Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:12][CH2:13][N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1.C([Li])CCC.[Cu]C#N.Cl[C:23](=[O:28])[C:24]([O:26][CH3:27])=[O:25].C(=O)(O)[O-].[Na+]>O1CCCC1.ClCCl.O>[CH3:27][O:26][C:24](=[O:25])[C:23](=[O:28])[C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:12][CH2:13][N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1
Reactant: COC(=O)C(=O)Cl
Reactant: Brc1cc2c3c(c1)CCN3CCC2
Agent: N#C[Cu]
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(=O)c1cc2c3c(c1)CCN3CCC2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 85.6 %

Procedure:
A solution 8-bromo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline (9.53 g, 40.0 mmol) in anhydrous tetrahydrofuran (317 ml) cooled to −78° C. was treated with n-butyllithium (36.1 ml, 90.1 mmol; 2.5M solution in hexanes) then stirred for 20 minutes. The reaction was treated with copper (I) cyanide (10.88 g, 120.1 mmol) then allowed to warm to between 0 and 10° C. before cooling back to −78° C. Methyl chlorooxoacetate (11.1 ml, 120.7 mmol) was added and the mixture was allowed to warm to room temperature. Water (250 ml) was added to the reaction and then the reaction was basified with saturated aqueous sodium bicarbonate. Dichloromethane (200 ml) was added and the mixture was filtered through a bed of celite. The organic layer was removed and the aqueous layer was extracted with dichloromethane (2×200 ml). The combined organic layers were dried with anhydrous sodium sulfate and evaporated to dryness to give a dark green oil which was purified by flash column chromatography (SiO2, 20% EtOAc in hexanes to 25% EtOAc in hexanes) to afford oxo-(1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-acetic acid methyl ester as a yellow/brown solid (8.4 g). M.p=102-105° C.; 400 MHz 1H NMR (CDCl3) δ: 7.55 (s, 1H), 7.50 (s, 1H), 3.92 (s, 3H), 3.58 (t, 2H), 3.19 (m, 2H), 3.01 (t, 2H), 2.66 (t, 2H), 2.02 (m, 2H); LCMS: 246 [M+H].
Reaction SMILES: C([O:4][CH2:5][CH:6]=[C:7]([CH3:16])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:15])[C:12]([OH:14])=[O:13])(=O)C.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl.Cl>CO.O>[OH:4][CH2:5][CH:6]=[C:7]([CH3:16])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:15])[C:12]([OH:14])=[O:13]
Reactant: CC(=O)OCC=C(C)CCC=C(C)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(=CCO)CCC=C(C)C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a solution of acid 232a (20.0 g, 88.4 mmol) in 400 mL of methanol was added a solution of potassium carbonate (24.4 g, 177 mmol) in 100 mL of water. The resulting mixture was vigorously stirred overnight at room temperature. The reaction was cooled to 0° C., methylene chloride (200 mL) was added, and the aqueous layer was acidified to pH 3 with 1 M HCl. The organic layer was separated, and the aqueous layer was extracted with methylene chloride (2×200 mL). The combined organic extracts were washed with brine, dried over MgSO4, and reduced to dryness in vacuo. The crude product (9.65 g, 52.4 mmol, 59% yield) was used in the next step without further purification: 1H NMR (500 MHz, CDCl3) δ: 6.86 (t of q, J=7.25 Hz, J=1.50 Hz, 1H, ═CH), 5.43 (t of q, J=7.00 Hz, J=1.50 Hz, 1H, ═CH), 4.16 (d, J=7.00 Hz, 2H, —CH2O—), 2.33 (q, J=7.50 Hz, 2H, —CH2—), 2.16 (t, J=7.50 Hz, 2H, —CH2—), 1.83 (s, 3H, —CH3), 1.68 (s, 3H, —CH3). LC/MS (ESI): m/z 207 [M+Na]+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:11]1[C@@H:14]([C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[NH:13][C:12]1=[O:21])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.Cl>ClCCl.O.C(OCC)(=O)C>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C:15]#[C:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[NH:13][C:12]1=[O:21])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1C(=O)N[C@@H]1C#C[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.7 %

