Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[I:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.[Cu]I>[I:10][C:11]1[CH:16]=[CH:15][C:14]([O:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[CH:13][CH:12]=1
Reactant: OC1CN2CCC1CC2
Reactant: Ic1ccc(I)cc1
Agent: [Cu]I
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Ic1ccc(OC2CN3CCC2CC3)cc1
Temperature: 110 °C
Reaction time: 40 h

Procedure:
Under N2, the mixture of 3-hydroxy quinuclidine (Aldrich, 2.54 g, 20 mmol), 1,4-diiodobenzene (Aldrich, 7.9 g, 24 mmol), CuI (Strem Chemicals, 0.38 g, 2 mmol) and 1,10-phenanthroline (Aldrich, 0.72 g, 4 mmol) in toluene (anhydrous, Aldrich, 50 mL) was stirred at 110° C. for 40 h. After the reaction went to completion, the reaction mixture was diluted with chloroform (100 mL) and washed with water (2×10 mL). The organic solution was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.20) as oil (3.7 g, yield, 56%). 1H NMR (300 MHz, CD3OD) δ 1.40-1.56 (m, 1H), 1.64-1.80 (m, 2H), 1.90-2.08 (m, 1H), 2.10-2.21 (m, 1H), 2.60-3.00 (m, 5H), 3.34-3.40 (m, 1H), 4.46 (m, 1H), 6.73 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8, Hz, 2H), ppm. MS (DCI/NH3) m/z 330 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][N:20]2[CH:25]3[CH2:26][NH:27][CH2:28][CH:21]2[CH2:22][O:23][CH2:24]3)[NH:12][C:11]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[N:10]1.[N:34]([Si](C)(C)C)=[C:35]=[O:36]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][N:20]2[CH:25]3[CH2:26][N:27]([C:35](=[O:36])[NH2:34])[CH2:28][CH:21]2[CH2:22][O:23][CH2:24]3)[NH:12][C:11]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[N:10]1
Reactant: C[Si](C)(C)N=C=O
Reactant: COC(=O)C1=C(CN2C3CNCC2COC3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Br
Product: COC(=O)C1=C(CN2C3COCC2CN(C(N)=O)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Br
Yield: 70.9 %

Procedure:
The title compound was prepared in analogy to Example 18 starting from methyl (4R)-4-(2-bromo-4-fluoro-phenyl)-6-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 53b (50 mg, 0.09 mmol) and isocyanato(trimethyl)silane (43 mg, 0.37 mmol). 37 mg of the title compound was isolated as a light yellow powder.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>>[N+:9]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])([O-:11])=[O:10]
Reactant: CCOP(OCC)OCC
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Product: CCOP(=O)(Cc1cccc([N+](=O)[O-])c1)OCC
Temperature: 100 °C
Yield: 63.2 %

Procedure:
A stirring suspension of 1-(bromomethyl)-3-nitrobenzene (46.3 mmol, 10 g) in triethyl phosphite (69.4 mmol, 12.08 mL, 11.54 g) was heated at 100° C. for 4 hours. The reaction mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic layer was separated, dried and concentrated under vacuum. The residue was purified by silica column chromatography (eluent: 0-5% methanol in dichloromethane) to afford the title compound (8 g).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Br:10][C:11]1[CH:12]=[N:13][C:14](Cl)=[N:15][CH:16]=1.[NH:18]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1>FC(F)(F)C1C=CC=CC=1.C(Cl)Cl>[Br:10][C:11]1[CH:12]=[N:13][C:14]([N:18]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]2)=[N:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)CC1CCNC1
Reactant: Clc1ncc(Br)cn1
Solvent: FC(F)(F)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC1CCN(c2ncc(Br)cn2)C1
Temperature: 120 °C
Yield: 69 %

