Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH:12]([CH3:14])[CH3:13])(=[O:3])[CH3:2].[I:15]Cl>C(Cl)Cl.CCOCC>[C:1]([O:4][C:5]1[CH:10]=[C:9]([I:15])[CH:8]=[CH:7][C:6]=1[O:11][CH:12]([CH3:14])[CH3:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1OC(C)C
Reactant: ClI
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)Oc1cc(I)ccc1OC(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-isopropoxyphenyl acetate (10 mmol) in CH2Cl2 at 0° C., iodine monochloride (1.0 M in CH2Cl2, 11.0 mL) was added dropwise in 20 min. The mixture was stirred at 0° C. for 2.0 h, diluted with ether, washed with saturated Na2S2O3 and brine. The organic extract was dried over MgSO4 and evaporated to give 5-iodo-2-isopropoxyphenyl acetate as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+].[ClH:26]>CO.O>[ClH:26].[CH3:23][N:20]1[CH2:21][CH2:22][CH:17]([CH2:16][O:15][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1cc2cc(OCC3CCN(C)CC3)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CCC(COc2ccc3[nH]c(C(=O)O)cc3c2)CC1
Temperature: 25 °C
Yield: 69 %

Procedure:
A suspension of ester 26 (1.00 g, 3.16 mmol) in MeOH (8 mL) was treated with a solution of NaOH (155 mg, 3.88 mmol) in water (4 mL) and heated at reflux for 3.5 h. After cooling to room temperature, the solution was adjusted to pH 6 with 2 M HCl and the solvent was removed under reduced pressure. The residue was dissolved in MeOH, 2 M HCl was added dropwise, and the formed precipitate was collected by filtration to give 27 (712 mg, 69%) as a brown solid. The residue obtained after evaporation of the mother liquor was purified by column chromatography (CH2Cl2/MeOH, 6:1, 1% cone. HCl) to provide a second batch of 27 (226 mg, 22%). 1H NMR (300 MHz, DMSO-d6): δ=1.56-1.77 (m, 2 H, 3′-Hax, 5′-Hax), 1.89-2.09 (m, 3 H, 3′-Heq, 41-H, 5′-Heq), 2.69 (s, 3 H, NMe), 2.87-3.05 (m, 2 H, 2′-Hax, 6′-Hax) 3.24-3.48 (m, 2 H, 2′-Heq, 6′-Heq), 3.79-3.92 (m, 2 H, ArOCH9), 6.90 (dd, J=9.0, 2.2 Hz, 1 H, 6-H), 6.98 (d, J=1.7 Hz, 1 H, 3-H), 7.12 (d, J=2.2 Hz, 1 H, 4-H), 7.34 (d, J=9.0 Hz, 1 H, 7-H), 10.84 (sbr, 1H, NH+), 11.59 (s, 1H, NH), 12.74 (sbr, 1 H, CO2H) ppm. —13C NMR (75.5 MHz, DMSO-d6): δ=25.8 (C-3′, C-5′), 32.8 (C-4′), 42.5 (NMe), 52.8 (C-2′, C-6′), 71.6 (OCH2), 103.4 (C-4), 106.8 (C-3), 113.3 (C-7), 116.0 (C-6), 127.1 (C-2), 128.7 (C-3a), 132.6 (C-7a), 152.9 (C-5), 162.5 (C═O) ppm. −MS (70 eV, EI): m/z (%)=288 (14) [M−HCl]+, 112 (100) [C7H14N]+. —C16H21ClN2O3 (324.80): calcd. 288.1474 [M−HCl]+; found 288.1474.
Reaction SMILES: O[C:2]([C:19]1[C:20](=[O:56])[NH:21][C:22](=[O:55])[N:23]([CH:54]=1)[C@@H:24]1[O:53][C@H:43]([CH2:44][O:45][Si](C(C)(C)C)(C)C)[C@@H:34]([O:35][Si](C(C)(C)C)(C)C)[C@H:25]1[O:26][Si](C(C)(C)C)(C)C)([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:19]2[C:20](=[O:56])[NH:21][C:22](=[O:55])[N:23]([CH:54]=2)[C@@H:24]2[O:53][C@H:43]([CH2:44][OH:45])[C@@H:34]([OH:35])[C@H:25]2[OH:26])[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[CH:4][CH:5]=1
Reactant: COc1ccc(C(O)(c2ccc(OC)cc2)c2cn([C@@H]3O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c(=O)[nH]c2=O)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(c2ccc(OC)cc2)c2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c(=O)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
The product of step (i) (3.8 g) was dissolved in dichloromethane (75 ml) and triethylsilane (0.8 ml) and was treated with trifluoroacetic acid(3.59 ml). After stirring for 1 hour at room temperature, the volatiles were removed under reduced pressure and any remaining traces removed by azeotroping four times with toluene. The residue was treated with 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (15 ml). After stirring for 36 hours, the solvent was removed under reduced pressure and the residue was purified by silica-gel chromatography eluting with 2% methanol in ethyl acetate to afford 5-(1,1-bis(4-methoxyphenyl)methyl)uridine as a white solid (1.4 g).
Reaction SMILES: [C:1]([O:4][CH:5]([CH:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:10][O:11][C:12](=[O:14])[CH3:13])[C:6](O)=[O:7])(=[O:3])[CH3:2].S(Cl)([Cl:21])=O>>[C:16]([O:15][CH:9]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]([Cl:21])=[O:7])[CH2:10][O:11][C:12](=[O:14])[CH3:13])(=[O:18])[CH3:17]
Reactant: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(=O)O
Reactant: O=S(Cl)Cl
Product: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(=O)Cl
Reaction time: 48 h

