Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.[NH2:29][C:30]1[S:40][C:33]2[CH2:34][N:35]([CH2:38][CH3:39])[CH2:36][CH2:37][C:32]=2[C:31]=1[C:41]([NH2:43])=[O:42]>C(Cl)Cl.CN(C)C=O.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH:29][C:30]3[S:40][C:33]4[CH2:34][N:35]([CH2:38][CH3:39])[CH2:36][CH2:37][C:32]=4[C:31]=3[C:41]([NH2:43])=[O:42])=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: CCN1CCc2c(sc(N)c2C(N)=O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN1CCc2c(sc(NC(=O)C3(c4ccc(Cl)cc4)CC3)c2C(N)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.3 %

Procedure:
To a solution of 1-(4-chlorophenyl)cyclopropanecarboxylic acid (K1, 131 mg, 0.666 mmol) in anhydrous methylene chloride (3 mL) was added oxalyl chloride (0.100 mL, 1.17 mmol) followed by 2 drops of N,N-dimethylformamide at room temperature under nitrogen. After stirring at room temperature for 1 h, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in anhydrous tetrahydrofuran (3 mL). To the resulting solution was added diisopropylethylamine (0.200 mL, 1.12 mmol) followed by a suspension of compound F4 (150 mg, 0.666 mmol) in anhydrous tetrahydrofuran (3 mL). After stirring at room temperature for 3 h, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel eluting with methylene chloride to methanol/methylene chloride (1:19). Further purification by trituration with acetonitrile gave compound K2 as a light yellow solid (87 mg, 32%): 1H NMR (500 MHz, CDCl3) δ 11.79 (bs, 1H), 7.47-7.42 (s, 4H), 5.56 (bs, 2H), 3.57 (s, 2H), 2.82-2.77 (m, 4H), 2.62 (q, J=7.0 Hz, 2H), 1.78-1.74 (m, 2H), 1.20-1.12 (m, 5H). MS (M+H) 404.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][S:21][C:3]=12.[CH2:22]([O:29][CH2:30][CH:31]1[CH2:33][CH:32]1[S:34](Cl)(=[O:36])=[O:35])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:34]([CH:32]2[CH2:33][CH:31]2[CH2:30][O:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:36])=[O:35])=[C:3]2[S:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: O=S(=O)(Cl)C1CC1COCc1ccccc1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCS2
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC2COCc2ccccc2)c2n(c1=O)CCS2
Yield: 844.4 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 19A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (I-19f: 0.2 g, 0.048 mmol) in pyridine (2 mL) was reacted with 2-benzyloxymethyl-cyclopropanesulfonyl chloride (0.13 g, 0.52 mmol) to afford the crude product. Purification by column chromatography on silica gel (60% ethylacetate in hexane) afforded 0.26 g of the product (86% yield).
Reaction SMILES: OS(O)(=O)=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][NH:13][C:12]([CH2:19]Br)(CBr)[CH:11]=2.[OH-:21].[Na+]>O>[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH:19]=[O:21])[N:13]=[CH:14]2)=[CH:9][CH:8]=1
Reactant: [OH-]
Reactant: Clc1ccc2c(c1)=CNC(CBr)(CBr)C=2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=Cc1cc2ccc(Cl)cc2cn1
Temperature: 150 °C

