Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14]([OH:18])=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].O>C(O)(=O)C>[CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14]([OH:18])=[C:15]([N+:20]([O-:22])=[O:21])[C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(O)nc2sc(SCc3ccccc3)nn12
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=c1c([N+](=O)[O-])c(O)nc2sc(SCc3ccccc3)nn12
Temperature: 40 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
Twenty-four (24) grams of 2-benzylthio-7-hydroxy-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was suspended in 250 ml of acetic acid and warmed to 40° C. To this suspension, 7.9 g of fuming nitric acid was added dropwise. After the addition of the nitric acid was finished, the reaction mixture was stirred at 40° C. for 5 hours. After the reaction was finished, the reaction mixture was cooled, and water was added thereto. The deposited crystals were collected by filtration, washed with water and dried under reduced pressure. Thus 24 g of 2-benzylthio-7-hydroxy-6-nitro-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 87%.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[C:20]([CH3:28])[CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO.O.C(OCC)C>[CH3:28][C:20]1[CH:19]=[C:18]([C@H:10]2[CH2:9][C@H:8]([C:6]3[O:7][NH:32][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])[CH:23]=[CH:22][C:21]=1[C:24]([F:27])([F:26])[F:25]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(F)(F)F)c(C)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)c(C)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 84.6 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-methyl-4-(trifluoromethyl)phenyl)-piperidine-1-carboxylate (0.69 g, 1.66 mmol) (from example 67, step 1) was dissolved in MeOH (8 mL) and cooled to −40° C. under nitrogen. NaOH (0.066 g, 1.66 mmol) dissolved in water (0.7 mL) was added during 10 min and the resulting colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.110 g, 1.66 mmol) was added dropwise. The resulting solution was stirred at −40° C. for 30 min. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M HCl and the mixture continued to stir at 80° C. for 20 min. The mixture was dissolved between diethyl ether and water. The phases were separated and the organic phase was dried over Na2SO4, filtered through celite and evaporated to yield crude trans-methyl 2-(3-methyl-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.54 g, 85%). 1H NMR (600 MHz, cdcl3) δ 1.60-1.72 (m, 1H), 1.89-1.97 (m, 1H), 1.99-2.07 (m, 1H), 2.48 (s, 3H), 2.58-2.71 (m, 1H), 2.80 (s, 1H), 2.93 (t, 1H), 3.73 (s, 3H), 4.23 (s, 1H), 5.49-5.73 (m, 2H), 7.06-7.16 (m, 2H), 7.60 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19]O)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][Cl:23])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCCCCCl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 37.9 %

