1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(c2nn(-c3ccccc3)c3cc(F)ccc23)CC1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
To a stirred solution of 3.0 g of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine phenylhydrazone in 30 ml of dimethylformamide, under nitrogen, was added 0.44 g of a 50% oil dispersion of sodium hydride. The reaction mixture was heated, and at about 40° C. a vigorous evolution of hydrogen occurred. The temperature was then raised to 80° C. and held there for 1.5 hrs. The reaction mixture was poured into water and the aqueous suspension was extracted with ethyl acetate. The ethyl acetate extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated to yield an oil. The oil was combined with the oil from another experiment and a total of 13.5 g of material was chromatographed on a Water's Prep LC 500. Two silica gel columns were utilized and dichloromethane-methanol (3%) was used as the eluent. The appropriate fractions were evaporated. The residue was recrystallized twice from isopropyl alcohol-water (one charcoal treatment) to yield 2.4 g (18%) of product, mp 126°-128° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19]>CN(C=O)C.C(OCC)(=O)C>[N+:18]([C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:8]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:12]([O:14][CH3:15])=[O:13])([O-:20])=[O:19]
Reactant: C1CCNCC1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Piperidine (1.24 ml) was added to a solution of methyl 4-fluoro-3-nitrobenzoate (1.00 g) in DMF (20 ml) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, sequentially washed with water and brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (1.50 g).
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][CH:6]([NH2:15])[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14])C.P([O-])(O)(O)=O.[K+]>O>[NH2:15][C@H:6]([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14])[CH2:5][C:4]([OH:16])=[O:3]
Reactant: CCOC(=O)CC(N)c1cc(F)ccc1F
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Product: N[C@@H](CC(=O)O)c1cc(F)ccc1F
Reaction time: 8 h
Yield: 49.4 %

Procedure:
3-Amino-3-(2,5-difluorophenyl)propionic acid ethyl ester (3 g) was emulsified in water (pH=9.2) and admixed with potassium dihydrogenphosphate (5 mg) (pH=8.5). After addition of Amano Lipase PS (150 mg), the mixture was stirred overnight. The pH remains at 7.5. The mixture was then admixed with water (30 ml) and filtered through kieselguhr and washed several more times with water. The aqueous phase was then extracted with dichloromethane (3×30 ml), and the organic phase was dried (Na2SO4) and concentrated. This gave the product (1.3 g) with an ee=90% by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:38]([O:40][C:41]([C:43]1([CH2:47][CH2:48]Br)[CH2:46][CH2:45][CH2:44]1)=[O:42])[CH3:39]>CN(C=O)C>[CH2:38]([O:40][C:41]([C:43]1([CH2:47][CH2:48][O:29][C:26]2[CH:25]=[CH:24][C:23]([C:22]([N:15]3[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:12]([N:8]([C:9](=[O:11])[CH3:10])[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:13][CH:14]3[CH3:31])=[O:30])=[CH:28][CH:27]=2)[CH2:46][CH2:45][CH2:44]1)=[O:42])[CH3:39]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: CCOC(=O)C1(CCBr)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CCOc2ccc(C(=O)N3c4ccccc4C(N(C(C)=O)c4ccc(Cl)cc4)CC3C)cc2)CCC1
Temperature: 80 °C
Yield: 67.5 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.17 g, 0.39 mmol) was dissolved in 5 ml DMF at room temperature and K2CO3 (0.323 g, 2.34 mmol) was added. 1-(2-Bromo-ethyl)-cyclobutanecarboxylic acid ethyl ester (0.184 g, 0.78 mmol) prepared according to the procedure from Tetrahedron 1994, 50(32), 9825-30 was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (50% EtOAc/50% Hexane) to afford the 1-[2-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-ethyl]-cyclobutanecarboxylic acid ethyl ester (0.155 g, 67%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[N:5]=[C:4]([CH3:14])[N:3]=1.[C:15](O)(=O)[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>P(Cl)(Cl)(Cl)=O>[CH2:10]([N:9]([CH2:12][CH3:13])[C:6]1[N:5]=[C:4]([CH3:14])[N:3]=[C:2]2[C:7]=1[NH:8][C:15]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[N:1]2)[CH3:11]
Reactant: O=C(O)c1ccncc1
Reactant: CCN(CC)c1nc(C)nc(N)c1N
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CC)c1nc(C)nc2nc(-c3ccncc3)[nH]c12
Yield: 31.8 %