Procedure:
A 20 mL of 80% H2SO4 is added 7-chloro-3,3-dibromomethyl isoquinoline (0.69 g, 2.06 mmol) is heated to 150° C. for 16 hours. The solution is then cooled to ambient temperatures and diluted with 40 mL of H2O. The resulting solution is basified to pH=11 with 1N NaOH. The aqueous solution is extracted with CH2Cl2. The organic solution is washed with H2O and a saturated NaCl solution. The organic layer is dried over MgSO4, filtered and concentrated to give the product as an oil (0.25 g, 1.3 mmol). 1H NMR (CDCl3, 300 MHz) δ10.0 (s, 1H), 9.30 (s, 1H), 8.36 (s, 1H), 8.07 (s, 1H), 7.95 (d, 1H), 7.78 (d, 1H). MS (EI): m/z 191, 193 (M+), Cl pattern.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:27](=[N:30]O)([NH2:29])[CH3:28]>CN(C=O)C>[CH3:28][C:27]1[N:30]=[C:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=2)[O:14][N:29]=1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: CC(N)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1noc(Cc2ccc(S(C)(=O)=O)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(methylsulfonyl)phenylacetic acid (15 g, 70 mmol) in DMF (300 mL) at r.t., was added carbonyldiimidazole (12.5 g, 77 mmol). After 0.5 h at r.t., acetamide oxime (5.7 g, 77 mmol) was added. After stirring the resulting mixture overnight at r.t., the mixture was heated to 120° C. for 6 h. After cooling to r.t., the mixture was quenched with H2O, and extracted with EtOAc. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (Hex:EtOAc, 1:1) yielded (3-Methyl-1,2,4-oxadiazol-5-yl) [4-(methylsulfonyl)phenyl]methane.
Reaction SMILES: Cl.[O:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH2:18]([O:20][C:21]([C:23]1[NH:24][C:25]([CH3:33])=[C:26]([S:29](Cl)(=[O:31])=[O:30])[C:27]=1[CH3:28])=[O:22])[CH3:19].O>C(Cl)Cl>[CH2:18]([O:20][C:21]([C:23]1[NH:24][C:25]([CH3:33])=[C:26]([S:29]([N:5]2[CH2:6][CH2:7][CH2:8][O:2][CH2:3][CH2:4]2)(=[O:30])=[O:31])[C:27]=1[CH3:28])=[O:22])[CH3:19]
Reactant: CCOC(=O)c1[nH]c(C)c(S(=O)(=O)Cl)c1C
Reactant: C1CNCCOC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1[nH]c(C)c(S(=O)(=O)N2CCCOCC2)c1C
Yield: 101 %

Procedure:
To [1,4]oxazepane hydrochloride (400 mg) in DCM (45 mL) was added DIEA (2.70 mL) followed by 4-chlorosulfonyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (1.05 g). The mixture was stirred for 1 h at RT after which water was added and the resulting two phases were separated. The organic phase was washed two times with saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated to give crude) 3,5-dimethyl-4-([1,4]oxazepane-4-sulfonyl)-1H-pyrrole-2-carboxylic acid ethyl ester (970 mg) which was used directly in the following step.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH:14]C(=O)C(Cl)(Cl)Cl)[C:5]=2[N:21]=1.C[O-].[Na+].C>CO>[CH3:1][C:2]1[S:3][C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:21]=1
Reactant: Cc1nc2c(NC(=O)C(Cl)(Cl)Cl)nc3ccccc3c2s1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2c(N)nc3ccccc3c2s1

Procedure:
Trichloroacetyl isocyanate (2.0 mL, 16.8 mmol) was added to a suspension of 2-methylthiazolo[4,5-c]quinoline-5N-oxide (3.03 g, 14.0 mmol) in dichloromethane (150 mL). The reaction mixture was stirred at ambient temperature for about 50 minutes. The dichloromethane was concentrated under vacuum to provide crude N-(2-methylthiazolo[4,5-c]quinolin-4-yl)trichloroacetamide. The amide was dissolved in methanol and then sodium methoxide (1 mL of 25% sodium methoxide in methanol) was added. The reaction was heated at reflux for 40 minutes then the methanol was evaporated under vacuum. The resulting brown solid was washed with water and dried to provide 2.85 g of crude product. This material was treated with charcoal and then recrystallized from ethyl acetate to provide 2-methylthiazolo[4,5-c]quinolin-4-amine as a solid, m.p. 184–186° C. Analysis: Calculated for C11H9N3S: % C, 61.37; % H, 4.21; % N, 19.52; Found % C, 61.48; % H, 4.17; % N, 19.60.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@@H:6]1Br)(=[O:3])[CH3:2].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1.C(O)C>C(Cl)Cl.[Cl-].[Zn+2].[Cl-].[N-]1C=CN=C1.[Ag+]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Agent: [Ag+]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(C#N)cc1
Temperature: 40 °C
Reaction time: 24 h
Yield: 112.5 %