Procedure:
N-Ethyl-N,N-diisopropylamine (1.80 mL, 10.34 mmol) was added dropwise at room temperature to a solution of 5-bromo-2-chloropyrimidine B-5 (1.00 g, 5.17 mmol) and tert-butyl 2-(pyrrolidin-3-yl)acetate (1.00 g, 5.40 mmol) in anhydrous α,α,α-trifluorotoluene (10.2 mL) under an argon atmosphere, in a 20 mL microwave reactor vial. The reaction mixture was sealed and heated at 120° C. for 30 mins under microwave irradiation, then successively cooled to room temperature, diluted with methylene chloride (100 mL), quenched with a 1 N aqueous solution of hydrogen chloride (30 mL) and decanted. The aqueous layer was extracted with methylene chloride (2×150 mL); the combined extracts were sequentially washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes to ethyl acetate gradient) to give tert-butyl 2-(1-(5-bromopyrimidin-2-yl)pyrrolidin-3-yl)acetate B-6 (1.22 g, Yield=69%). MS (ESI), [M+1]+ 342, 344.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:31](=[O:32])[N:11]3[NH:12][CH:13]([CH3:30])[C:14]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[C:10]3=[N:9]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:46](Cl)(=[O:48])[CH3:47]>C(Cl)Cl>[F:36][C:2]([F:35])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:31](=[O:32])[N:11]3[N:12]([C:46](=[O:48])[CH3:47])[CH:13]([CH3:30])[C:14]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:15]([C:16]4[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=4)[C:10]3=[N:9]2)=[CH:33][CH:34]=1
Reactant: CC1Nn2c(nn(Cc3ccc(C(F)(F)F)cc3)c2=O)C(c2ccc(Cl)cc2)=C1c1ccc(Cl)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1C(C)C(c2ccc(Cl)cc2)=C(c2ccc(Cl)cc2)c2nn(Cc3ccc(C(F)(F)F)cc3)c(=O)n21
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
To a solution of 2-(4-(trifluoromethyl)benzyl)-7,8-bis(4-chlorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (8 mg, 0.015 mmol), prepared as described in Example 469 in CH2Cl2 (0.2 mL) at RT was added diisopropyl ethyl amine (5.8 mg, 0.045 mmol), followed by acetyl chloride (2.4 mg, 0.030 mmol). The reaction was stirred at RT for 2 h. LC-MS showed the completion of the reaction. The solvent was evaporated and the residue was purified using reverse phase HPLC to give the title compound, 2-(4-(Trifluoromethyl)benzyl)-5-acetyl-7,8-bis(4-chlorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (6 mg, 70%) as a white solid. HPLC retention time: 4.23 min; MS [M+H]+: found 573. 1H NMR (CDCl3, 400 MHz) δ 7.65 (d, 2H), 7.51 (d, 2H), 7.30-7.22 (m, 4H), 7.17 (dd, 2H), 7.06 (dd, 2H), 5.70 (q, 1H), 5.14-5.11 (m, 2H), 2.28 (s, 3H), 1.28 (s, 3H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:35])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([CH:32]=[N:33][CH3:34])=[CH:28][CH:27]=3)=[CH:4][C:3]=2[O:2]1.[BH3-]C#N.[Na+].C(O)(=O)C>CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:35])/[CH:24]=[CH:25]/[C:26]3[CH:27]=[CH:28][C:29]([CH2:32][NH:33][CH3:34])=[CH:30][CH:31]=3)=[CH:4][C:3]=2[O:2]1
Reactant: CN=Cc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Yield: 9.8 %

