Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][N:7]([S:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)(=[O:11])=[O:10])[CH2:6][CH2:5][N:4]1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:31]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH3:1].[S:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[S:9]([N:7]1[CH2:6][CH2:5][N:4]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([OH:29])([CH3:28])[C:24]([F:26])([F:27])[F:25])=[CH:21][CH:22]=2)[C@@H:3]([CH2:2][NH:1][S:36]([C:32]2[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=2)(=[O:38])=[O:37])[CH2:8]1)(=[O:10])=[O:11]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN)cc1)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CNS(=O)(=O)c2cccnc2)cc1)C(F)(F)F
Product: N
Temperature: 60 °C
Yield: 140.6 %
Yield: 5 %

Procedure:
To a solution of 2-(4-((2S)-2-(aminomethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.130 g, 0.289 mmol) in CH2Cl2 (5.0 mL) was added 4-dimethylaminopyridine (7.0 mg, 0.062 mmol, Aldrich, St. Louis, Mo.), 3-pyridinesulfonyl chloride (0.077 g, 0.43 mmol, WAKO, Richmond, Va.), and diisopropylethylamine (0.50 mL, 2.9 mmol). The reaction mixture was heated at 60° C. for 30 min. The solvent was then removed in vacuo, The residue was dissolved in MeOH (5.0 mL) then potassium carbonate (0.240 g, 1.74 mmol) was added. The reaction mixture was heated at 60° C. for 1 h. Then the solvent was removed in vacuo. The residue was partitioned between water (20 mL) and CH2Cl2 (40 mL). The aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude product was purified by column chromatography (24 g of silica gel, 100% first then 5% to 8% 2M NH3 in MeOH in CH2Cl2) to afford N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-pyridinesulfonamide (0.120 g) as a mixture of two isomers:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]1[CH:22]=[C:23]([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])[CH:24]=[CH:25][CH:26]=1>CN(C=O)C>[C:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)(=[O:28])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(c1ccccc1)c1cccc(CBr)c1
Reactant: Nc1ccc(CCC(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCc1ccc(NCc2cccc(C(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged 25 mL of DMF. To the stirred solvent was added 3-(4-Amino-phenyl)-propanoic acid (0.6 g, 3.635 mmol) followed by K2CO3 (1.507 g, 10.905 mmol) and the mixture stirred at RT for 30 minutes. To the resulting mixture was added (3-bromomethyl-phenyl)-phenyl-methanone (1.0 g, 3.635 mmol) and the stirring continued at RT for further 20 h. After completion of the reaction (reaction monitored by TLC), solvent was removed under reduced pressure, and the resulting crude compound was dissolved in water (15 mL). This aqueous layer was acidified with saturated citric acid solution in water (1.5 g in 3 mL water) to pH 5. The compound was obtained after extracting the residue with diethyl ether (100 mL×3). The combined ether layer was washed with saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude mass thus obtained was purified by column chromatography on silica gel (100/200 mesh), using petroleum ether (60-80) and ethyl acetate as eluent. The product was obtained as brown sticky solid (0.3 g, Yield: 22.9%): MS (ESI, 120 eV): m/z=360.1 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 12.04 (s, 1H), 7.72 (s, 1H), 7.64-7.68 (t, 4H), 7.57-7.60 (d, 1H), 7.48-7.54 (m, 3H), 6.89-6.91 (d, 2H), 6.46-6.49 (d, 2H), 6.18-6.22 (t, 1H), 4.32-4.34 (d, 2H), 2.61-2.66 (d, 2H), 2.38-2.43 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]2[N:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:50][CH2:51][C@H:52]([OH:55])[CH2:53][OH:54].C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:50][CH2:51][C@H:52]([OH:55])[CH2:53][OH:54])=[O:24])=[C:16]2[N:15]=1