Procedure:
A suspension of 6.5 g (12.3.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 6 g (50.4.10-3 mol) of 4-hydroxybenzonitrile, 6.9 g (50.5.10-3 mol) of zinc chloride and 4.4 g (25.1.10-3 mol) of silver imidazolate in 200 ml of anhydrous methylene chloride is stirred at 40° C., under an inert atmosphere, in the absence of light and in the presence of a molecular sieve (400 pm). After 7 h at this temperature, 6.9 g (50.5.10-3 mol) of zinc chloride, 4.4 g (25.1.10-3 mol) of silver imidazolate and 6.5 g (18.3.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide are added. The reaction medium is left overnight under these conditions and 6.5 g (12.3.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide are then added. After 24 h, the reaction mixture is filtered on Celite® , washed with a 1N aqueous solution of hydrochloric acid and then water and dried over magnesium sulfate. After evaporation under reduced pressure, the residue is purified by chromatography on silica gel using a hexane/ethyl acetate mixture (3/1 v/v) as the eluent. 8.1 g (yield: 41%) of the expected product are obtained by crystallization from ethanol.
Reaction SMILES: C[Mg]Br.O1C2[C:8](=CC=CC=2)[C:7](=[S:14])[CH:6]=[CH:5]1.F[B-](F)(F)F.[H+].C[CH2:22][O:23][CH2:24][CH3:25]>C1COCC1>[CH3:22][O:23][C:24]1[CH:25]=[CH:8][C:7]([SH:14])=[CH:6][CH:5]=1
Reactant: CCOCC
Reactant: S=c1ccoc2ccccc12
Agent: C[Mg]Br
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: C1CCOC1
Product: COc1ccc(S)cc1
Temperature: 10 °C
Reaction time: 6 h
Yield: 55 %

Procedure:
Methyl magnesium bromide (50 mL of a 3M solution in ether, 0.15 mmol) was added to a solution of the crude thiochromone (20 g, prepared in Part C above) in THF (100 mL) with cooling to 10° C. The reaction mixture was then allowed to warm to room temperature and stirred for 6 hours. The mixture was then added, with vigorous stirring, to tetrafluoroboric acid (125 mL of a 50% aqueous solution) which had been diluted with ice/water (600 mL). A yellow precipitate formed, which was collected by vacuum filtration, washed thoroughly with hexanes and dried under reduced pressure to yield the desired salt (18.5 g, 55% yield over three steps from the 4-methoxybenzene thiol). The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: C[C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[CH2:2]([O:3][CH2:4][CH:5]([OH:6])[CH2:7][OH:8])[CH2:9][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCBr
Reactant: CC1(C)OCC(CO)O1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOCC(O)CO
Temperature: 0 °C
Yield: 71 %

