Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:3]1[C:7](=[O:8])[CH2:6][CH2:5][C:4]1=[O:9])=[CH2:2].C(Cl)(Cl)(Cl)[Cl:11]>>[Cl:11][CH:1]([N:3]1[C:7](=[O:8])[CH2:6][CH2:5][C:4]1=[O:9])[CH3:2]
Reactant: C=CN1C(=O)CCC1=O
Reactant: ClC(Cl)(Cl)Cl
Product: CC(Cl)N1C(=O)CCC1=O
Reaction time: 24 h
Yield: 59 %

Procedure:
N-vinylsuccinimide, 50.0 g (0.40 mole) is dissolved in 100 ml carbon tetrachloride, 5.20 g (0.020 mole) of stannic chloride is added and the mixture is stirred while saturating with hydrogen chloride gas for 6 hours at 20°-30° C. After 24 hours, the mixture is resaturated with hydrogen chloride gas for 1.5 hours. At the end of 48 hours, the solution is decanted and the gummy residue is washed with ten 100 ml portions of carbon tetrachloride. The combined extracts are slurried with 10 g of diatomaceous earth, filtered and the filtrate is concentrated under reduced pressure to approximately 400 ml. The N-(1-chloroethyl)-succinimide is filtered and dried at 20°-30° C. under reduced pressure to yield 38.4 g (59%) of white solid melting at 83.5°-84.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[C:13]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:18]=CC=C[CH:14]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(O)(C)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH:13]([CH3:18])[CH3:14])[CH:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(OC(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl(3-hydroxyphenyl)acetate (200 mg) in tetrahydrofuran (5 ml), 0.15 ml of isopropyl alcohol, 480 mg of triphenylphosphine, and 0.82 ml of diethyl azodicarboxylate (45% toluene solution) were added, and the reaction solution was stirred overnight at room temperature. The reaction solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-25:75-60/40)) to afford the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH3:12]
Reactant: CCc1ccccc1O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccccc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 110 °C