Procedure:
To a solution of (3R,4S)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-trimethylsilylethynyl-2-azetidinone (0.73 g) in dichloromethane (10 ml) was added triethylamine (1 ml). To the solution, trimethylsilyl trifluoromethanesulfonate (1.2 ml) was added at 5° C. and the mixture was stirred for 15 hours at ambient temperature. The reaction mixture was poured into a mixture of ethyl acetate (100 ml), 10% hydrochloric acid (10 ml) and water (100 ml). After stirring for 30 minutes at ambient temp., the organic layer was separated, washed successively with brine, aqueous solution of sodium bicarbonate and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from n-hexane to give 0.64 g of (3S,4S)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-trimethylsilylethynyl-2-azetidinone.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[C:17]([S:22](=[O:32])(=[O:31])[N:23]([CH3:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:6]1[CH3:33].[OH-].[Na+].CO>Cl>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:34])=[O:2])[C:6]([CH3:33])=[C:7]2[CH2:15][C:16]1[C:17]([S:22](=[O:32])(=[O:31])[N:23]([CH3:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)Cn1c(C)c(Cc2cccnc2S(=O)(=O)N(C)c2ccccc2)c2cc(F)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(Cc2cccnc2S(=O)(=O)N(C)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.6 %

Procedure:
A mixture of {5-fluoro-2-methyl-3-[2-(methylphenylsulfamoyl)pyridin-3-ylmethyl]indol-1-yl}acetic acid methyl ester (0.14 g), 1.0 M aqueous sodium hydroxide solution (1.0 mL) and methanol (10 mL) was stirred at room temperature for 1.5 hours. The mixture was diluted with 1.0 M aqueous hydrochloric acid solution and concentrated under reduced pressure. The residue was diluted with 1.0 M aqueous hydrochloric acid solution and the resulting precipitate was collected by filtration and dried to give the title compound as a white solid (0.10 g).
Reaction SMILES: Cl.CN(C)S([N:7]1[CH:11]=[C:10]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:9]=[C:8]1[C:17]([OH:40])([CH3:39])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]([NH:31]C(=O)OC(C)(C)C)=[N:27][N:28]([CH3:30])[CH:29]=2)=[CH:21][CH:20]=1)(=O)=O>CO>[NH2:31][C:26]1[C:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:17]([C:8]3[NH:7][CH:11]=[C:10]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:9]=3)([OH:40])[CH3:39])=[CH:20][CH:21]=2)=[CH:29][N:28]([CH3:30])[N:27]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)Cc1ccc(-c2cn(C)nc2NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CO
Product: Cn1cc(-c2ccc(CC(C)(O)c3nc(CC(C)(C)C)c[nH]3)cc2)c(N)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (2 μL, 8 mmol) was added to an ambient temperature solution of tert-butyl [4-(4-{2-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylpropyl)-1H-imidazo 1-2-yl]-2-hydroxypropyl}phenyl)-1-methyl-1H-pyrazol-3-yl]carbamate (33 mg, 0.06 mmol) in methanol (2 mL). After stirring at 70° C. for 1 h, volatiles were removed. The residue was purified with high pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid. The residue was partitioned between methanol/ethyl acetate and 10% aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford the title compound. (M+H) found: 368.
Reaction SMILES: C([O:4][N:5]([CH:9]([C:11]1[CH:12]=[CH:13][C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][C:15]=2[CH:23]=1)[CH3:10])[C:6](=[O:8])[CH3:7])(=O)C.C(OC(=O)C)(=O)C.NO.C(N(CC)CC)C>C(Cl)Cl>[OH:4][N:5]([CH:9]([C:11]1[CH:12]=[CH:13][C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][C:15]=2[CH:23]=1)[CH3:10])[C:6](=[O:8])[CH3:7]
Reactant: CC(=O)ON(C(C)=O)C(C)c1ccc2c(c1)oc1ccccc12
Agent: NO
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(O)C(C)c1ccc2c(c1)oc1ccccc12
Reaction time: 8 h

