Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)=[CH:20][CH:19]=3)[C:16](=[O:31])[C:15]3[C:10](=[CH:11][C:12]([O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)=[CH:13][CH:14]=3)[O:9]2)=[CH:4][CH:3]=1.[CH3:39][Mg]Cl>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)=[CH:22][CH:23]=3)[C:16]([CH3:39])([OH:31])[C:15]3[C:10](=[CH:11][C:12]([O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)=[CH:13][CH:14]=3)[O:9]2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccc(OC3CCCCO3)cc2OC(c2ccc(I)cc2)C1c1ccc(OC2CCCCO2)cc1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC1(O)c2ccc(OC3CCCCO3)cc2OC(c2ccc(I)cc2)C1c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C

Procedure:
To a solution of 90.0% 2-(4-iodophenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)chroman-4-one (104.891 g, 150.7 mmol, 1.0 equiv.) in THF (1.2 L) at 5° C., was added Methylmagnesium chloride 3.0 M solution in THF (160.000 ml, 480.0 mmol, 3.2 equiv.) by addition funnel over 30 minutes. The temperature did not rise about 8° C. during the addition. The reaction was removed from the ice bath and stirred at room temperature and stirred for another hour. TLC (20% ethyl acetate in hexanes) showed the reaction had no starting material. The solution was cooled in an ice bath, and carefully quenched with saturated ammonium chloride (35 mL). Ethyl acetate (1.2 L) and water (1.2 L) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with EA (1 L). The combined organic layer was washed with brine (1 L), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield a pale yellow foam (111.26 g crude). This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH:26]([OH:28])[CH3:27])[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:29]([O:28][CH:26]([C:23]1[S:24][CH:25]=[C:21]([C:19](=[O:20])[NH:18][C@@H:16]([CH3:17])[CH2:15][N:12]2[CH:13]=[CH:14][C:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=3)=[N:11]2)[N:22]=1)[CH3:27])(=[O:31])[CH3:30]
Reactant: CC(O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC(C)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Temperature: 0 °C
Yield: 24.09 %

Procedure:
N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-hydroxy-ethyl)thiazole-4-carboxamide (250 mg, 0.601 mmol), 4-dimethylaminopyridine (7.34 mg, 0.060 mmol) and pyridine (3 ml) were added into a flask and the mixture was cooled to 0° C. Acetic anhydride (0.063 ml, 0.661 mmol) was added dropwise and the mixture was allowed to warm to RT with stirring. The reaction was left to react overnight. Next morning more acetic anhydride (10 μl, 0.106 mmol) was added and the reaction was stirred for another hour in RT. The mixture was evaporated and dried overnight in vacuum at 40° C. The product was purified by recrystallization twice from ethanol/heptanes to yield 24.09% of final product. 1H-NMR (400 MHz; DMSO-d6): δ 1.14 (d, 3H), 1.62 (dd, 3H), 2.11 (s, 3H), 4.29-4.53 (m, 3H), 6.02-6.10 (m, 1H), 6.94-6.98 (m, 1H), 7.84-7.87 (m, 1H), 7.92-8.00 (m, 2H), 8.07 (d, 1H), 8.22 (d, 1H), 8.38-4.49 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:9]2[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[H][H]>CO>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:23][CH:24]=1
Reactant: Fc1ccc(C(=C2CCN(Cc3ccccc3)CC2)c2ccc(F)cc2)cc1
Reactant: [H][H]
Solvent: CO
Product: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1

Procedure:
A mixture of 1.6 parts of 4-[bis(4-fluorophenyl)methylene]-1-(phenylmethyl)piperidine and 80 parts of methanol was hydrogenated at normal pressure and at room temperature with 1 part of rhodium-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 1.2 parts of 4-[bis(4-fluorophenyl)methylene]piperidine as a residue (intermediate 14).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[C@@H:21]([OH:36])[C@@H:22]([NH:32][C:33](=[O:35])[CH3:34])[CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][C:38]1C=CC(S([O-])(=O)=O)=C[CH:39]=1.C1C=C[NH+]=CC=1.COC(C)C>ClCCl.CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][C@@H:9]1[C@H:21]1[O:36][C:38]([CH3:39])([CH3:37])[N:32]([C:33](=[O:35])[CH3:34])[C@H:22]1[CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: COC(C)C
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](OCc3ccccc3)CN2C(=O)OC(C)(C)C)OC1(C)C
Yield: 734.4 %