Procedure:
In a 20 mL microwave vial 2-chloro-5-nitropyridine (500 mg, 3.15 mmol) was dissolved in N,N-dimethylformamide (10 mL) to give a light brown solution. 2-ethylphenol (0.378 mL, 3.15 mmol) and K2CO3 (1308 mg, 9.46 mmol) were added. The reaction vessel was sealed and heated in Biotage Initiator at 110° C. for 1 hour. After cooling the reaction was complete. The reaction mixture was quenched with 10 mL of water and diluted with 10 mL of Et2O. Phases were separated through a separating funnel. The organic phase was washed with 3×10 mL of water, 10 mL of brine, dried over sodium sulphate, filtered and evaporated under vacuum to give the title compound as a pale orange oil. (623 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][C:4]=1[OH:11].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:20]([N:28]=[C:29]=[S:30])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO.[Pt]>[CH2:12]([N:19]([CH2:9][C:7]1[CH:6]=[CH:5][C:4]([OH:11])=[C:3]([O:2][CH3:1])[CH:8]=1)[C:29]([NH:28][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[S:30])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: COc1cc(C=O)ccc1O
Reactant: S=C=NCCc1ccccc1
Agent: [Pt]
Solvent: CO
Product: COc1cc(CN(Cc2ccccc2)C(=S)NCCc2ccccc2)ccc1O
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Vaniline (200 mg) and benzylamine (129 mg) were dissolved in methanol (3 ml) and the solution was stirred for 30 minutes. To the solution was added a catalytic amount of 10% platinum/carbon to be subjected to the hydrogenation reaction (1 atm). After the completion of the reaction, the resulting mixture was filtered and evaporated under reduced pressure to remove methanol. The obtained residue was dissolved in dichloromethane (3 ml) and to the solution was added phenethylisothiocyanate (196 mg, 1.2 mmol), followed by stirring at room temperature for 5 hours. Then, dichloromethane was evaporated under reduced pressure and the obtained residue was column-chromatographed (hexane/ethyl acetate=1/1) to yield the compound 25-1 (400 mg, 82%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][N:6]([C:30]([S:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:7][P:8]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=1)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)=[O:9])[CH3:2].ClC1C=CC=C(C(OO)=[O:49])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:40])[CH2:5][N:6]([C:30]([S:32]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:49])=[O:31])[CH2:7][P:8]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=1)=[O:9])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CN(CP(=O)(Oc1cccc([N+](=O)[O-])c1)Oc1cccc([N+](=O)[O-])c1)C(=O)SCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)CN(CP(=O)(Oc1cccc([N+](=O)[O-])c1)Oc1cccc([N+](=O)[O-])c1)C(=O)S(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
To a solution of ethyl-N-[(benzylthio)carbonyl]-N-[bis(3-nitrophenoxy)phosphinylmethyl]-glycinate (2.0 g.; 0.0034 mol.) dissolved in 50 ml. of methylene chloride was added metachloroperbenzoic acid (0.69 g.; 0.0034 mol.) at 0° C. The reaction mixture was stirred for 4 hours while allowed to gradually warm to 25° C., then filtered. The filtrate was washed with 5% sodium hydroxide, dried, and concentrated in vacuo to yield ethyl-N-[(benzylsulfinyl)carbonyl]-N-[bis(3-nitrophenoxy)phosphinylmethyl]-glycinate (1.3 g.) as an oil (nD25 =1.5654) having the following analysis:
Reaction SMILES: C(OC1C(C(O)=O)=NC=CC=1OC)C1C=CC=CC=1.C([O:27][C:28]1[C:29]([C:36]([OH:38])=O)=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)C1C=CC=CC=1.COC1C=CC(O[C:46]2[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=2)=CC=1.C1(N)CCCCC1>>[OH:27][C:28]1[C:29]([C:36]([NH:50][CH:49]2[CH2:51][CH2:52][CH2:46][CH2:47][CH2:48]2)=[O:38])=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1
Reactant: COc1ccc(OCc2ccccc2)c(C(=O)O)n1
Reactant: COc1ccc(Oc2ccc(N)cc2)cc1
Agent: COc1ccnc(C(=O)O)c1OCc1ccccc1
Solvent: NC1CCCCC1
Product: COc1ccc(O)c(C(=O)NC2CCCCC2)n1

Procedure:
The procedure of Example 29 was repeated, except that 3-benzyloxy-4-methoxypicolinic acid was changed to 3-benzyloxy-6-methoxypicolinic acid and 4-(4′-methoxyphenoxy)aniline was changed to cyclohexylamine. Thus, the title compound was prepared.
Reaction SMILES: [Mg:1].Br[C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.C([Br:15])C.[CH2:16]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>>[CH2:16]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].[C:3]12([Mg:1][Br:15])[CH2:12][CH:7]3[CH2:6][CH:5]([CH2:11][CH:9]([CH2:8]3)[CH2:10]1)[CH2:4]2
Reactant: CCBr
Reactant: [Mg]
Reactant: BrC12CC3CC(CC(C3)C1)C2
Solvent: CCCCOCCCC
Product: Br[Mg]C12CC3CC(CC(C3)C1)C2
Reaction time: 1 h

Procedure:
2.92 g (0.120 mol) of magnesium and 30 ml of dibutyl ether were charged in a 200 ml Schlenk tube equipped with a reflux condenser, a dropping funnel and a stirring apparatus in an atmosphere of nitrogen, and a solution having 21.5 g (0.100 mol) of 1-bromoadamantane and 1.09 g (0.0100 mol) of ethyl bromide dissolved in 40 ml of dibutyl ether was dropwise added thereto from the dropping funnel at 80° C. over a period of 1 hour, and stirring was carried out further for 2 hours at 120° C. to obtain a dibutyl ether solution of 1-adamantyl magnesium bromide.
Reaction SMILES: [O:1]=[C:2]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[CH:13]=2)[CH2:7]1.Br.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[O:1]=[C:2]([C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH2:7]1
Reactant: COc1cccc(C2CCCN(CCCC(=O)c3ccc(F)cc3)C2)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C(CCCN1CCCC(c2cccc(O)c2)C1)c1ccc(F)cc1
Yield: 39.5 %