Procedure:
Isopropylidineglycerol (solketal, 26.4 g, 0.20 mol) in 60 mL of toluene was added dropwise to a solution of powdered KOH (22.4 g, 0.04 mol) in 150 mL toluene. The resulting mixture was refluxed for 4 hours. 1-Bromodecane (50 g, 0.20 mol) in 40 mL of toluene was then added dropwise, and the solution was refluxed for 10 hours. After cooling, the reaction mixture was diluted with 200 mL of ice-water and extracted with diethyl ether (3×100 mL). The ether layers were dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was dissolved in 60 mL of diethyl ether and 260 mL of MeOH. Concentrated HCl (60 mL) was added, and the solution was refluxed for 16 hours. After cooling, ice water (150 mL) was added, and the layers were separated. The aqueous layer was extracted with diethyl ether (2×75 mL). The combined organic fractions were then dried over sodium sulfate, filtered, and concentrated in vacuo. The solid residue was recrystallized from MeOH to give 37 g (0.14 mol), 71% of a white solid.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]([N:13]1[CH2:17][C:16]([O:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])=[CH:15][C:14]1=[O:27])[CH2:6][C:7]1([F:12])[CH2:11][CH2:10][CH2:9][CH2:8]1)C.O.[OH-].[Li+].O>O1CCCC1.O>[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[O:18][C:16]1[CH2:17][N:13]([CH:5]([CH2:6][C:7]2([F:12])[CH2:8][CH2:9][CH2:10][CH2:11]2)[C:4]([OH:28])=[O:3])[C:14](=[O:27])[CH:15]=1
Reactant: CCOC(=O)C(CC1(F)CCCC1)N1CC(Oc2c(F)cccc2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CC1(F)CCCC1)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(1-fluoro-cyclopentyl)-propionic acid ethyl ester (0.440 g, 1.11 mol) in tetrahydrofuran:water (1:1, 10 mL) was added lithium hydroxide monohydrate (0.140 g 3.34 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water and washed with diethyl ether and the diethyl ether layer discarded. The aqueous phase was acidified with 1N aqueous hydrochloric acid (pH <2), and extracted with ethyl acetate (2×30 mL). The combined ethyl acetate layers were dried over magnesium sulfate, filtered and concentrated to afford 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(1-fluoro-cyclopentyl)-propionic acid, (0.358 g, 88%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.64 (br. s., 8H), 2.34 (dd, J=22.6, 6.9 Hz, 2H), 4.23 (d, J=18.4 Hz, 1H), 4.31 (d, J=18.4 Hz, 1H), 4.84 (t, J=6.9 Hz, 1H), 5.05 (s, 1H), 7.26-7.55 (m, 3H), 13.05 (br. s., 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:11]1[CH:20]=[N:19][C:18]2[C:13](=[C:14]([Cl:21])[CH:15]=[CH:16][CH:17]=2)[N:12]=1>C1COCC1>[Cl:21][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[N:12]=[C:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:20]=[N:19]2
Reactant: Nc1ccccc1
Reactant: Clc1cnc2cccc(Cl)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cccc2ncc(Nc3ccccc3)nc12
Temperature: 50 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
Aniline (0.810 ml, 8.89 mmol) was added to a mixture of NaH (60% w/w in mineral oil; 0.356 g, 8.89 mmol) in THF (59.3 ml) at 0° C.; the resulting mixture was stirred for 15 min before 2,8-dichloroquinoxaline (177a, 1.18 g, 5.93 mmol, Pharmabridge, Inc., Doylestown, Pa.) was added; the reaction mixture was stirred at 50° C. for 16 h. Purification by silica gel (100% hexanes to 40% EtOAc/hexanes) provided 8-chloro-N-phenylquinoxalin-2-amine (180a, 43% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 256.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:3]=12.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>N1C=CC=CC=1>[C:17]([N:14]1[CH2:15][CH2:16][C:3]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH2:12][CH2:13]1)(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: Cc1c2c(nc3ccccc13)CCNCC2
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCC(=O)N1CCc2nc3ccccc3c(C)c2CC1
Yield: 67 %

Procedure:
3-Butyryl-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline was prepared by acylation of 1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline with butyric acid chloride in pyridine.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[CH:17][N:18]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[NH4+].C([O-])=O>[OH-].[OH-].[Pd+2].CO>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[NH:15][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:18][CH:17]=2)=[CH:20][C:21]=1[C:26]([F:29])([F:27])[F:28]
Reactant: Fc1ccc(-c2cnc(N3CCN(Cc4ccccc4)CC3)[nH]2)cc1C(F)(F)F
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Fc1ccc(-c2cnc(N3CCNCC3)[nH]2)cc1C(F)(F)F
Temperature: 25 °C
Yield: 96.6 %