Procedure:
The 2,3,4-triacetoxy-butyric acid (25 g, 0.095 mol) was stirred in thionyl chloride (15.3 mL) at room temperature with a condenser fitted. The reaction was stirred for 48 hours and then the thionyl chloride was removed under reduced pressure to give an oil, which 1H and 13C NMR (CDCl3) showed to be the desired material (26.1 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24](O)=[O:25])=[CH:20][CH:19]=1>>[OH:17][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:25])=[CH:27][CH:28]=1
Reactant: O=C(O)COc1ccc(O)cc1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Product: O=C(COc1ccc(O)cc1)Nc1ccccc1-c1cc2ccccc2[nH]1
Yield: 30 %

Procedure:
Prepared from 2-(2-aminophenyl) indole and (4-hydroxyphenoxy) acetic acid in 30% yield following procedure 1. The product was crystallized from methanol. 89% Purity by LC/MS (230 DAD), Mass-spec [M+H+]=359, 1H NMR (MeOH-d4): 4.52 s (2H), 6.55 d, 9 Hz (2H), 6.58 s (1H), 6.61 d, 9 Hz (2H), 7.09 t, 8 Hz (1H), 7.18 t, 8 Hz (1H), 7.26 t, 8 Hz (1H), 7.37–7.43 m (2H), 7.56 t, 8 Hz (2H), 8.38 d, 8 Hz (1H).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:11]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([O:20][C:21]([F:24])([F:23])[F:22])[CH:13]=2)[N:10]=[N:9][N:8]=1>C1(C)C=CC=CC=1>[Cl:3][CH2:6][C:7]1[N:11]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([O:20][C:21]([F:24])([F:23])[F:22])[CH:13]=2)[N:10]=[N:9][N:8]=1
Reactant: N#Cc1ccc(-n2nnnc2CO)cc1OC(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-n2nnnc2CCl)cc1OC(F)(F)F
Yield: 76.3 %

Procedure:
Thionyl chloride (2.21 g, 18.6 mmol) was added to a stirred solution of 4-[5-(hydroxymethyl)-1H-tetrazol-1-yl]-2-[(trifluoromethyl)oxy]benzonitrile (Intermediate 54, 3.50 g, 12.3 mmol) in toluene (50 mL) at room temperature, and the reaction mixture was heated to reflux for 4 h. The reaction mixture was concentrated under vacuum. The residue was diluted with DCM and washed with ice-cooled water, saturated aq NaHCO3 and brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. This was purified by column chromatography (60-120 mesh silica gel), eluting with 20% EtOAc/pet.ether to give the title compound as an off-white powder (2.85 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23]3)[CH2:4][CH2:3]1.Cl.O1CCOCC1>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]([F:16])([F:15])[F:17])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH2:20][CH2:21][NH:22][CH2:23]3)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2cc(C(F)(F)F)ccc2-c2cccc3c2CCN(C(=O)OC(C)(C)C)C3)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CN1CCN(c2cc(C(F)(F)F)ccc2-c2cccc3c2CCNC3)CC1
Yield: 77.9 %

Procedure:
A solution of tert-butyl 5-(2-(4-methylpiperazin-1-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.680 g, 3.53 mmol) in 4 mL THF was treated with HCl 4N in dioxane (8.83 ml, 35.3 mmol) and was heated to reflux with a heat gun. The reaction mixture was allowed to stir for an additional hour then the reaction mixture was concentrated. Purification of the resulting residue by reverse phase column chromatography [RediSep Gold C18 150 g, 5-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 5-(2-(4-methylpiperazin-1-yl)-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (1.031 g, 2.75 mmol,) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[NH:10]N.O=[C:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]2[C:3]=1[NH:10][C:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[CH2:15][C:14]2=1
Reactant: CC(C)C(=O)NC1CCC(=O)CC1
Reactant: N#Cc1ccc(NN)c(Cl)c1
Product: CC(C)C(=O)NC1CCc2[nH]c3c(Cl)cc(C#N)cc3c2C1
Yield: 50 %