Reactant: NC[C@H](O)CO
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC[C@H](O)CO)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 42.3 %

Procedure:
A mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation C, 400 mg, 1.16 mmol), HATU (486 mg, 1.28 mmol), and (S)-3-aminopropane-1,2-diol (318 mg, 3.49 mmol) in dry DMF (3.0 mL) was stirred for 1-2 minutes at ambient temperature. Diisopropylethylamine (DIEA) (0.62 mL, 3.49 mmol) was added and the reaction was flushed with N2, sealed and stirred at ambient temperature for 18 hours. The reaction mixture was added to H2O (15 mL), mixed and extracted with EtOAc. The combined EtOAc extracts were washed with H2O, saturated NaHCO3 and dried over MgSO4/activated carbon. The solution was eluted through a SiO2 column eluting first with EtOAc then 10% MeOH/EtOAc. The 10% MeOH/EtOAc pool was concentrated and the residual, colorless glass was dissolved in a minimal amount of CH2Cl2. Hexane was added and the resulting white suspension was sonicated and concentrated to give the title product as a white solid (205 mg, 42%). MS (apci) m/z=418.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([CH3:9])[CH:3]=1.[Br-].[C:11]([C:13]1[CH:14]=[C:15]([Zn+])[CH:16]=[CH:17][C:18]=1[F:19])#[N:12].[Br-].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[Zn+]>>[C:11]([C:13]1[CH:14]=[C:15]([C:23]2[S:22][C:26]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[CH3:9])=[CH:25][CH:24]=2)[CH:16]=[CH:17][C:18]=1[F:19])#[N:12]
Reactant: Cc1cc(Br)ccc1I
Reactant: [Zn+]c1cccs1
Reactant: N#Cc1cc([Zn+])ccc1F
Agent: [Br-]
Product: Cc1cc(Br)ccc1-c1ccc(-c2ccc(F)c(C#N)c2)s1

Procedure:
The title compound was prepared using a procedure analogous to that described in EXAMPLE 127, Step A substituting 5-bromo-2-(4-bromo-2-methylphenyl)thiophene (from Step B) for 4-bromo-2-methyliodobenzene and 3-cyano-4-fluorophenylzincbromide for 2-thienylzinc bromide: 1H NMR (CDCl3) 7.85 (m, 2H), 7.47 (d, J=2.0, 1H), 7.40 (dd, J=2.0, 9.0, 1H), 7.29 (m, 3H), 7.07 (d, J=6.5, 1H), 2.47 (s, 3H). HPLC A 4.20 min.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[C:2]=[O:3].[N:11]1([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([NH:1][C:2]([N:14]2[CH2:13][CH2:12][N:11]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=3)[CH2:16][CH2:15]2)=[O:3])=[CH:5][CH:6]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(N2CCN(C(=O)Nc3ccc(C)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 2.7 %

Procedure:
A solution of 1-isocyanato-4-methyl-benzene (0.051 mol) in DCM p.a. (75 ml) was added dropwise to a solution of 4-(1-piperazinyl)-benzoic acid, ethyl ester (0.043 mol) and triethylamine (0.051 mol) in DCM p.a. (75 ml) while stirring at 0° C. (ice) for 20 minutes. The reaction mixture was stirred at room temperature for 1 hour and was then extracted with water. The organic layer was extracted with a saturated NaCl-solution and again with water, then separated, dried (MgSO4), filtered off and the filtrate was evaporated. The residue was stirred in DIPE and the formed precipitate was filtered off, washed with DIPE and dried. A part (0.5 g) of the residue (14.3 g, 90%) was crystallized from 2-propanol (10 ml) and the formed precipitate was filtered off and dried, yielding 0.42 g of 4-[4-[[(4-methylphenyl)amino]carbonyl]-1-piperazinyl]-benzoic acid, ethyl ester (interm. 1).