Procedure:
Dissolve (2R,4R)-2-[(1S,2S)-2-Acetylamino-3-(3,5-difluoro-phenyl)-1-hydroxy-propyl]-4-benzyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.150 g, 0.3 mmol) in 1:1 dichloromethane/acetone (5 mL). Add PPTS (pyridine/p-toluene sulfonic acid) (0.03 mmol) and 2-methoxypropane (1.5 mmol). When the reaction is complete by TLC (15 minutes), concentrate the reaction mixture under reduced pressure. Dissolve the residue in ethyl acetate and wash with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride. Dry over magnesium sulfate, concentrate under reduced pressure, and subject the residue to silica gel chromatography, eluting with ethyl acetate/hexane to provide the desired compound (0.120 g, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[N:27]=[C:28]=[O:29]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:28]([NH:27][C:18]2[CH:19]=[CH:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)=[O:29])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccc2ccccc2c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc3ccccc3c2)cc1-c1c(Br)cnn1C
Yield: 75 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.035 g, 0.12 mmol) was treated with 2-naphthyl isocyanate (0.023 g, 0.13 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 14 (0.040 g, 0.09 mmol, 70%) as a white solid. LCMS m/z (%)=451 (M+H79Br, 95), 453 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.30 (s, 1H), 8.20 (s, 1H), 8.19 (d, J=1.8 Hz, 1H), 7.56-7.84 (m, 3H), 7.72 (dd, J=2.7, 9.0 Hz, 1H), 7.56 (dd, J=2.1, 8.8 Hz, 1H), 7.50 (s, 1H), 7.48 (d, J=2.7 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 3.83 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH:12]3[CH2:14][CH2:15][N:9]2[CH2:10][CH2:11]3)[CH:5]=[N:6][CH:7]=1.[OH-].[NH4+:17]>CO.C(Cl)(Cl)Cl.C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Cu+2]>[NH2:17][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH:12]3[CH2:14][CH2:15][N:9]2[CH2:10][CH2:11]3)[CH:5]=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: Brc1cncc(C2CC3CCN2CC3)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1cncc(C2CC3CCN2CC3)c1
Temperature: 180 °C