Procedure:
A suspension of 4-(7-bromo-3-nitroquinolin-4-ylamino)butan-1-ol (20.75 g, 61.0 mmol) in dichloromethane (220 mL) was cooled to 0° C.; thionyl chloride (4.90 mL, 67.1 mmol) was added dropwise over a period of ten minutes. The reaction was stirred at 0° C. for five minutes, allowed to warm to ambient temperature, and stirred overnight. Aqueous sodium bicarbonate (500 mL of 50%) was slowly added. The aqueous layer was separated and extracted with dichloromethane (3×100 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield an orange semi-solid. An analysis by LCMS indicated the presence of starting material, and the semi-solid was dissolved in dichloromethane (150 mL) and treated with thionyl chloride (3.0 mL) as described above. Following the work-up procedure, the crude product was purified by column chromatography on silica gel (eluting with dichloromethane:methanol in a gradient from 100:0 to 95:5) to provide 8.3 g of (7-bromo-3-nitroquinolin-4-yl)-(4-chlorobutyl)amine as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+]([O-])=O)[CH:6]=1.ClC1C([N+]([O-])=O)C(C2C=CC=CC=2C(F)(F)F)([N+]([O-])=O)C=CC=1OC1C=CC([N+]([O-])=O)(C2C=CC=CC=2C(F)(F)F)C([N+]([O-])=O)C=1Cl.[CH3:72][P:73]([O:76]C)[O:74][CH3:75]>C(#N)C>[CH3:72][P:73]([C:7]1[CH:6]=[C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])[CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12])(=[O:76])[O:74][CH3:75]
Reactant: COP(C)OC
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: O=[N+]([O-])C1C(Cl)=C(OC2=C(Cl)C([N+](=O)[O-])C(c3ccccc3C(F)(F)F)([N+](=O)[O-])C=C2)C=CC1(c1ccccc1C(F)(F)F)[N+](=O)[O-]
Solvent: CC#N
Product: COP(C)(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene, (2-chloro-α,α,α-trifluoro-p-tolyl-3,4-dinitrophenyl ether) (1.2 g, 3.31 mmol) and dimethyl methylphosphonite (0.57 g, 5.3 mmol) in 3 ml of acetonitrile is refluxed overnight. The mixture is concentrated and the residue is purified by column chromatography (silica gel, eluting with 3% ethyl acetate/hexane) to yield methyl P-methyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate.
Reaction SMILES: [CH3:1][N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13](=[O:25])[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)=O.C[NH:28]N.C(O)(=O)C>C(O)C>[CH3:1][N:2]1[CH:3]=[CH:4][C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH:12][C:13](=[O:25])[CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[N:28]1
Reactant: CNN
Reactant: CN(C)/C=C/C(=O)c1sccc1NC(=O)Cc1cccc2ccccc12
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1ccc(-c2sccc2NC(=O)Cc2cccc3ccccc23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
To a solution of (E)-N-(2-(3-(dimethylamino)acryloyl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide (Example 7.3.1., 143 mg, 0.39 mmol) in abs. ethanol (2 mL) was added methyl hydrazine (0.2 mL, 3.80 mmol) and acetic acid (0.5 mL, 8.73 mmol). The reaction mixture was stirred at room temperature overnight under N2(g) inlet and then concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and H2O. The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, 20:80 ethyl acetate/hexane) yielded N-(2-(1-methyl-1H-pyrazol-3-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide (27 mgs, 20%). Method [7] m/z 348.0 (M+H); retention time=5.328. 1H-NMR (CDCl3) δ 7.96 (d, J=5.2 Hz, 2H), 7.94-7.91 (m, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.56-7.53 (m, 2H), 7.41 (d, J=7.8 Hz, 1H), 7.36 (d, J=9.1 Hz, 1H), 7.32 (d, J=5.2 Hz, 1H), 7.15 (s, 1H), 7.09 (d, J=1.9 Hz, 1H), 5.17 (d, J=1.9 Hz, 1H), 4.13 (s, 2H), 3.45 (s, 3H).
Reaction SMILES: [O-]S([C:5](F)(F)F)(=O)=O.[Na].[SH:10][C:11]1[C:12]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:14]2[C:19]([CH:20]=1)=[CH:18]C=CC=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>C1C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH2:24]([O:23][C:21](=[O:22])[C:12]1[CH:13]=[CH:14][C:19]([CH3:18])=[CH:20][C:11]=1[SH:10])[CH3:5]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: COC(=O)c1cc2ccccc2cc1S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Na]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(C)cc1S
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
To a solution of the triflate from step A (500 mg, 1.60 mmol) and tetrakistriphenylphosphine palladium(0) (0.05 equiv, 92 mg, 0.08 mmol) in dry benzene (2 mL) under nitrogen at room temperature, a solution of sodium triisopropilsilanethiolate in dry tetrahydrofuran [1.3 equiv, prepared from triisopropilsilanethi61 (396 mg, 2.08 mmol) and sodium hydride (95%, 52 mg, 2.08 mmol) in tetrahydrofuran (2 mL) as in Example 22, Step B] was added and the reaction mixture was warmed to reflux (bath temp 90° C.) for 3.5 h. The reaction mixture was cooled down to 0° C. and tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 1.5 equiv, 3.1 mL, 3.1 mmol) and glacial acetic acid (3.5 equiv, 437 mg, 0.405 mL, 7.28 mmol) were added and the reaction mixture stirred at 0° C. for 20 min. Work-up as in Example 22, Step B gave, after flash chromatography (silica gel, hexane-ethyl acetate 25:1), the desired thiol as an oil (220 mg, 70%). The product was kept under nitrogen at −18° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[N:19][CH:20]=2)[C:4]2[C:9]([C:10]=1[C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.C1C=C2N=NN(O)C2=CC=1.N.C(N(CC)CC)C.[NH2:39][CH2:40][C:41]1[C:42]([OH:49])=[N:43][C:44]([CH3:48])=[CH:45][C:46]=1[CH3:47]>ClCCl>[CH3:47][C:46]1[CH:45]=[C:44]([CH3:48])[NH:43][C:42](=[O:49])[C:41]=1[CH2:40][NH:39][C:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:14][C:15]2[CH:20]=[N:19][CH:18]=[N:17][CH:16]=2)[C:2]=1[CH3:1])=[O:13]
Reactant: Cc1c(C(=O)O)c2ccccc2n1Cc1cncnc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(Cc3cncnc3)c3ccccc23)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.2 %