Reaction SMILES: [C:1]1([C@@H:7]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:11][CH:10]3[C@@:8]2([C:23]([OH:25])=O)[CH2:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:28])=O>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]1([C@@H:7]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:11][CH:10]3[C@@:8]2([C:23]([Cl:28])=[O:25])[CH2:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)N2CC3C[C@@]3(C(=O)O)[C@@H]2c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CC3C[C@@]3(C(=O)Cl)[C@@H]2c2ccccc2)cc1
Temperature: 0 °C
Yield: 99.8 %

Procedure:
To racemic Intermediate 43, one enantiomer being (1S,2S)-2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid (10.0 g, 28.0 mmol) slurried in toluene (67 mL) was added DMF (3 drops). The mixture was cooled to 0° C. and thionyl chloride (5.72 mL, 78.4 mmol) was added dropwise with stirring. The homogeneous solution was heated to 73° C. for 2.5 hours. The solvent was removed at reduced pressure. The residue was brought up in toluene two times and the solvent was removed at reduced pressure each time to yield the title compounds (10.5 g, quantitative yield) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:26][CH2:25][CH2:24]3)=[O:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:33].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:33])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:26][CH2:25][CH2:24]3)=[O:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)C2CCC2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)C2CCC2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(cyclobutylcarbonyl)piperazin-1-yl]quinolin-7-yl}ethanone (0.018 g, 0.048 mmol) and ammonium acetate (0.0373 g, 0.484 mmol) in methanol (0.2 mL) and acetonitrile (0.2 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.12 mL, 0.12 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C20H26ClN4O (M+H)+: m/z=373.2; Found: 373.2.
Reaction SMILES: F[C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C(=O)(O)[O-]>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:32][N:33]1[CH:37]=[C:36]([C:9]2[NH:8][C:5]3=[N:6][CH:7]=[CH:2][C:3]([C:22]4[S:26][C:25]([C:27]5([OH:31])[CH2:28][CH2:29][CH2:30]5)=[N:24][CH:23]=4)=[C:4]3[CH:10]=2)[CH:35]=[N:34]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)ccnc3[nH]2)cn1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 1-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 107C) (150 mg, 0.272 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (85 mg, 0.408 mmol) in N,N-dimethylformamide (2.04 mL) was added saturated aqueous bicarbonate solution (680 μL) followed by bis(triphenylphosphine) palladium dichloride (13.37 mg, 0.019 mmol). The mixture was heated to 70° C. for 1.5 hours and was quenched by the addition of water and dichloromethane. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organics were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 100% ethyl acetate in hexane. A solution of the crude material in methanol (2.0 mL) and 2N aqueous sodium hydroxide solution (700 μL) was heated by microwave irradiation (Biotage, Initiator) to 120° C. for 30 minutes. The reaction was cooled to room temperature, and the pH adjusted to ˜3 with 10% aqueous HCl solution. The resulting solution was purified by reverse phase high performance liquid chromatography (RP HPLC, eluting with a gradient of 5% B in A to 75% B in A over 25 minutes, wherein A is water containing 0.1% v/v trifluoroacetic acid and B is acetonitrile) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.48 (bs, 1H), 8.43 (s, 1H), 8.31 (s, 1H), 8.18 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.32 (d, J=5.1 Hz, 1H), 3.93 (s, 3H), 2.64-2.55 (m, 2H), 2.45-2.35 (m, 2H), 2.05-1.92 (m, 2H); MS ESI(+) m/z 352.7 [M+H]+.