Procedure:
Prepare the title compound by essentially following the procedure as described in Preparation 4 (Method 2) with 2-chloro-4-cyanophenylhydrazine (Preparation 13) and N-(4-oxo-cyclohexyl)-isobutyramide, to obtain the title compound as a pink powder in 50% yield. MS (ES): m/z 316 (M+H), 314 (M−H); HPLC (Method A): Rt=1.96, (90%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:16]C(=O)C(F)(F)F)[CH:7]=[C:8]([S:10]([F:15])([F:14])([F:13])([F:12])[F:11])[CH:9]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O>O.C(#N)C>[NH2:16][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[C:8]([S:10]([F:15])([F:11])([F:12])([F:13])[F:14])[CH:7]=1
Reactant: CC(=O)c1cc(NC(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: CC(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1
Temperature: 75 °C
Reaction time: 4 h
Yield: 86.5 %

Procedure:
N-(3-Acetyl-5-pentafluorosulfanylphenyl)-2,2,2-trifluoroacetamide (4 g, for preparation see example 4d) was suspended in 6 ml of water and 12 ml of acetonitrile, and 6 ml of concentrated sulfuric acid were added dropwise to this suspension. After stirring at 75° C. for 4 h and leaving to stand at RT overnight, the reaction was completed by adding another 2 ml of concentrated sulfuric acid and heating the mixture at 75° C. for 3 h. The reaction mixture was poured onto ice-water and extracted with ethyl acetate. The ethyl acetate phase was washed to neutrality with saturated sodium hydrogencarbonate solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by means of chromatography on silica gel. The product-containing fractions were combined and the solvent (heptane/ethyl acetate) was concentrated under reduced pressure. 2.53 g of 1-[3-amino-5-(pentafluorosulfanyl)phenyl]ethanone were obtained.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:14]([NH:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:16])[CH3:15].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>>[C:14]([NH:17][C:18](=[CH:1][C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1)[C:19]([OH:21])=[O:20])(=[O:16])[CH3:15]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: CC(=O)NCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C=C(NC(C)=O)C(=O)O)cc(OC)c1O
Temperature: 90 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
A 1.8 g (9.88 mmol) of syringaldehyde, 1.4 g (12.0 mmol) of N-acetylglycine, 1 g (12.2 mmol) of sodium acetate and 5 ml of acetic anhydride were stirred at 120° C. for 6 hours. A precipitate was washed with water and ethanol in this order and dried under reduced pressure. To the product was added 80 ml of 0.1N hydrochloric acid, and the mixture was stirred at 90° C. for 1 hour. A crystal formed was washed with water and acetone in this order to give 880 mg (yield 31.7%) of objective αacetylamino-3,5-dimethoxy-4-hydroxycinnamic acid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[N:8]([CH3:11])=[C:9]=[S:10]>O1CCCC1>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:9]([NH:8][CH3:11])=[S:10]
Reactant: CN=C=S
Reactant: COC(CN)OC
Solvent: C1CCOC1
Product: CNC(=S)NCC(OC)OC
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A mixture of 4.2 g of 2,2-dimethoxyethanamine, 3.6 g of isothiocyanatomethane and 100 ml of tetrahydrofuran was stirred overnight. The reaction mixture was evaporated, yielding 7.1 g (99%) of N-(2,2-dimethoxyethyl)-N'-methylthiourea as an oily residue (interm. 34);
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[O:27][N:26]=[C:25]([CH3:28])[CH:24]=1>>[CH3:28][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:6][CH:7]=2)[O:27][N:26]=1
Reactant: Cc1cc(CCCCCBr)on1
Reactant: Oc1ccc(-c2nc3ccccc3s2)cc1
Product: Cc1cc(CCCCCOc2ccc(-c3nc4ccccc4s3)cc2)on1