Procedure:
Combine 1-Benzyl-4-[5-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperazine (260 mg, 1.00 equiv; 0.643 mmoles), 20 wt % Pd(OH)2/C Degussa E101NE/W (250 mg); methanol (10 mL), formic acid, ammonium salt (20 equiv, 12.8 mmoles; 810 mg) and heated to 50° C. for 2 hours, then cooled to room temperature. Filter the reaction mixture through Celite®, evaporate under reduced pressure and coevaporate once with methanol to give 195.2 mg (0.621 mmol, 97%) 1-[5-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperazine as a yellow foam.
Reaction SMILES: C(O[C@@H:5]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]1OC(=O)C)(=O)C.[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[CH:27]=[CH:26][C:25](=[O:32])[C:24]=2[C:23]2([O:36][CH2:35][CH2:34][O:33]2)[CH2:22]1)(=[O:19])[CH3:18]>C1(C)C(C)=CC=CC=1>[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[C:27]3[C:26](=[CH:6][C:7]4[C:8]([CH:5]=3)=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:25](=[O:32])[C:24]=2[C:23]2([O:36][CH2:35][CH2:34][O:33]2)[CH2:22]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC1(C(C)=O)CC2=C(C(=O)C=CC2=O)C2(C1)OCCO2
Reactant: CC(=O)O[C@@H]1c2ccccc2[C@H]1OC(C)=O
Solvent: Cc1ccccc1C
Product: CC(=O)OC1(C(C)=O)CC2=C(C(=O)c3cc4ccccc4cc3C2=O)C2(C1)OCCO2
Yield: 56.6 %

Procedure:
A mixture of 165 mg (0.75 mmol) of trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene and 160 mg (0.50 mmol) of rac-3-acetoxy-3-acetyl-1,1-ethylenedioxy-1,2,3,4,5,8-hexahydro-5,8-dioxonaphthalene [prepared as described in Example 7(A)] in 15 ml of xylene was stirred and heated under reflux under an atmosphere of nitrogen for 16 hours. The solution was evaporated to dryness and the yellow residue was stirred with 5 ml of diethyl ether and filtered to give 119 mg (57%) of rac-3-acetoxy-3-acetyl-1,1-ethylenedioxy-1,2,3,4,5,12-hexahydro-5,12-dioxonaphthacene in the form of a bright yellow solid of melting point 232°-236° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:31]1[C:36]([CH:37]([OH:47])[CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:35][CH:34]=[CH:33][N:32]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:31]4[C:36]([CH:37]([OH:47])[CH2:38][CH2:39][CH2:40][C:41]5[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=5)=[CH:35][CH:34]=[CH:33][N:32]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OC(CCCc1ccccc1)c1cccnc1Br
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4ncccc4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 1-(2-bromo-pyridin-3-yl)-4-phenyl-butan-1-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[N:15][C:16]([NH2:20])=[N:17][CH:18]=2)[N:13]([CH3:21])[N:12]=1.[Cl:22]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(#N)C>[Cl:22][C:6]1[C:7]([O:9][CH3:10])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH2:20])=[N:17][CH:18]=3)[N:13]([CH3:21])[N:12]=2)[CH:5]=1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: COc1ccc(-c2nn(C)c3nc(N)ncc23)c(OC)c1
Solvent: CC#N
Product: COc1cc(OC)c(-c2nn(C)c3nc(N)ncc23)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-(2,4-Dimethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Example 89) is suspended in acetonitrile (10 ml), trichloroisocyanuric acid (0.021 g, 0.09 mmol) is added and the reaction mixture is stirred for 1.5 hours at room temperature then stood overnight. The solvents are removed in vacuo, the residue is dissolved in EtOAc, washed with water and brine, dried over MgSO4, filtered, concentrated in vacuo and dried under vacuum (45° C.) to afford the title compound.
Reaction SMILES: I[C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(N(CC)CC)C.[F:25][C:26]([F:34])([F:33])[C:27]([NH:29][CH2:30][C:31]#[CH:32])=[O:28].N(CO[C@@H]1[C@@H](CO)O[C@@H](N2C=C(C#CCNC(=O)C(F)(F)F)C(=O)NC2=O)C1)=[N+]=[N-].C(=O)(O)[O-]>CN(C=O)C.[Cu]I>[F:25][C:26]([F:34])([F:33])[C:27]([NH:29][CH2:30][C:31]#[C:32][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1)=[O:28]
Reactant: C#CCNC(=O)C(F)(F)F
Reactant: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Agent: [Cu]I
Agent: O=C([O-])O
Agent: [N-]=[N+]=NCO[C@H]1C[C@H](n2cc(C#CCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)O[C@@H]1CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C#CCNC(=O)C(F)(F)F
Reaction time: 18 h