Procedure:
A solution of (E)-1-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-methyliminomethylphenyl)propene-1-one (0.46 g, 1.1 mmol), NaBH3CN (0.14 g, 2.3 mmol) and acetic acid (0.11 mL) in 20 mL of MeOH was stirred at rt for one hour. The reaction mixture was quenched with 50 mL of an aqueous saturated solution of NaHCO3. Extraction with 2×30 mL of DCM, washing with brine, drying over Na2SO4 and concentration in vacuo gave a residue that was purified via flash chromatography of silica gel using DCM:MeOH (97:3) as eluting solvent. Recrystallization from DCM:cyclohexane gave the title compound (0.05 g, 10%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][C:12]1[CH:25]=[CH:24][C:23]2[C:14](=[CH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=1>C(#N)C>[Br-:10].[CH:13]1[C:14]2[C:23](=[CH:22][C:21]3[C:16]([CH:15]=2)=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:24]=[CH:25][C:12]=1[CH2:11][N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([CH2:11][C:12]2[CH:25]=[CH:24][C:23]3[C:14](=[CH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:13]=2)[CH:4]=1
Reactant: BrCc1ccc2cc3ccccc3cc2c1
Reactant: Clc1nc[nH]c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Clc1c(Cl)[n+](Cc2ccc3cc4ccccc4cc3c2)cn1Cc1ccc2cc3ccccc3cc2c1
Product: [Br-]

Procedure:
4,5-Dichloroimidazole (0.18 g, 1.33 mmol) and potassium hydroxide (0.08 g, 1.46 mmol) will be dissolved in a minimum volume of acetonitrile and stirred at reflux for 30 min. 2-(Bromomethyl)anthracene (2.71 g, 10.0 mmol) will be added and the mixture will be returned to reflux for 3 h. The mixture will be filtered hot to remove the KBr generated. A second equivalent of 2-(bromomethyl)anthracene will be added to the filtrate and the mixture will be returned to reflux for 6 h. The volatile components will be removed under reduced pressure to yield the product.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].Cl>ClCCl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:15])[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
At room temperature, 4-chloro-3-trifluoromethyl-aniline (4.9 g, 25 mmol, 1 eq) was dissolved in dichloromethane (50 mL). A solution of phenyl chloroformate (3.9 g, 25 mmol, 1 eq) in dichloromethane (10 mL) was added, and the mixture was stirred for 1 h at room temperature. Dilute hydrochloride (1 N, 50 mL) was added, and the mixture was washed with water (40 mL×3) and separated. The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent in the filtrate was removed to give the title compound (7.5 g, purity 99%, yield 94%) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([OH:8])=[N:6][CH:7]=1.IC.[C:12]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](=[O:8])[N:6]([CH3:12])[CH:7]=1
Reactant: Oc1ncc(Br)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(Br)cc(F)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.3 %

Procedure:
A mixture of 5-bromo-3-fluoropyridin-2-ol (1 g, 5.2 mmol), iodomethane (356 mg, 5.7 mmol) and K2CO3 (1.4 g, 10.4 mmol) in DMF (10 mL) was stirred at rt for 12 h. The mixture was treated with water (70 ml) and extracted with EtOAc (3×50 ml). The combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (1 g, 93%) as a white solid which was carried forward without purification. LCMS (M+H)+=207.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)[C:10]2[C:5](=[N:6][C:7]([C:24]3[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:8][CH:9]=2)[N:4]=1.Cl>CCOCC.C(O)(C)C>[F:33][C:30]([F:31])([F:32])[C:29]1[C:24]([C:7]2[N:6]=[C:5]3[C:10]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][N:15]=4)=[CH:12][C:3]([OH:2])=[N:4]3)=[CH:9][CH:8]=2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc(Nc2ccc(C(F)(F)F)cn2)c2ccc(-c3ncccc3C(F)(F)F)nc2n1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: Oc1cc(Nc2ccc(C(F)(F)F)cn2)c2ccc(-c3ncccc3C(F)(F)F)nc2n1