Procedure:
A mixture of 2-methyl-1-(pyrimidin-5-ylmethyl)-1H-indole-3-carboxylic acid (60 mg, 0.22 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (65 mg, 0.34 mmol), N-hydroxybenzotrizole (180 mg, 1.33 mmol) and triethylamine (46 mg, 0.34 mmol) in dichloromethane (30 mL) was stirred for 30 minutes at room temperature. Then to the mixture, 3-(aminomethyl)-4,6-dimethyl pyridin-2-ol (33.44 mg, 0.22 mmol) was added. The resultant mixture was stirred at room temperature for 12 hours. Then the mixture was washed with water (20 mL×3). The organic layer was concentrated to give a residue which was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(pyrimidin-5-ylmethyl)-1H-indole-3-carboxamide (17 mg, 19%). LRMS (M+H+) m/z: calcd 401.19. found 401. HPLC purity (214 nm): 92%. 1H.NMR (300 MHz, CD3OD): δ 9.03 (s, 1H), 8.43 (s, 2H), 7.80-7.78 (m, 1H), 7.39-7.36 (m, 1H), 7.19-7.16 (m, 2H), 5.56 (s, 2H), 4.55 (s, 2H), 2.62 (s, 3H), 2.42 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: C([O-])=O.[NH4+].C1(C[N:12]2[C:16](=[O:17])[CH:15]([CH2:18][CH2:19][CH3:20])[N:14]([CH3:21])[S:13]2(=[O:23])=[O:22])C=CC=CC=1>CO.[Pd]>[CH2:18]([CH:15]1[N:14]([CH3:21])[S:13](=[O:23])(=[O:22])[NH:12][C:16]1=[O:17])[CH2:19][CH3:20]
Reactant: CCCC1C(=O)N(Cc2ccccc2)S(=O)(=O)N1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCC1C(=O)NS(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 128.3 %

Procedure:
To a suspension of 3.5 g of 10% Pd/C in 150 ml of methanol containing ammonium formate (14 g) was added a solution of 2-phenylmethyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (8.7 g) in 40 ml of methanol. The mixture was stirred at room temperature for 15 hours, filtered through a pad of CELITE® and the residue was washed with methanol. The combined filtrate was concentrated in vacuo to afford 7.6 g of 4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula IV: R1 =H; R2 =propyl; R3 =CH3) as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:11])[CH2:5][CH2:4]1.C[Si](C)(C)[Cl:32]>CC(CC)=O>[ClH:32].[CH3:29][N:2]([CH3:1])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2cccc(F)c2)CCC(=CC(=O)NCCCc2ccccc2)CC1
Solvent: CCC(C)=O
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[4-Dimethylamino-4-(3-fluorophenyl)cyclohexylidene]-N-(3-phenylpropyl)acetamide (150 mg, 0.35 mmol) was dissolved in ethyl methyl ketone (10 ml) with gentle heating and trimethylchlorosilane (0.082 ml, 0.65 mmol) was added. After stirring at RT for 2 h, the reaction mixture was concentrated to dryness. The residue was stirred briefly with ether (10 ml) and the hydrochloride was isolated as a colourless solid with an m.p. of 230-233° C. in a yield of 98% (184 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][N:7]=[CH:6]2)=[CH2:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[O:13]=[C:9]1[C:10]2[C:5](=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:12][CH:11]=2)[CH:6]=[N:7][N:8]1[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CBr
Reactant: C=Cc1ccc2c(=O)[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=Cc1ccc2c(=O)n(CC(=O)OCC)ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a stirred solution of 6-vinylphthalazine-1(2H)-one (0.5 g, 2.90 mmol) in DMF (5.0 mL) was added Cs2CO3 (0.94 g, 2.90 mmol) and the reaction was stirred for 10 min Ethyl bromoacetate (0.48 g, 2.90 mmol) was added to the reaction mixture at ambient temperature and the reaction was stirred for 8 h at ambient temperature. The reaction mixture was diluted and extracted with ethyl acetate, and the ethyl acetate layer was washed with water and brine solution (2×). The separated ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 25% ethyl acetate/petroleum ether) to afford the title compound as a brown solid (0.34 g, 45%): 1H NMR (400 MHz, DMSO-d6) δ 8.45 (m, 1H), 8.24 (m, 1H), 8.04 (m, 2H), 7.01 (m, 1H), 6.17 (d, J=2.1 Hz, 1H), 5.56 (d, J=10.8 Hz, 1H), 4.92 (s, 2H), 4.19 (m, 2H), 1.23 (m, 3H). ESIMS m/z 259.10 ([M+H]±); IR (thin film) 1750, 1660 cm−1.
Reaction SMILES: [C:1]([Sn:3]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH2:6][CH3:7])#[CH:2].[CH2:16]([N:23]=[N+:24]=[N-:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[CH:2]=[C:1]([Sn:3]([CH2:8][CH2:9][CH2:10][CH3:11])([CH2:4][CH2:5][CH2:6][CH3:7])[CH2:12][CH2:13][CH2:14][CH3:15])[N:25]=[N:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: [N-]=[N+]=NCc1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(Cc2ccccc2)nn1