Procedure:
2-{4-[[5-(3-Methyl-5-isoxazolyl)pentyl]oxy]phenyl}benzothiazole [II; R1 and R2 =H, Het=benzothiazol-2-yl] was prepared from 5 g 2-(4-hydroxyphenyl)benzothiazole and 5.1 g 5-(5-bromopentyl)-3-methylisoxazole according to the procedure of Example 1: yield 6.9 g, m.p. 120°-121° C. when recrystallized from triethylamine and then from isopropyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]([C:24](O)=[O:25])[CH:15]=[N:16][C:17]=1[O:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:58][C@@H:59]1[CH2:64][CH2:63][CH2:62][CH2:61][C@H:60]1[OH:65]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:9])[F:11])=[CH:4][C:3]=1[C:12]1[C:17]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[N:16][CH:15]=[C:14]([CH:13]=1)[C:24]([NH:58][C@@H:59]1[CH2:64][CH2:63][CH2:62][CH2:61][C@H:60]1[OH:65])=[O:25]
Reactant: O=C(O)c1cnc(OC2CCCC2)c(-c2cc(C(F)(F)F)ccc2Cl)c1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OC2CCCC2)c(-c2cc(C(F)(F)F)ccc2Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.9 %

Procedure:
5-(2-Chloro-5-trifluoromethyl-phenyl)-6-cyclopentyloxy-3-pyridinecarboxylic acid (0.14 g, 0.3 mmol) was dissolved in DMF (5 mL). To the solution was added TBTU (0.12 g, 0.4 mmol), N,N-diisopropylethyl amine (0.3 mL, 1.7 mmol) and (1R,2R)-2-amino-cyclohexanol (58 mg, 0.4 mmol). The reaction mixture was stirred for 18 h at room temperature. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate gradient) to yield 0.11 g of the title compound as a colorless solid oil, MS (ISP) 483.4 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:8]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16](=[O:24])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[F:25])[N:9]=1)[CH2:3][C:4]([F:7])([F:6])[F:5].Br[C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[N:29]=[CH:30][NH:31]2.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:35]1[C:27]([NH:1][C@H:2]([C:8]2[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:16](=[O:24])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[F:25])[N:9]=2)[CH2:3][C:4]([F:6])([F:5])[F:7])=[C:28]2[C:32]([NH:31][CH:30]=[N:29]2)=[N:33][CH:34]=1
Reactant: N[C@@H](CC(F)(F)F)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: O=c1c2c(F)cccc2nc([C@H](CC(F)(F)F)Nc2ncnc3[nH]cnc23)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 21.3 %

Procedure:
Under nitrogen, to (S)-2-(1-amino-3,3,3-trifluoropropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (5) (35 mg, 0.10 mmol, 1.0 equiv) in t-BuOH (0.5 mL) at 23° C. was added 6-bromo-9H-purine (6) (30 mg, 0.15 mmol, 1.5 equiv) and diisopropylethylamine (35 μL, 0.20 mmol, 2.0 equiv). After stirring for 3 days at 80° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 10 mg of compound 2A as a colorless solid (21%).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]([CH2:17][NH:18][CH3:19])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CC1C=CC=C(C)N=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(Cl)Cl>[Br:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]([CH3:19])[S:35]([C:32]2[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CNCc1ccc(OCC(=O)OC(C)(C)C)c(Br)c1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CN(Cc1ccc(OCC(=O)OC(C)(C)C)c(Br)c1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
To a solution of t-butyl 2-(2-bromo-4-((methylamino)methyl)phenoxy)acetate (2) (4.4 g, 13.4 mmol, 1 eq) in DCM (50 mL) was added 2,6-lutidene (3.1 ml, 26.8 mmol, 2 eq) and 4-fluorobenzenesulfonyl chloride (2.9 g, 14.7 mmol. 1.1 eq, Aldrich, Milwaukee, Wis., USA). After the mixture was stirred for 18 h at room temperature, it was washed with 1 N HCl (100 mL), saturated NaHCO3 (100 mL), and brine (100 mL). The washed DCM layer was dried over Na2SO4 and concentrated in vacuo. Silica gel purification (linear gradient of 0% EtOAc/hexanes to 100% EtOAc/hexanes) of the resultant residue yielded 2.95 g (44.8%) of t-butyl 2-(2-bromo-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetate (3) as a white solid. 1HNMR (CDCl3, 300 MHz): δ 7.82 (m, 2H), 7.44 (d, 1H), 7.22 (m, 3H), 6.72 (d, 1H), 4.57 (s, 2H), 4.04 (s, 2H), 2.58 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[S:6][CH2:5][CH2:4][O:3]1.[OH:17]O>O>[CH3:1][C:2]1([CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[S:6](=[O:17])[CH2:5][CH2:4][O:3]1
Reactant: OO
Reactant: CC1(CC(=O)Nc2ccccc2)OCCS1
Solvent: O
Product: CC1(CC(=O)Nc2ccccc2)OCCS1=O