Procedure:
Heat 2-methoxy-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-[1,8]naphthyridin-4-amine (128 mg), 1M hydrochloric acid in ether (0.25 mL) and isopropanol at 80° C. overnight. Cool and collect the precipitate by filtration to give the hydrochloride salt of the title compound.
Reaction SMILES: [C:1]([C:3]1([N:12]([C:16](=[O:27])[CH2:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[N:13]([CH3:15])[CH3:14])[CH2:8][CH2:7][N:6]([N:9]([CH3:11])[CH3:10])[CH2:5][CH2:4]1)#N.S(=O)(=O)(O)[OH:29].[CH3:33][OH:34]>>[CH3:33][O:34][C:1]([C:3]1([N:12]([C:16](=[O:27])[CH2:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[N:13]([CH3:15])[CH3:14])[CH2:8][CH2:7][N:6]([N:9]([CH3:11])[CH3:10])[CH2:5][CH2:4]1)=[O:29]
Reactant: O=S(=O)(O)O
Reactant: CO
Reactant: Cc1cc(C)c(CC(=O)N(N(C)C)C2(C#N)CCN(N(C)C)CC2)c(C)c1
Product: COC(=O)C1(N(C(=O)Cc2c(C)cc(C)cc2C)N(C)C)CCN(N(C)C)CC1
Temperature: 25 °C

Procedure:
2.2 g (2,4,6-Trimethyl-phenyl)-acetic acid N-(4-cyano-1-dimethylamino-piperidin-4-yl)-N′,N′-dimethyl-hydrazide (from Step 3) is dissolved in 35 ml methanol and 8.7 g concentrated sulfuric acid is added dropwise. The mixture is heated to reflux for 18 hours, then cooled to room temperature, most of the solvent evaporated, then poured on ice, the pH adjusted to 7 by the addition of aqueous sodium hydroxide, and made alkaline by the addition of aqueous sodium bicarbonate. The mixture is then extracted with ethyl acetate, the organic layer dried over sodium sulfate and the solvent evaporated. The residue is chromatographed on silica gel with ethyl acetate/acetone (2:1) as a solvent, to give 1.55 g 1-Dimethylamino-4-{N′,N′-dimethyl-N-[2-(2,4,6-trimethyl-phenyl)-acetyl]-hydrazino}-piperidine-4-carboxylic acid methyl ester. 1H-NMR (CDCl3): 6.84 ppm (s, 2H), 3.70 ppm (s, 2H), 3.65 ppm (s, 3H), 3.05 ppm (s, 6H), 2.25 ppm (s, 3H), 2.21 ppm (s, 6H), 2.10-3.10 ppm (broad multiplets, total of 14H).
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[N:13]([CH2:14][CH3:15])[C:12](=[O:16])[NH:11][C:10](=[O:17])[C:9]=1[NH:18][C:19](=O)[CH:20]([CH3:22])[CH3:21].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1.C(Cl)C1C=CC=CC=1.Cl>>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:11]2[C:10](=[O:17])[C:9]3[NH:18][C:19]([CH:20]([CH3:22])[CH3:21])=[N:7][C:8]=3[N:13]([CH2:14][CH3:15])[C:12]2=[O:16])=[CH:27][CH:26]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCn1c(N)c(NC(=O)C(C)C)c(=O)[nH]c1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: ClCc1ccccc1
Product: CCn1c(=O)n(Cc2ccc(Cl)cc2)c(=O)c2[nH]c(C(C)C)nc21
Reaction time: 3 h
Yield: 56.7 %

Procedure:
3.17 g (28.2 mM) of potassium t-butoxide (t-BuOK) were added to a solution of 6.11 g (27.5 mM) of 6-amino-1-ethyl-5-isobutyrylamino-uracil. At 0° C., 4.90 g (30.4 mM) of 4-chlorobenzylclhloride were added. After 3 hours at 0-5° C., further 1.22 g t-BuOK and 2.45 g of 4-chloro-benzylchloride were added. After further 3 hours another 2.45 g of benzylchloride are supplemented. After 3 days, the solution was neutralized with 1N HCl and the solvents evaporated. The residue was suspended in water, the solid collected and washed. The crude intermediate amide was heated under reflux in 100 ml of 1N NaOH and 10 ml of 1-propanol. After 1 hour, the mixture was neutralized to pH 7 and extracted with chloroform. Crystallization from dichloromethane (mainly evaporated)--methanol gave 2.99 g (31.3%) of the title xanthine, mp 194-5° C. The mother liquors gave 6.33 g of impure material which was separated on 15 g of silica gel elutions with dichloromethane and gave additional 0.78 g (8.2%) of the xanthine.
Reaction SMILES: [C:1]1([C:17]([C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)=[O:18])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[OH-:29].[K+].Cl>C1C=CC=CC=1.CO>[C:1]1([C:17]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][O:29][C:1]([CH3:17])([CH3:14])[CH3:2])=[O:24])=[CH:27][CH:28]=2)=[O:18])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(C(=O)c2ccc3ccc4cccc5ccc2c3c45)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: c1ccccc1
Product: CC(C)(C)OOC(=O)c1ccc(C(=O)c2ccc3ccc4cccc5ccc2c3c45)cc1
Yield: 142.9 %