Procedure:
Ethynyltributylstannane (1 mL, 3.4 mmol) and benzyl azide (0.65 mL, 5.2 mmol) were heated to 130° C. for 24 hours. The mixture was adsorbed onto silica gel, and purified by silica gel chromatography eluting with 1:4 ethyl acetate:hexanes to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:15]([O-:17])=[O:16])=[C:9]2[O:13][CH:12](O)[CH2:11][C:10]=12)=[O:4]>P(=O)(O)(O)O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:15]([O-:17])=[O:16])=[C:9]2[O:13][CH:12]=[CH:11][C:10]=12)=[O:4]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c2c1CC(O)O2
Agent: O=P(O)(O)O
Product: COC(=O)c1ccc([N+](=O)[O-])c2occc12
Temperature: 0 °C
Yield: 40 %

Procedure:
2-Hydroxy-7-nitro-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester prepared above was heated in phosphoric acid (60 mL) at 100° C. for one hour. The reaction mixture was poured into ice water and the aqueous solution was extracted with ethyl acetate. The organic phase was washed with brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 15% ethyl acetate in hexane to give 7-nitro-benzofuran-4-carboxylic acid methyl ester as solid (2.3 g, 40%). 1H (CDCl3) δ: 4.04 (s, 3H), 7.54 (d, 1H, J=2.0 Hz), 7.95 (d, 1H, J=1.9 Hz), 8.07 (d, 1H, J=8.5 Hz), 8.17 (d, 1H, J=8.5 Hz).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[S:16][CH:17]=2)=[CH:9][CH:8]=1>N1C=CC=CC=1>[OH:5][S:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[S:16][CH:17]=2)=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(-c2nc(-c3ccc(O)cc3)cs2)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(-c3ccc(OS(=O)(=O)O)cc3)cs2)cc1OC
Temperature: 50 °C
Reaction time: 12 h