Procedure:
N-acetoxy-N-(1-dibenzofur-3-ylethyl) acetamide. Acetic anhydride (9.0 mL) was added to a solution of the crude hydroxylamine, prepared as in step c, and triethyl amine (12.4 mL) in methylene chloride (50 mL). The reaction was stirred overnight, then washed with cold water and 3 N HCl. The methylene chloride layer was dried (Na2SO4) and concentrated to give a yellowish oil. This residue was chromatographed on 100 g of silica gel, eluting with 20% ethyl acetate in hexanes to give the desired product.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][CH:12]([C:44](OC)=[O:45])[C@H:13]([NH:24][C:25]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>C1COCC1>[OH:45][CH2:44][C@@H:12]([CH3:11])[C@H:13]([NH:24][C:25]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: COC(=O)C(C)[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@H](CO)[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 20 h
Yield: 34.6 %

Procedure:
Diisobutylaluminum hydride (20.57 ml of 1.0 M in hexanes, 20.57 mmol) was added drop-wise over 10 min to a cooled (−78° C.) THF (120 mL) solution of (2S)-1-benzyl 4-methyl 3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)succinate (3.37 g, 6.86 mmol) prepared above, and stirred at −78° C. for 20 hr. The reaction mixture was removed from the cooling bath and rapidly poured into ˜1M H3PO4/H2O (250 mL) with stirring, and the mixture was extracted with ether (100 mL, 2×). The combined organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. A silica gel mesh of the crude material was prepared and submitted to chromatography (25% EtOAc/hexanes; gravity elution) to afford 1.1 g of (2S,3 S)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate, contaminated with benzyl alcohol, as a colorless viscous oil and (2S,3R)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate containing the (2S,3R) stereoisomer as an impurity. The later sample was resubmitted to the same column chromatography purification conditions to afford 750 mg of purified material as a white foam. [Note: the (2S,3S) isomer elutes before the (2S,3R) isomer under the above condition]. (2S,3S) isomer: 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): 7.81 (m, 2H), 7.39-7.08 (m, 16H), 4.67 (d, J=12.3, 1H), 4.43 (d, J=12.4, 1H), 4.21 (app t, J=5.2, OH), 3.22 (d, J=10.1, NH), 3.17 (m, 1H), 3.08 (m, 1H), ˜2.5 (m, 1H, overlapped with the solvent signal), 1.58 (m, 1H), 0.88 (d, J=6.8, 3H). LC (Cond. 1): RT=2.00 min; LC/MS: Anal. Calcd. for [M+H]+ C31H30NO3: 464.45. found 464.22. (2S,3R) isomer: 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): 7.81 (d, J=7.5, 2H), 7.39-7.10 (m, 16H), 4.63 (d, J=12.1, 1H), 4.50 (app t, J=4.9, 1H), 4.32 (d, J=12.1, 1H), 3.59-3.53 (m, 2H), 3.23 (m, 1H), 2.44 (dd, J=9.0, 8.3, 1H), 1.70 (m, 1H), 0.57 (d, J=6.8, 3H). LC (Cond. 1): RT=1.92 min; LC/MS: Anal. Calcd. for [M+H]+ C31H30NO3: 464.45. found 464.52.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2(SC)[S:20][CH3:21])[C@H:12]2[C@H:3]1[C@:4]1([CH3:25])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:24])[CH:6]=[CH:5]1>C(C1C=CC=CC=1CC)C>[OH:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH:15]=[C:16]2[S:20][CH3:21])[C@H:12]2[C@H:3]1[C@:4]1([CH3:25])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:24])[CH:6]=[CH:5]1
Reactant: CSC1(SC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: CCc1ccccc1CC
Product: CSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]12C
Temperature: 200 °C
Yield: 92.5 %