Procedure:
2-(5-Bromo-3-pyridyl)-1-azabicyclo[2.2.2]octane (120 mg, 0.449 mmol) was mixed with aqueous ammonium hydroxide (20 mL, 28%) in a sealed tube, then copper sulfate (200 mg) was added and the reaction mixture was heated at 180° C. for 14 h. The reaction mixture was allowed to cool to ambient temperature and then extracted with chloroform (4×20 mL). The combined organic extracts were dried (K2CO3), filtered and concentrated by rotary evaporation to afford a dark syrup. This crude product was subjected to column chromatography, using chloroform methanol: triethylamine (9:1:1) as eluent, to yield 2-(5-amino-3-pyridyl)-1-azabicyclo[2.2.2]octane as a light brown solid (20 mg). An impure fraction was also obtained, which afforded a brown solid (40 mg), found to be mostly the desired compound with minor impurities (total yield ˜65%). A sample of the free base (20 mg, 0.098 mmol) was dissolved in ethanolic HCl (2 mL) and the mixture sonicated for 5 min. The solvent was removed by rotary evaporation to yield a viscous oil, which solidified upon standing. Recrystallization from ethanol: ether (9:1) afforded the trihydrochloride salt of the product as a brown solid (20 mg), m.p. 210° C. with decomposition.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>>[F:21][C:22]1[CH:23]=[C:24]([CH2:25][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=4)[N:13]=3)[CH2:2][CH2:3]2)[CH:27]=[CH:28][CH:29]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Reactant: O=Cc1cccc(F)c1
Product: Fc1cccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-fluorobenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-fluorophenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH:1]1([C:4]#[C:5][Si:6]([CH3:9])([CH3:8])[CH3:7])[CH2:3][CH2:2]1.[Li][CH2:11]CCC.S(OC)(OC)(=O)=O>CCOCC>[CH3:7][Si:6]([CH3:9])([CH3:8])[C:5]#[C:4][C:1]1([CH3:11])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C#CC1CC1
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Product: CC1(C#C[Si](C)(C)C)CC1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To a solution of cyclopropylethynyl-trimethyl-silane (3.0 g, 22 mmol) in ether (20 mL) was added dropwise n-BuLi (8.6 mL, 21.7 mol, 2.5 M solution in hexane) at 0° C. The reaction mixture was stirred at ambient temperature for 24 h before dimethyl sulfate (6.85 g, 54.3 mmol) was added dropwise at −10° C. The resulting solution was stirred at 10° C. and then at 20° C. for 30 min each. The reaction was quenched by adding a mixture of sat. aq. NH4Cl and 25% aq. ammonia (1:3, 100 mL). The mixture was then stirred at ambient temperature for 1 h. The aqueous phase was extracted with diethyl ether (3×50 mL) and the combined organic layers were washed successively with 5% aqueous hydrochloric acid (100 mL), 5% aq. NaHCO3 solution (100 mL), and water (100 mL). The organics were dried over anhydrous NaSO4 and concentrated at ambient pressure. After fractional distillation under reduced pressure, trimethyl-(1-methyl-cyclopropylethynyl)-silane (1.7 g, 52%) was obtained as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 1.25 (s, 3H), 0.92-0.86 (m, 2H), 0.58-0.56 (m, 2H), 0.15 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[C:15]([O:19][C:20](=[O:25])[C@@H:21]([NH2:24])[CH2:22][CH3:23])([CH3:18])([CH3:17])[CH3:16].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CN=CC=1)C.C(Cl)CCl>[C:15]([O:19][C:20](=[O:25])[C@@H:21]([NH:24][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12])[CH2:22][CH3:23])([CH3:17])([CH3:16])[CH3:18]
Reactant: CC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1cc(Cl)ccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
To a stirred solution of 5-chloro-2-nitro-benzoic acid (4.68 g) in anhydrous tetrahydrofuran (100 ml) at 0° C., was added (S)-2-amino-butyric acid-tert-butyl ester hydrochloric acid salt (5 g), HOBt (3.45 g), DMAP (2.98 g), followed by EDC (4.88 g) and diisopropylethylamine (3.30 g). The reaction mixture was stirred for 10 minutes then warmed to room temperature and stirred for 16 hours before concentration at reduced pressure. The resulting residue was partitioned between EtOAc (100 ml) and saturated sodium bicarbonate solution (100 ml), the organic layer separated and further washed with 1M hydrochloric acid and saturated brine solution, dried (MgSO4), filtered and concentrated to give the sub-title compound as a pale yellow oil (6.82 g, 68% yield). 1H NMR (400 MHz, CDCl3) δ 8.05 (1H, d), 7.55 (2H, m), 6.4 (1H, m) 4.7 (1H, m), 2.1 (1H, m), 1.95 (1H, m), 1.5 (9H, s), 1.0 (3H, t) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19]([OH:21])=[O:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.O=S(Cl)Cl.[CH3:26]O>>[CH3:26][O:20][C:19](=[O:21])[CH2:18][C:8]1[N:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1
Reactant: CO
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reaction time: 2 h
Yield: 80 %

Procedure:
To a magnetically stirred solution of (6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid 1a (5.0 g, 17.85 mmol) in methanol (MeOH) (25 mL) at 0° C. under Ar atmosphere was slowly added SOCl2 (2.60 mL, 35.7 mmol). The reaction mixture was stirred for 2 h and then concentrated in vacuo. Aqueous 10% Na2CO3 solution (100 mL) was added, and the aqueous phase was extracted with EtOAc (2×200 mL). The combined organic layers were washed with aqueous NaHCO3 solution, dried (MgSO4), and concentrated in vacuo to the provide the title compound (4.2 g, 80%) as yellow solids. 1H NMR (400 MHz, CDCl3) δ 2.37 (s, 3H), 2.40 (s, 3H), 3.76 (s, 3H), 4.03 (s, 2H), 7.07 (dd, J=1.7, 9.1 Hz, 1H), 7.28 (d, J=8.3 Hz, 2H), 7.55 (d, J=9.1 Hz, 1H), 7.70 (dd, J=1.8, 6.3 Hz, 2H), 7.85 (s, 1H). 13C-NMR (100 MHz, CDCl3) δ 18.7, 21.5, 30.8, 52.7, 112.4, 117.0, 121.5, 122.2, 127.8, 128.5, 129.6, 131.6, 137.7, 144.2, 144.6, 170.3.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14](=[O:16])[CH3:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][C:19]=1[S:27](=[O:30])(=[O:29])[NH2:28].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:14]([N:12]1[C:11]2[CH:10]=[C:9]([C:22]([C:21]3[CH:25]=[CH:26][C:18]([Cl:17])=[C:19]([S:27]([NH2:28])(=[O:29])=[O:30])[CH:20]=3)=[O:23])[CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)(=[O:16])[CH3:15]
Reactant: CC(=O)n1c2ccccc2c2ccccc21
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)n1c2ccccc2c2ccc(C(=O)c3ccc(Cl)c(S(N)(=O)=O)c3)cc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 1 g of 1-carbazol-9-yl-ethanone and 2.43 g of 4-chloro-3-sulfamoyl-benzoyl chloride in methylene chloride (20 mL) is added 2.55 g of aluminum chloride. The mixture is stirred at 50° C. overnight. The solution is then cooled at −78° C., quenched with a 6 N HCl solution and allowed to warm up to room temperature. Methylene chloride is added to dissolve the precipitate and the solution is extracted, washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is loaded on Celite and purified by silica gel chromatography (1:1 hexanes/ethyl acetate) to afford 5-(9-acetyl-9H-carbazole-2-carbonyl)-2-chloro-benzenesulfonamide as yellow foam. MS (m/z): 427 (M+1). HPLC Reverse Phase (Nucleosil 100-5 C18, gradient 10->100% CH3CN in 5 min) room temperature=5.35 minutes.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])[CH2:8][CH:9]1[CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1([CH3:28])[NH:25][C:24](=[O:26])[NH:23][C:22]1=[O:27]>[Cl-].[Li+]>[OH:10][CH:9]([CH2:8][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:14]([OH:15])=[C:13]([C:16]([CH3:19])([CH3:17])[CH3:18])[CH:12]=1)[CH2:11][N:23]1[C:22](=[O:27])[C:21]([CH3:28])([CH3:20])[NH:25][C:24]1=[O:26]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: CC(C)(C)c1cc(CC2CO2)cc(C(C)(C)C)c1O
Agent: [Cl-]
Agent: [Li+]
Product: CC1(C)NC(=O)N(CC(O)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Reaction time: 1 h
Yield: 79.4 %