Procedure:
4-[(1-Pyrenyl)carbonyl]benzoic acid, methyl ester (2.55 g; 7 mmol) was dissolved in 25 ml of benzene. A solution of 354 mg (6.4 mmol) of KOH in 5 ml MeOH was added, and the mixture boiled. Precipitation of the potassium salt occurred. The mixture was extracted with water to give a yellow water layer which was acidified with dilute HCl to give a light yellow precipitate. Filtration gave 1.73 g (5 mmol) of the 4-[(pyrenyl)carbonyl]benzoic acid.
Reaction SMILES: Cl.Cl.[CH:3]1([C:6]2[N:11]=[CH:10][C:9](OC3C=CC(CCN)=CC=3)=CN=2)CC1.[CH2:22]1[CH2:26]OC[CH2:23]1.[CH3:27]N1C(=O)CCC1>>[CH3:9][CH2:10][N:11]([CH:22]([CH3:26])[CH3:23])[CH:6]([CH3:3])[CH3:27]
Reactant: NCCc1ccc(Oc2cnc(C3CC3)nc2)cc1
Reactant: C1CCOC1
Reactant: CN1CCCC1=O
Agent: Cl
Product: CCN(C(C)C)C(C)C

Procedure:
Crude {4-[(2-cyclopropylpyrimidin-5-yl)oxy]benzyl}methylamine dihydrochloride (0.115 g, 0.35 mmol) was dissolved in NMP (2.0 mL), THF (2.0 mL) and DIPEA (0.30 mL, 1.8 mmol) to form a yellow solution. (4S)-(4-Cyclopropyl-2,5-dioxoimidazolidin-4-yl)methanesulfonyl chloride (WO 2006/065215; 0.070 g, 0.28 mmol) was added portionwise during 5 minutes and the reaction mixture was stirred for 1 hour. The solvent was removed by evaporation and the residue was diluted with water and extracted twice with EtOAc. The combined organic phases were washed with water and concentrated. The crude product was purified by HPLC, using a 35 minutes gradient of 20% to 90% MeCN in water to give 0.081 g (61% yield) of the title compound as a colourless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C@H:13]([C:23]([O:25]CC)=[O:24])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C@H:13]([C:23]([OH:25])=[O:24])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC)cc1)NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C[C@H](NS(=O)(=O)c2ccc(Cl)c(Cl)c2)C(=O)O)cc1

Procedure:
5 g of 3,4-dichlorophenylsulphonyl chloride are introduced, with stirring, into a mixture of 3,8 g of ethyl O-methyltyrosinate in 35 ml of CH2Cl2 and 50 ml of a saturated aqueous potassium carbonate solution. After one night, the solid is removed, the organic phase separated and the aqueous phase reextracted with CH2Cl2. The dried organic phases are concentrated and the residue is chromatographed on a silica column, eluting with a mixture of CH2Cl2 and CH3OH (95/5-V/V). 6.8 g of racemic ethyl N-(3,4-dichlorophenylsulphonyl)-O-methyltyrosinate are obtained, which product melts at 99° C. This ester is hydrolysed in 100 ml of C2H5OH containing 9.5 ml of a 5N aqueous KOH solution to give, after acidification, 5.5 g of the corresponding acid which melts at 183° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[C:5]([F:13])=[CH:4][CH:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:12][CH2:11][CH:8]2[CH2:7][C:6]3[C:5]([F:13])=[CH:4][CH:3]=[C:2]([Br:1])[C:10]=3[O:9]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1Cc2c(F)ccc(Br)c2O1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)ccc(Br)c3O2)cc1
Yield: 88.2 %