Procedure:
A suspension of 11β-hydroxy-17,17-bis-(methylthio)androsta-1,4-diene-3-one (2.6 g) in dry diethylbenzene (120 ml) is refluxed for 1.0 hour in a bath at about 200° C. The resulting solution is then cooled to room temperature and subsequently in an ice bath to afford the title compound as needles (2.1 g), after filtration and washing with hexane. The filtrate is subsequently chromatographed on a column of silica gel (30 g) to afford another 100 mg of product. The total yield is thus 2.2 g of product, melting point 240°-241° C., dec., with a consistent nmr spectrum.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:13]([C:15]#[N:16])=[CH:12][N:11]=[C:10]([O:17][CH3:18])[C:9]=3[C:8]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:29][C:30]([NH2:32])=[O:31].O>CN(C=O)C>[C:15]([C:13]1[C:14]2[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:29][C:30]([NH2:32])=[O:31])=[CH:21][CH:20]=3)[C:9]=2[C:10]([O:17][CH3:18])=[N:11][CH:12]=1)#[N:16]
Reactant: NC(=O)CBr
Reactant: COc1ncc(C#N)c2c1c(-c1ccc(O)cc1)cn2C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(C#N)c2c1c(-c1ccc(OCC(N)=O)cc1)cn2C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
To a solution of 1-cyclopentyl-3-(4-hydroxyphenyl)-4-methoxy-1H-pyrrolo[3,2-c]pyridine-7-carbonitrile (120 mg) and sodium hydride (dispersion in mineral oil, 22 mg) in DMF (3.0 mL) was added 2-bromoacetamide (120 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (37 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:14][O:13][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([NH:1][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH:25]([CH3:26])[CH3:27])=[O:22])[CH:3]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12]
Reactant: CC(C)CNC(=O)CCCCCBr
Reactant: COc1cc(N)c2nccc(C)c2c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(NCCCCCC(=O)NCC(C)C)c2nccc(C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
A stirred mixture of 22.6 g (0.120 mole) of 8-amino-6-methoxy-4-methylquinoline and 29.6 g (0.118 mole) of 6-bromo-N-(2-methyl-1-propyl)-hexanamide was heated in an oil bath (130° ) while 12.2 g (16.8 ml; 0.120 mole) of triethylamine was added dropwise over 30 minutes. The temperature of the bath was kept at 130° for 30 minutes, at 150° for 60 minutes, between 150° and 190° for 30 minutes, and at 190° for 30 minutes. The mixture was cooled to room temperature then diluted with 25 ml of ethyl acetate. The solid that separated was collected on a filter, extracted with boiling ethyl acetate (3×100 ml), then discarded. The filtrate and extracts were combined, then concentrated in vacuo to a solid; yield 44 g. The solid was dissolved in 130 ml of dichloromethane and purified by elution chromatography on a column (8 cm dia× 40 cm) of silica gel (1000 g; activity III) using 1 l of dichloromethane-ether (1:1), followed by 2 l of ether, as eluents. The fractions (100 ml each) containing pure product were combined then concentrated in vacuo. The fractions containing mixtures were concentrated in vacuo then triturated with diethyl ether to yield 25.4 g (60.2%) of crude product. The product was suitable for further transformation. Analytically pure compound was readily obtained (84% recovery) by recrystallization from methylene chloride and ether; mp 111°-112°.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[O:9])=[N:4][CH:3]=1.[Cl:17][C:18]1[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:20][C:21]2[O:25][C:24]([CH3:26])=[N:23][C:22]=2[CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(=O)OCC.[Cl-].[Na+].O>CN(C=O)C.O>[Cl:17][C:18]1[C:19]([C:2]2[S:6][C:5]([NH:7][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])=[O:9])=[N:4][CH:3]=2)=[CH:20][C:21]2[O:25][C:24]([CH3:26])=[N:23][C:22]=2[CH:27]=1
Reactant: O=C(Nc1ncc(Br)s1)c1ccccc1Cl
Reactant: Cc1nc2cc(Cl)c(B3OC(C)(C)C(C)(C)O3)cc2o1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc2cc(Cl)c(-c3cnc(NC(=O)c4ccccc4Cl)s3)cc2o1
Temperature: 150 °C
Yield: 9.6 %