Procedure:
25 mg of lithium chloride are added to 5.25 g (0.02 mol) of 3,5-di-tert.-butyl-4-hydroxybenzyl-oxirane and 2.56 g (0.02 mol) of 5,5-dimethylhydantoin and the mixture is kept as a melt at 220°-230°C for 60 minutes whilst stirring in a nitrogen atmosphere. After cooling, a glassy residue is obtained, which when recrystallised from toluene/isopropanol gives 6.2 g (78% of theory) of 3-[2-hydroxy-3(3,5-di-tert.-butyl-4-hydroxyphenyl)-propyl] -5,5-dimethylhydantoin of melting point 175°-76°C in the form of colourless crystals.
Reaction SMILES: O.NN.[CH3:4][C:5]1[NH:6][C:7]([CH3:40])=[C:8]([C:24]([O:26][CH2:27][CH2:28][N:29]2C(=O)C3=CC=CC=C3C2=O)=[O:25])[CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]>C(O)C>[CH3:4][C:5]1[NH:6][C:7]([CH3:40])=[C:8]([C:24]([O:26][CH2:27][CH2:28][NH2:29])=[O:25])[CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2C(=O)c3ccccc3C2=O)C1c1ccccc1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
1.5 ml (30 mmol) of hydrazine hydrate in 7.5 ml of ethanol are added dropwise to a boiling solution of 5.05 g (10 mmol) of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(2-nitrophenyl)-5-(2-phthalimidoethoxy)carbonylpyridine in 50 ml of ethanol. Boiling is continued for 2 hours and the reaction mixture is then cooled and concentrated by evaporation under vacuum. The residue is stirred up with 25 ml of 2N-hydrochloric acid for 30 minutes at room temperature and the precipitated solid is removed by suction filtration and the filtrate is adjusted to pH 10 with conc. ammonia. The product is extracted three times with 30 ml portions of methylene chloride and the organic phases obtained are then dried and concentrated by evaporation. 2.91 g (77%) of a yellow amorphous solid is obtained as residue which is used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:25]([NH2:32])=[N:26][C:27]([S:30][CH3:31])=[N:28][CH:29]=1)=[O:23].C(N(C(C)C)CC)(C)C.Cl[C:43](Cl)([O:45]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1.CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[CH:11]=2)=[CH:4][C:3]=1[N:21]1[C:22](=[O:23])[C:24]2[C:25](=[N:26][C:27]([S:30][CH3:31])=[N:28][CH:29]=2)[NH:32][C:43]1=[O:45]
Reactant: CSc1ncc(C(=O)Nc2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2C)c(N)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CSc1ncc2c(=O)n(-c3cc(NC(=O)c4cccc(C(F)(F)F)c4)ccc3C)c(=O)[nH]c2n1
Temperature: 100 °C
Reaction time: 12 h
Yield: 54.9 %