Procedure:
To a solution of 5-iodo-2′-deoxycytidine (10 g, 28.32 mmol) in DMF (200 ml) in a light protected round bottom flask under Argon atmosphere, was added CuI (1.08 g, 5.67 mmol), triethylamine (7.80 ml, 55.60 mmol), 2,2,2-trifluoro-N-prop-2-ynyl-acetamide (12.8 g, 84.76 mmol) and at last Pd(PPh)3)4 (3.27 g, 2.83 mmol). After 18 hours at room temperature, dowex bicarbonate (20 mg) was added and the mixture was stirred for a further 1 h. Filtration and evaporation of the volatiles under reduced pressure gave a residue that was purified by flash chromatography on silica gel (CH2Cl2, CH2Cl2:EtOAc 1:1, EtOAc:MeOH 9:1). The expected product (7) was obtained as a beige solid in quantitative yield. 1H NMR (D2O) δ 2.24-2.17 (m, 1H, H-2′), 2.41-2.37 (m, 1H, H-2′), 3.68 (dd, J=12.5, 5.0 Hz, 1H, H-5′), 3.77 (dd, J=12.5, 3.2 Hz, 1H, H-5′), 3.99 (m, 1H, H-4′), 4.27 (s, 2H, CH2N), 4.34 (m, 1H, H-3′), 6.11 (t, J=6.3 Hz, 1H, H-1′), 8.1 (br s, 1H, NH); MS (ES): m/z (%) (M−H) 375 (100).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[O:7][C@H:6]1[N:26]1[CH:34]=[N:33][C:32]2[C:27]1=[N:28][CH:29]=[N:30][C:31]=2N)(=[O:3])[CH3:2].C[Si]([Br:40])(C)C.C(ON=O)(C)(C)C.C(=O)(O)[O-].[Na+]>BrCBr.ClCCl>[C:1]([O:4][C@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[O:7][C@H:6]1[N:26]1[CH:34]=[N:33][C:32]2[C:27]1=[N:28][CH:29]=[N:30][C:31]=2[Br:40])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Br
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](CO[Si](C(C)C)(C(C)C)C(C)C)O[C@H]1n1cnc2c(N)ncnc21
Agent: CC(C)(C)ON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: BrCBr
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](CO[Si](C(C)C)(C(C)C)C(C)C)O[C@H]1n1cnc2c(Br)ncnc21
Reaction time: 2.5 h
Yield: 59.1 %

Procedure:
(2R,3S,4R,5R)-2-(6Amino-9H-purin-9-yl)-5-{[(triisopropylsilyl)oxy]methyl}-tetrahydrofuran-3,4-diyl diacetate (0.605 g, 1.19 mmol) was dissolved in dibromomethane (24 mL). Trimethylsilyl bromide (0.17 mL, 1.35 mmol) was added dropwise followed by tert-butylnitrite (0.97 mL, 8.12 mmol). The orange solution was stirred for 2.5 hours then slowly poured into a 1:1 mixture of saturated sodium bicarbonate and dichloromethane and extracted. The pale yellow organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated. The yellow solid was purified by flash chromatography eluting with 25% ethyl acetate/hexanes to give the title compound as a yellow solid (0.402 g, 52%).