Procedure:
A mixture of N-(5-bromo(1,3-thiazol-2-yl))(2-chlorophenyl)carboxamide (47, 25 mg, 0.08 mmol), 2-(5-chloro-2-methylbenzoxzzol-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4) (29 mg, 0.1 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (1:1) (12 mg) and potassium phosphate (21 mg) in 1 ml DMF and 0.2 ml water was heated under Ar in microwave reactor at 150° C. for 30 min. The reaction mixture was worked up with EA/brine. Org. phase was concentrated and then subjected to prep HPLC purification to give 3.1 mg N-[5-(5-chloro-2-methybenzoxazol-6-yl)(1,3-thiazol-2-yl)](2-chlorophenyl)carboxamide (49) as pale brown solid (yield: 9.6%; purity>90%). LC-MS: calcd. for C18H11Cl2N3O2S: 405 (M+1).
Reaction SMILES: [S:1](=[O:4])(=[O:3])=[O:2].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH:7]=[CH:6]1>>[S:1]([C:7]1[C:8]([O:10][C:5](=[O:11])[CH:6]=1)=[O:9])([OH:4])(=[O:3])=[O:2]
Reactant: O=C1C=CC(=O)O1
Reactant: O=S(=O)=O
Product: O=C1C=C(S(=O)(=O)O)C(=O)O1

Procedure:
Sulfur trioxide reacts with maleic anhydride to afford sulfo maleic anhydride (SMA) according to the following reaction scheme: ##STR4##
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10](/[C:14](=[CH:47]\[CH:48]=[C:49]2\[N:50]([CH2:72][CH2:73]CS([O-])(=O)=O)[C:51]3[CH:52]=[CH:53][C:54]4[C:63]([S:64]([O-:67])(=[O:66])=[O:65])=[CH:62][C:61]([S:68]([O-:71])(=[O:70])=[O:69])=[CH:60][C:55]=4[C:56]=3[C:57]\2([CH3:59])[CH3:58])/[CH:15]=[CH:16]/[C:17]2[C:25]([CH3:27])([CH3:26])[C:24]3[C:23]4[CH:28]=[C:29]([S:36]([O-:39])(=[O:38])=[O:37])[CH:30]=[C:31]([S:32]([O-:35])(=[O:34])=[O:33])[C:22]=4[CH:21]=[CH:20][C:19]=3[N+:18]=2[CH2:40][CH2:41][CH2:42]S([O-])(=O)=O)[CH:11]=CC=1)([OH:3])=[O:2].[Na+:79].[Na+].[Na+].[Na+].[Na+].B(C1C=C(C[CH2:94][C:95](O)=O)C=CC=1)(O)O>>[C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[C:10](/[C:14](=[CH:47]\[CH:48]=[C:49]2\[N:50]([CH2:72][CH2:73][CH2:95][CH2:94][S:36]([O-:39])(=[O:38])=[O:37])[C:51]3[CH:52]=[CH:53][C:54]4[C:63]([S:64]([O-:67])(=[O:66])=[O:65])=[CH:62][C:61]([S:68]([O-:71])(=[O:70])=[O:69])=[CH:60][C:55]=4[C:56]=3[C:57]\2([CH3:58])[CH3:59])/[CH:15]=[CH:16]/[C:17]2[C:25]([CH3:27])([CH3:26])[C:24]3[C:23]4[CH:28]=[C:29]([S:36]([O-:39])(=[O:38])=[O:37])[CH:30]=[C:31]([S:32]([O-:35])(=[O:33])=[O:34])[C:22]=4[CH:21]=[CH:20][C:19]=3[N+:18]=2[CH2:40][CH2:41][CH2:42][CH2:31][S:32]([O-:35])(=[O:34])=[O:33])[CH:9]=[CH:8][CH:7]=1)([OH:3])=[O:2].[Na+:79].[Na+:79].[Na+:79].[Na+:79].[Na+:79]
Reactant: O=C(O)CCc1cccc(B(O)O)c1
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCCCC(=O)O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCC(=O)O)c2)=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21