Procedure:
bringing together the 2-methyl-N-phenyl-1,3-oxathiolane-2-acetamide and hydrogen peroxide under basic conditions, in the presence of a catalytic quantity of a suitable heavy metal compound oxidation catalyst effective to catalyze the oxidation of said 2-methyl-N-phenyl-1,3-oxathiolane-2-acetamide by the said hydrogen peroxide, in a liquid medium comprising water, or water plus at least one nonprotic organic liquid selected from the group consisting of (a) aromatic hydrocarbon solvent having a boiling point not greater than 145° C., (b) chlorinated hydrocarbon solvent having a boiling point not greater than 130° C., and (c) a solvent having a boiling point not greater than 130° C. which is an alkyl ester of an aliphatic carboxylic acid, and subjecting the resulting mixture while agitating to a temperature of from 0°-25° C., whereby 2-methyl-N-phenyl-1,3-oxathiolane-2-acetamide 3-oxide is formed;
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9](=[C:16]1[N:24]2[CH:20]3[CH2:21][CH2:22][CH:23]2[CH2:25][CH:18]([CH2:19]3)[C:17]1=[O:26])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>CCOCC.C1(C)C=CC=CC=1>[C:1]1([CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]2[N:24]3[CH:20]4[CH2:21][CH2:22][CH:23]3[CH2:25][CH:18]([CH2:19]4)[C:17]2=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C(=Cc2ccccc2)N2C3CCC2CC1C3
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C1C2CC3CCC(C2)N3C1C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a 100 ml three-necked round-bottomed flask equipped with a rubber septum and nitrogen inlet were added 5 ml dry toluene and 4.43 ml (13.3 mmol) of a 3.0M solution of phenyl magnesium bromide in ether. The solution was cooled to 0° C., and a solution of 2.07 g (8.87 mmol) 8-benzylidene-9-azatricyclo[4.3.1.04,9 ]decan-7-one in 20 ml toluene was added over 5 min. The reaction was allowed to stir at 0° C. for 1 hour and then poured into saturated aqueous ammonium chloride. The mixture was extracted into ethyl acetate, and the organic layer washed with saturated aqueous ammonium chloride and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using hexane/ethyl acetate as eluent and the product fractions combined to afford 1.47 g (53%) of a white solid, mp 137°-138° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:13]1[CH2:22][CH:14]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(O)C>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:10][CH2:22][CH:14]([OH:13])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: c1ccc(CC2CO2)cc1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(CNCC(O)Cc2ccccc2)cc1
Yield: 45 %

Procedure:
A solution (60 ml) of 4-methanesulfonylbenzylamine (5.8 g) and (2,3-epoxypropyl)benzene (5.0 g) in 2-propanol was heated under reflux for 12 hrs. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=10:1) to give the title compound (4.5 g).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:24][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([CH:22]=O)[CH:17]=[CH:16]3.[O:25]=[C:26]1[CH2:35][C:34]2([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:36][NH:37][C:32]3[C:33]2=[C:28]([CH:29]=[CH:30][CH:31]=3)[NH:27]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:25]=[C:26]1[CH2:35][C:34]2([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:36][N:37]([CH2:22][C:18]3[CH:17]=[CH:16][C:15]4[C:20](=[CH:21][C:12]5[CH2:11][C@:3]6([C:4]7[C:5](=[N:6][CH:7]=[CH:8][CH:9]=7)[NH:10][C:2]6=[O:1])[CH2:24][C:13]=5[CH:14]=4)[N:19]=3)[C:32]3[C:33]2=[C:28]([CH:29]=[CH:30][CH:31]=3)[NH:27]1
Reactant: CCOC(=O)CC12CNc3cccc(c31)NC(=O)C2
Reactant: O=Cc1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)CC12CC(=O)Nc3cccc(c31)N(Cc1ccc3cc4c(cc3n1)C[C@]1(C4)C(=O)Nc3ncccc31)C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of (S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carbaldehyde (339 mg, 1.08 mmol, described in Intermediate 10), ethyl (4-oxo-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3H)-yl)acetate, enantiomer A (200 mg, 0.768 mmol, described in Intermediate 22), and AcOH (0.44 mL, 7.68 mmol) in DCE (5 mL) was added sodium triacetoxyborohydride (228 mg, 1.08 mmol) and the mixture was stirred for 90 min at ambient temperature. The reaction mixture was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (20 mL). The organic layer was removed and the aqueous layer was extracted further with CH2Cl2 (3×20 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 95:5, to give the title compound. MS: m/z=560 (M+1). HRMS: m/z=560.2303; calculated m/z=560.2293 for C33H30N5O4.