Reaction SMILES: Cl.O1CCOCC1.C(OC(=O)[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[C:26]([NH2:28])[N:25]=[CH:24][N:23]=2)=[CH:17][CH:16]=1)(C)(C)C.N>C(Cl)Cl>[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[N:23]=[CH:24][N:25]=[C:26]([NH2:28])[CH:27]=2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cc2cc(N)ncn2)cc1
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1ccc(Cc2cc(N)ncn2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 4 N solution of HCl in dioxane (19.2 mL, 76.4 mmol, 30 equiv) is added to a solution of [4-(6-amino-pyrimidin-4-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (770 mg, 2.56 mmol) in CH2Cl2 (23 mL), under an argon atmosphere. The resulting white suspension is stirred at rt for 1.5 h and concentrated in vacuo. To the residue is added a 2 M methanolic solution of ammonia (3.8 mL, 7.68 mmol, 3 equiv) and the resulting yellow solution is concentrated in vacuo. The crude product is purified by silica gel (90 g) column chromatography CH2Cl2/MeOH, 90/10, then 80/20). The title compound is obtained as a white solid: ES-MS: 201.0 [M+H]+; single peak at tR=2.00 min (System 2); Rf=0.20 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:20]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=[C:23]([F:29])[C:24]=1[C:25]([F:28])([F:27])[F:26].C(Cl)Cl>CO.Cl[Pd]Cl.O>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:22]=[C:23]([F:29])[C:24]=1[C:25]([F:26])([F:27])[F:28]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: CC1(C)OB(c2cc(F)c(C(F)(F)F)c(F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)c1ccnc(-c2cc(F)c(C(F)(F)F)c(F)c2)c1
Temperature: 100 °C
Yield: 53.3 %

Procedure:
Methyl 2-chloroisonicotinate (1,838 g, 10.71 mmol), potassium carbonate (0.888 g, 6.43 mmol) and PdCl2 (dppf) (0.233 g, 0.32 mmol) were added to a microwave vial. 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.3 g, 10.71 mmol) dissolved in MeOH (15 mL) was added and the reaction heated in a single node microwave reactor at 100° C. for a total of 40 min. DCM (100 mL) and water (100 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (100 mL). The combined organic phases were washed with brine (200 mL), dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. A gradient from 5% EtOAc in heptane over 3 CV followed by 5% to 30% of EtOAc in heptane over 9 CV was used as mobile phase. The product was collected using the wavelength 250 nm. Methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)isonicotinate (1.810 g, 53%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 3.99 (s, 3H), 7.74 (d, 2H), 7.86-7.89 (m, 1H), 8.27 (s, 1H), 8.86 (d, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([CH3:12])[CH:5]=1.CS(O[CH:18]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]1)(=O)=O.O>CN(C=O)C>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([O:3][CH:18]2[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21]2)=[CH:5][C:6]=1[CH3:12])=[O:9]
Reactant: Cc1cc(O)ccc1C=O
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1C=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A slurry of sodium hydride (60%, 0.12 g, 3.10 mmol) in DMF (4 ml) was cooled by an ice-bath. Under nitrogen, 4-hydroxy-2-methylbenzaldehyde in DMF (2 ml) was added. The mixture was stirred for 30 min and then tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate in DMF (4 ml) was added. The mixture was heated to 100° C. using an oil bath for 3 days and then cooled to RT. Water (100 ml) was added while stirring. The mixture was extracted trice with EtOAc. The combined organic solutions were dried (MgSO4) and then evaporated. The residue was purified by silica gel chromatography eluting with EtOAc/heptane (10:90). There was obtained 120 mg (20%) of partly purified 69A as an oil. 1H NMR (500 MHz, CDCl3): δ 1.46 (s, 9H), 2.64 (s, 3H), 4.01 (m, 2H), 4.33 (m, 2H), 4.94 (m, 1H), 6.60 (d, 1H), 6.66 (dd, 1H), 7.76 (d, 1H), 10.13 (s, 1H).