Procedure:
A homogeneous mixture obtained by grinding 5 g of 4,5-diamino-6-diethylamino-2-methylpyrimidine and 3.4 g of isonicotinic acid in a mortar is added to 110 ml of phosphorus oxychloride under stirring, and refluxed with heating for 3 hours. The reaction solution is concentrated and 180 ml of water is added to the residual oil. The aqueous solution is neutralized with an ammonia solution and the crystals precipitated are filtered and purified by column chromatography on silica gel with a mixture of chloroform and methanol (10:1) as an eluent. Recrystallization from methanol gives 2.3 g of 6-diethylamino-2-methyl-8-(4-pyridyl)purine, melting at 228°-230° C.
Reaction SMILES: [CH:1](N(C(C)C)CC)([CH3:3])[CH3:2].CC(C)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:28][C:29]1[CH:38]=[C:37]([CH2:39][C:40]2[CH:57]=[CH:56][C:43]([C:44]([NH:46][C@@H:47]3[CH2:51][NH:50][CH2:49][C@@H:48]3[C:52]([O:54][CH3:55])=[O:53])=[O:45])=[CH:42][CH:41]=2)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1>ClCCl.C(OCC)(=O)C>[CH:1]([N:50]1[CH2:51][C@@H:47]([NH:46][C:44](=[O:45])[C:43]2[CH:42]=[CH:41][C:40]([CH2:39][C:37]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:28])[CH:38]=3)=[CH:57][CH:56]=2)[C@@H:48]([C:52]([O:54][CH3:55])=[O:53])[CH2:49]1)([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1CNC[C@H]1NC(=O)c1ccc(Cc2cc(C)nc3ccccc23)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@H]1CN(C(C)C)C[C@H]1NC(=O)c1ccc(Cc2cc(C)nc3ccccc23)cc1
Yield: 61.5 %

Procedure:
Diisopropylethylamine (28 mg, 38 μL, 0.22 mmol), acetone (6 mg, 8 μL) and NaBH(OAc)3 (23 mg, 0.11 mmol) were added to a solution of the TFA salt (403a) (46 mg, 0.073 mmol) in 1 mL of dichloromethane. The whole mixture was stirred until the reaction went to completion. The solution was diluted with ethyl acetate and washed with saturated NaHCO3, H2O and brine. The organic layer was dried over MgSO4. After filtration and concentration, the residue was purified on silica gel to provide methyl (3S,4S)-1-isopropyl-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-3-pyrrolidinecarboxylate (20 mg, 63%). MS (ES+): 446(M+1).
Reaction SMILES: Br[CH2:2][CH2:3][F:4].[Cl:5][C:6]1[C:14]([CH3:15])=[N:13][C:12]2[N:8]([N:9]=[C:10]3[CH2:18][N:17]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:20])[CH2:16][C:11]3=2)[C:7]=1[CH3:35].C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:5][C:6]1[C:14]([CH3:15])=[N:13][C:12]2[N:8]([N:9]=[C:10]3[CH2:18][N:17]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH:29]4[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][F:4])[CH2:31][CH2:30]4)=[O:20])[CH2:16][C:11]3=2)[C:7]=1[CH3:35]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OC1CCNCC1)C3
Reactant: FCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OC1CCN(CCF)CC1)C3
Temperature: 100 °C
Yield: 48.1 %

Procedure:
1-Bromo-2-fluoro-ethane (19 mg; 0.15 mmol; 1.1 eq.) was added to a suspension of Example 64 (60 mg; 0.14 mmol; 1 eq.) and NaHCO3 (114 mg; 1.35 mmol; 10 eq.) in DMF (2 mL) and the reaction mixture was stirred at 100° C. (MW heating) for 30 minutes. 1-Bromo-2-fluoro-ethane (9 mg; 0.07 mmol; 0.5 eq.) was added and the reaction mixture was stirred at 100° C. (MW heating) for 30 minutes. The precipitate was filtered off and the mother liquor was concentrated in vacuo. The residue was diluted with DCM, washed with 1M NaOH, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (5% to 20% MeOH in DCM) followed by crystallization from EA afforded the title compound (33 mg, 49%) as yellow solid. 1H NMR (CDCl3) δ 7.40-7.28 (m, 1H), 6.84-6.61 (m, 2H), 5.11-4.90 (m, 2H), 4.66 (br s, 2H), 4.56 (t, J=4.9 Hz, 1H), 4.46-4.29 (m, 2H), 2.91 (s, 1.8H), 2.86 (s, 1.2H), 2.73-2.48 (m, 7H), 2.47-2.30 (m, 2H), 2.07-1.91 (m, 2H), 1.91-1.73 (m, 2H). HPLC (max plot) 98.5%, Rt 2.96 min. UPLC/MS: (MS+) 490.3 ([M+H]+).