Procedure:
Compound 10 was prepared analogously to compound 8 (Example 8), except that 3-(3-boronophenyl)propionic acid is used as a starting material.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[C:16]([N:19]1[CH2:24][CH2:23][CH:22]([C:25](Cl)=[O:26])[CH2:21][CH2:20]1)(=[O:18])[CH3:17]>>[C:16]([N:19]1[CH2:20][CH2:21][CH:22]([C:25]([NH:15][C:13]2[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)[N:11]3[N:12]=2)=[O:26])[CH2:23][CH2:24]1)(=[O:18])[CH3:17]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: CC(=O)N1CCC(C(=O)Nc2nc3cccc(-c4ccoc4)n3n2)CC1

Procedure:
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 1-acetylpiperidine-4-carbonyl chloride (57 mg; 0.3 mmol; 1.2 eq.) as a white powder (41.3 mg, 46%). HPLC, Rt: 2.15 min. (purity 93.3%). LC/MS, M+(ESI): 354.4, M−(ESI): 352.4.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH2:16][N:15]([CH2:17][C:18](=[O:29])[NH:19][CH:20]2[CH2:24][C:23](=[O:25])[O:22][CH:21]2[O:26]CC)[C:14](=[O:30])[CH:13]([NH:31][C:32]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][N:35]=2)=[O:33])[CH2:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>CC#N.O>[CH2:1]([NH:8][CH2:9][C:10]1[CH2:16][N:15]([CH2:17][C:18](=[O:29])[NH:19][CH:20]2[CH2:24][C:23](=[O:25])[O:22][CH:21]2[OH:26])[C:14](=[O:30])[CH:13]([NH:31][C:32]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][N:35]=2)=[O:33])[CH2:12][CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC1OC(=O)CC1NC(=O)CN1CC(CNCc2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(CN1CC(CNCc2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O)NC1CC(=O)OC1O
Yield: 38 %

Procedure:
Isoquinoline-1-carboxylic acid {6-(benzylamino-methyl)-1-[(2-ethoxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide, 26, prepared herein above, is treated with TFA in CH3CN/H2O. The solution is then concentrated in vacuo and the resulting residue it purified by preparative reverse phase HPLC to afford 30 mg (38% yield) of the desired product. 1H NMR (CD3OD) δ 9.20–9.17 (d, J=8.7 Hz, 1H), 8.57–8.56 (d, J=5.7 Hz, 1H), 8.06–8.02 (m, 2H), 7.88–7.83 (d, d, d, J=8.1, 6.6, 0.9 Hz, 1H), 7.79–7.73 (d, d, d, J=6.9, 6.9, 0.9 Hz, 1H), 7.64–7.60 (m, 2H), 7.55–7.47 (m, 3H), 6.14 (bs, 1H), 5.56–5.50 (d, d, J=12.3, 3.9 Hz, 1H), 4.85–4.79 (d, d, J=16.2, 1.8 Hz, 1H), 4.66–4.62 (d, d, J=9.0, 3.6 Hz, 1H), 4.39–4.25 (m, 4H), 3.89–3.68 (m, 4H), 2.99–2.93 (m, 1H), 2.74–2.45 (m, 4H), MS 557 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12](O)[N:11]=[C:10]([CH3:15])[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O.O>C(#N)C>[Cl:18][C:12]1[CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[C:10]([CH3:15])[N:11]=1
Reactant: Cc1nc(O)cc(-c2ccc(F)cc2)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CC#N
Product: Cc1nc(Cl)cc(-c2ccc(F)cc2)n1
Reaction time: 4 h
Yield: 97 %

Procedure:
13.8 kg of 4-(4-fluorophenyl)-6-hydroxy-2-methylpyrimidine and 11.5 kg of phosphorus oxychloride were refluxed in acetonitrile, and stirred for 4 hours. The reaction solution was combined with water, and the precipitated crystal was separated, and the resultant crystal was washed and dried to obtain 14.6 kg of the target compound as a pale yellow crystal.