Reaction SMILES: C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][NH:21]2)=[C:17]([NH:24][CH2:25][CH:26]2[CH2:28][CH2:27]2)[N:16]=1.[N:29]([C@@H:32]1[C@@H:36]([CH2:37][OH:38])[O:35][C@@H:34](N2C=C(C)C(=O)NC2=O)[CH2:33]1)=[N+:30]=[N-:31]>>[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:34]2[O:35][C@H:36]([CH2:37][OH:38])[C@@H:32]([N:29]=[N+:30]=[N-:31])[CH2:33]2)=[C:17]([NH:24][CH2:25][CH:26]2[CH2:27][CH2:28]2)[N:16]=1
Reactant: Nc1nc(NCC2CC2)c2nc[nH]c2n1
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(NCC4CC4)nc(N)nc32)O[C@@H]1CO
Temperature: 50 °C
Yield: 85.8 %

Procedure:
To 800 mL of an aqueous pH 6.0, 50 mM citrate buffer, prepared as described in Example 2c, was added 2-amino-6-(cyclopropylmethylamino)-9H-purine (0.204 g, 0.8 mmol) and 3'-azido-3'-deoxythymidine (1.069 g, 4.0 mmol). Solution was achieved by heating the mixture at 50° C. with sonication. A sample was removed as a control. A 40 mL solution of trans-N-deoxyribosylase (Example 2b) with an activity of 1500 units/mL was added. The reaction was heated at 50° C. Six days later, 0.204 g, 0.8 mmol, of 2-amino-6-cyclopropylmethylpurine was added to the reaction. Twenty-one days after the reaction was started, another 0.204 g, 0.8 mmol, of 2-amino-6-cyclopropylpurine and 0.428 g, 1.6 mmol, of 3'-azido-3'-deoxythymidine were added to the reaction. The reaction was stopped after thirty-three days by heating to 80° C. to precipitate the enzyme. The aqueous solution was extracted with ethyl acetate to remove the product. The combined ethyl acetate fractions were dried with magnesium sulfate, filtered and the solvent was removed in vacuo to give a foam. The foam was chromatographed on basic alumina grade 1 eluted with chloroform/methanol (97:3, v/v). The product containing fractions were combined and the solvent was removed in vacuo to give the product as a foam 0.237 g, 29% yield. mp=104°-106° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:27][C:26](=[O:28])[C:25]3[C:20](=[CH:21][C:22]([F:30])=[CH:23][C:24]=3F)[N:19]=2)[CH:15]=[C:14]([CH3:31])[N:13]=1.O>CN(C=O)C.C(O)(=O)C>[CH3:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:27][C:26](=[O:28])[C:25]3[C:20](=[CH:21][C:22]([F:30])=[CH:23][C:24]=3[O:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:19]=2)[CH:15]=[C:14]([CH3:31])[N:13]=1
Reactant: OCCN1CCCC1
Reactant: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3cc(F)cc(OCCN4CCCC4)c3c(=O)[nH]2)cc(C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-pyrrolidin-1-yl-ethanol (5.09 g, 44.2 mmol) in DMF (10 mL) was added sodium hydride (60% suspension in mineral oil, 0.88 g, 22.1 mmol) in small portions and the reaction mixture was stirred at room temperature for 30 minutes. To this mixture was added 2-(2,6-dimethyl-pyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one 0.63 g, 2.21 mmol) and the reaction mixture was stirred at room temperature for 16 hours. Water (20 mL) was added, and the mixture was neutralized, to pH approximately 6 with acetic acid. Solvent was evaporated, and the residue was dissolved in ethyl acetate, washed with water, and dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude compound was purified by the Simpliflash system (0-4% methanol in CH2Cl2 as eluent) to give 2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-(2-pyrrolidin-1-yl-ethoxy)-3H-quinazolin-4-one as a yellow solid. Yield: 0.61 g (72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[C@H:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C@H:10]2[C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])=[C:5]([O:37]COC)[CH:4]=1>C(O)C=C.Cl>[OH:37][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=2)[C@H:11]([C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C@H:10]1[C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32]
Reactant: C=CCOC(=O)[C@H]1[C@H](c2ccc(OC)cc2OCOC)c2cc(OCCC)ccc2[C@@H]1c1ccc2c(c1)OCO2
Agent: Cl
Solvent: C=CCO
Product: C=CCOC(=O)[C@H]1[C@H](c2ccc(OC)cc2O)c2cc(OCCC)ccc2[C@@H]1c1ccc2c(c1)OCO2
Temperature: 65 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
Allyl (1S, 2R, 3S)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (1.7 g, 3.11 mmol) was dissolved in allyl alcohol (20 ml) and then 15 drops of conc. HCl was added. The resulting solution was stirred at 65° C. for 2 h. After removing the solvent the residue was partitioned between water and ethyl acetate. The organic layers were washed with water, 5% aqueous NaHCO3 and brine; then dried (MgSO4 anhyd.), filtered and evaporated to give an oil. The product was purified by column chromatography to provide the title compound as a pale yellow oil (1.26 g, 81%).