Procedure:
2 ml of chlorosulfonic acid was dropwise added to 40 ml of pyridine at room temperature. The mixture was stirred at 50° C. for 12 hours. Thereto was added 0.33 g of 4-(4-hydroxyphenyl-2-(3,4-dimethoxyphenyl)thiazole. The mixture was stirred at 50° C. for 6 hours and then at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure. The residue was mixed with water and the resulting crystals were collected by filtration. The resulting 4-(4-hydroxysulfonyloxyphenyl)-2-(3,4-dimethoxyphenyl)thiazole pyridinium salt was suspended in 3 ml of methanol. Thereto was added 5 ml of a 0.1N aqueous potassium hydroxide solution. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was dissolved in water. The solution was treated with 0.5 g of an ion exchange resin (Dowex 50W×8). The filtrate was concentrated to obtain 0.04 g of 4-(4-hydroxysulfonyloxyphenyl)-2-(3,4-dimethoxyphenyl)thiazole.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:5]1[CH:4]=[CH:3][C:2]([C:13]2[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=2)=[CH:7][N:6]=1
Reactant: Fc1ccc(Br)cn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(F)nc2)cn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
A mixture of 5-bromo-2-fluoropyridine (1.75 g, 9.94 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.069 g, 9.94 mmol), Pd(PPh3)4 (1.149 g, 0.994 mmol) and K2CO3 (2.75 g, 19.89 mmol) in 1,4-dioxane (20 ml) was bubbled with argon for 10 min. The suspension was then stirred at 90° C. for 8 h. The mixture was filtered and the filtrate was diluted with EA, washed with water and brine. The organic phase was dried over anhydrous MgSO4, filtered and concentrated. The residue was recrystallized from MeOH to give the title compound as white solid (1.2 g, 61.3% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.46 (s, 1H), 8.22 (s, 1H), 8.15 (dd, 1H), 7.93 (s, 1H), 7.18 (dd, 1H). LCMS (method B): [M+H]+=178, tR=1.80 min.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:24])=[C:11]([NH:13][C:14]([C:16]3[S:20][C:19](B(O)O)=[CH:18][CH:17]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Br[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[CH3:32]>>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:24])=[C:11]([NH:13][C:14]([C:16]3[S:20][C:19]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][C:31]=4[CH3:32])=[CH:18][CH:17]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(B(O)O)s1
Reactant: Cc1ccncc1Br
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(-c2cnccc2C)s1

Procedure:
The title compound was prepared by coupling 5-(5-(cyclopropylcarbamoyl)-2-methylphenylcarbamoyl)thiophen-2-ylboronic acid (Example 210, Step A) with commercially available 3-bromo-4-methylpyridine using the method described in Step B of Example 136 to afford a white solid after purification by reverse phase preparative HPLC (Example 212). HPLC Ret time=1.99 min. LCMS [M+H]+ 392.3.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([CH:19]=C)[CH:16]=[C:15]([F:21])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:10]=1.B1C2CCCC1CCC2.[OH-:31].[Na+].OO>C1COCC1>[F:1][C:2]1[CH:18]=[C:17]([CH:16]=[C:15]([F:21])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:10]=1)[CH:19]=[O:31]
Reactant: [OH-]
Reactant: C=Cc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 152.4 %

Procedure:
To the solution of 5-(2,6-difluoro-4-vinylphenoxy)-2-(trifluoromethyl)pyrimidine (1.67 g, 5.53 mmol) in dry THF (25 mL), was added 9-BBN (20 ml, 10.00 mmol) at 0° C. The mixture was stirred at room temperature overnight, and quenched with water (2 mL), followed by aq. NaOH (7 mL, 21.0 mmol), and 30% H2O2 (7 mL, 5.53 mmol). The reaction mixture was heated at 50° C. for 3 h. Then THF was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (2.7 g, 8.43 mmol, 153% yield) as a white oil. LCMS: rt=2.97 min, [M+H+]=321
Reaction SMILES: CC1(C)CO[CH:5]([CH2:8][CH2:9][CH2:10][S:11][C:12]2[N:13]([CH3:27])[C:14]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][CH:21]=[CH:20]4)=[N:15][N:16]=2)[O:4]C1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:27][N:13]1[C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)=[N:15][N:16]=[C:12]1[S:11][CH2:10][CH2:9][CH2:8][CH:5]=[O:4]
Reactant: Cn1c(SCCCC2OCC(C)(C)CO2)nnc1-c1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cn1c(SCCCC=O)nnc1-c1ccc2ncccc2c1
Yield: 95 %

Procedure:
6-{5-[3-(5,5-Dimethyl-[1,3]dioxan-2-yl)-propylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-quinoline (0.51 g, 1.28 mmol) was heated in water (30 ml) and sulphuric acid (1.92 mmol) at 100° C. for 3 h. The mixture was cooled and basified with sodium carbonate. The aqueous mixture was extracted with dichloromethane (3×50 ml) and the combined organic portions were dried (Na2SO4), filtered and evaporated to give the title compound as a colourless oil (0.38 g, 95%).