Procedure:
Treatment of (±)-(7-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl)methanol (6.21 g, 0.025 mol) with p-toluenesulfonyl chloride (5.26 g, 0.028 mol) in pyridine (120 mL) generally according to the procedure described for Intermediate 10 afforded 8.85 g (88%) of (±)-(7-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Rf=0.60 (silica, ethyl acetate:hexanes 1:1); mp 100-103° C.; Anal. calcd. for C16H14BrFO4S: C, 47.89; H, 3.52. Found: C, 47.89; H, 3.68.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.C(Cl)(=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[Cl:22])[CH2:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:24]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[O:26])[N:8]([C:6](=[O:7])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Reactant: C1COCCN1
Reactant: O=C(Cl)c1ccccc1
Product: O=C([C@@H]1CC(=NOCc2ccc(Cl)c(Cl)c2)CN1C(=O)c1ccccc1)N1CCOCC1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, benzoyl chloride, and morpholine the title compound was obtained in 69% purity by LC/MS. MS(ESI+): m/z=476.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[CH:22]=[CH:23]/[C:24](O)=O)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CC#N>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[CH:22]=[CH:23]/[C:24]2[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8](=[O:9])(=[O:10])[N:11]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(/C=C/C(=O)O)cc1OC
Reactant: Nc1ccccc1S(N)(=O)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(/C=C/C2=NS(=O)(=O)c3ccccc3N2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 14 %

Procedure:
2-Aminobenzenesulfonamide (0.25 g, 1.4 mmol) was added to a suspension of (E)-3-(3,4-dimethoxyphenyl)acrylic acid (0.25 g, 1.2 mmol), HBTU (0.55 g, 1.4 mmol) and NEt3 (0.67 mL, 4.8 mmol) in MeCN (5 mL) and the reaction was stirred at rt for 16 h. Extra NEt3 (0.67 mL, 4.8 mmol) in MeCN (5 mL) was added and the reaction was stirred at rt for 64 h. The solution was acidified and the precipitate was collected by filtration. Hot EtOH (15 mL) was added to the crude product and the undissolved solid was collected by hot filtration, providing (E)-3-[2-(3,4-dimethoxyphenyl)ethenyl]-4H-1,2,4-benzothiadiazine-1,1-dioxide (58 mg, 14%) as a colourless crystalline solid; mp 276-279° C.; δH (500 MHz, DMSO-d6) 3.81 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 6.75 (d, J=15.6 Hz, 1H, CH═CHCO), 7.05 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.29 (d, J5′,6=8.0 Hz, 1H, H6′), 7.31 (s, 1H, H2′), 7.38 (d, J5,6=8.0 Hz, 1H, H5), 7.45 (t, J5,6=J6,7=8.0 Hz, 1H, H6), 7.68 (t, J6,7=J7,8=8.0 Hz, 1H, H7), 7.80 (d, J7,8=8.0 Hz, 1H, H8), 7.82 (d, J=15.6 Hz, 1H, CH═CHCO), 12.13 (s, 1H, NH); δC (125 MHz, DMSO-d6) 55.4, 55.6, 110.3, 111.8, 116.6, 117.6, 122.0, 122.7, 123.3, 126.3, 126.9, 133.0, 135.2, 142.2, 149.0, 151.1, 153.5; HRMS (ESI) calculated for C17H16N2O4S [M+H]+ 345.0904, found 345.0900; νmax 756, 1134, 1263, 1513, 1568, 1600, 3024, 3117, 3163, 3200 cm−1.