Procedure:
To a stirred solution of 4-amino-2-methylsulfanyl-pyrimidine-5-carboxylic acid [2-methyl-5-(3-trifluoromethyl-benzoylamino)-phenyl]-amide (286 mg, 0.62 mmol) and diisopropylethylamine (864 μL, 4.96 mmol) in dioxane (10 mL) is added a solution of triphosgene (184 mg, 0.62 mmol) in dioxane (2 mL) at 0° C., and the mixture is stirred for 12 h at 100° C. The reaction mixture is diluted with EtOAc (50 mL), and washed with saturated NaHCO3 solution. The organic layer is dried over MgSO4, filtered, concentrated under reduced pressure, and crystallized from MeOH to give N-[4-Methyl-3-(7-methylsulfanyl-2,4-dioxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-phenyl]-3-trifluoromethyl-benzamide (166 mg, 55%) as a white crystalline solid.
Reaction SMILES: C1(C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1P1C(C)(C)CC2(OCCO2)CC1(C)C.C(N(CC)CC)C.Br[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[CH2:49]([O:51][P:52]([O-:56])[O:53][CH2:54][CH3:55])[CH3:50]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C>[C:43]1([P:52](=[O:56])([O:53][CH2:54][CH3:55])[O:51][CH2:49][CH3:50])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CCOP([O-])OCC
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)CC2(CC(C)(C)P1c1ccc3ccccc3c1-c1cccc3ccccc13)OCCO2
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccccc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
In a nitrogen-atmosphere glovebox, a microwave vial equipped with a magnetic stir bar was charged with palladium(II) acetate (1.4 mg, 0.00637 mmol, 0.02 equivalents), 8-(1,1′-binaphthyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane (3.6 mg, 0.00764 mmol, 0.024 equivalents) and ethanol (0.64 mL). To the slurry were added triethylamine (67 μL, 0.478 mmol, 1.5 equivalents), bromobenzene (34 μL, 0.318 mmol, 1 equivalent) and diethylphosphite (49 μL, 0.382 mmol, 1.2 equivalents). The vial was sealed with a crimp top and stirred at 80° C. After 24 hours, the vial was removed from the heating block, cooled to room temperature and brought out of the glovebox. The reaction solution was diluted with tetrahydrofuran (2 mL) and filtered into a tared 125-mL Erlenmeyer flask. The vial was rinsed with tetrahydrofuran (5×1 mL), followed by washing of the filter cake with tetrahydrofuran (5 mL). A wt % analysis was performed on the filtrate and an assay yield of 59% was measured versus commercially available diethyl phenylphosphonate.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.Br[C:20]1[C:21]([O:36][CH2:37][C:38]2[N:39]([CH2:43][CH3:44])[N:40]=[CH:41][N:42]=2)=[N:22][N:23]2[C:28]=1[CH:27]=[N:26][N:25]=[C:24]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35]>>[CH2:43]([N:39]1[C:38]([CH2:37][O:36][C:21]2[C:20]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)=[C:28]3[N:23]([C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])=[N:25][N:26]=[CH:27]3)[N:22]=2)=[N:42][CH:41]=[N:40]1)[CH3:44]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1Br
Product: CCn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1-c1cccs1
Yield: 59 %

Procedure:
This was prepared in 59% yield using a similar procedure to that described in Example 53 except using 2-(tributylstannyl)thiophene instead of 2-(tributylstannyl)pyridine and 3-bromo-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(2-fluorophenyl)pyrazolo[1,5-d][1,2,4]triazine instead of 3-bromo-7-(2-fluorophenyl)-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-pyrazolo[1,5-d][1,2,4]triazine. Data for title compound: mp=190-192° C. (CH2Cl2-EtOAc); 1H NMR (360 MHz, CDCl3) δ 1.39 (3H, t, J=7.3 Hz), 4.18 (2H, q, J=7.3 Hz), 5.60 (2H, s), 7.15 (1H, m), 7.29 (1H, t, J=9.4 Hz), 7.38-7.42 (2H, m), 7.46 (1H, d, J=3.6 Hz), 7.66 (1H, m), 7.81 (1H, m), 7.90 (1H, s), 9.56 (1H, s); MS (ES+) m/e 422 [MH]+; Anal. Found C, 57.30; H, 3,71; N, 23.35%. C20H16FN7OS requires C, 57.00; H, 3.83; N, 23.26%.