Procedure:
A mixture of 1.4 g (4 mmole) of 1-(4-oxo-4-[4-fluorophenyl]butyl)-3-(3-methoxyphenyl)piperidine, 10 ml of 48% aqueous hydrobromic acid and 5 ml of glacial acetic acid was heated under reflux for ca. 20 hours. The reaction mixture was then poured onto a mixture of ice and water. The resulting mixture was basified with potassium carbonate and then it was extracted with ethyl acetate. The extracts were washed with water, followed by saturated sodium chloride solution, and then they were dried (MgSO4) and evaporated in vacuo. The residue was purified by chromatography on 150 ml of silica gel, eluting with chloroform/methanol (95:5). The product was then recrystallized from chloroform to give 540 mg (30% yield) of the title compound as a chloroform solvate, m.p. 77°-78° C.
Reaction SMILES: [Br:1]Br.[S:3]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[N:9]=2)=[CH:6][C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]1=2>C(O)(=O)C>[Br:1][C:6]1[C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[S:3][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[N:9]=1
Reactant: CS(=O)(=O)c1nccc(-c2cc3ccccc3s2)n1
Reactant: BrBr
Solvent: CC(=O)O
Product: CS(=O)(=O)c1nccc(-c2sc3ccccc3c2Br)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.6 %

Procedure:
Bromine (0.48 g, 3.02 mmol) was slowly added at rt to a mixture of 4-(benzo[b]thiophen-2-yl)-2-(methylsulfonyl)pyrimidine (0.73 g, 2.52 mmol) in acetic acid (20 mL). The resulting mixture was stirred at rt for 15 h and then heated at 60° C. for 5 h. After cooling to rt, acetic acid was removed in vacuo. 100 mL of saturated sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×100 mL).). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate and filtered. The solvent was evaporated in vacuo and the solid treated with 20 mL of methanol, filtered and dried to give the title compound (0.75 g, 80%). MS (M+H)+ 369/371.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3[C:22](=[O:23])[C:21]4=[CH:24][S:25][CH:26]=[C:20]4[NH:19][C:18]3=[O:27])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:35][C:36]([CH3:41])([CH3:40])[C:37](Cl)=[O:38].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3[C:22](=[O:23])[C:21]4=[CH:24][S:25][CH:26]=[C:20]4[N:19]([C:37](=[O:38])[C:36]([CH3:41])([CH3:40])[CH3:35])[C:18]3=[O:27])[CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=c1[nH]c2cscc2c(=O)n1CCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)n1c(=O)n(CCN2CCC(=C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(=O)c2cscc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.5 %

Procedure:
A mixture of 3-[2-[4-[bis(4-fluorophenyl)methylene]piperidin-1-yl]ethyl]thieno[3,4-d]pyrimidine-2,4-dione of Example 4 (0.80 g, 1.7 mmol), trimethylacetyl chloride (0.25 ml, 2.0 mmol) and triethylamine (0.84 ml, 6.0 mmol) in methylene chloride (20 ml) was stirred at room temperature for 16 hours. The reaction mixture was washed with water (2×30 ml) and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel 60 (80 g) using 1% methanol in methylene chloride as the eluant, to give the title compound (0.35 g, 37% yield) as a colorless solid, mp 69°-72° C. IR(KBr): 1595, 1660 and 1715 cm-1 ; MS (DCI), m/z 564 (MH+); 1H NMR (CDCl3): δ 1.44 (s, 9H), 2.34 (t, J=5 Hz, 4H), 2.61 (t, J=5 Hz, 4H), 2.67 (t, J=7 Hz, 2H), 4.17 (t, J=7 Hz, 2H), 6.58 (d, J=3 Hz, 1H), 6.96-7.08 (m, 8H) and 8.25 (d, J=3 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C@@H:15]2[C@H:16]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:17][C@@:11]1([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:12]([OH:27])[CH:13]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:34][C:35]([F:49])([F:48])[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:39]Br.C(OCC)C>C1COCC1>[CH2:3]([N:10]1[C@@H:15]2[C@H:16]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH2:17][C@@:11]1([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:12]([O:27][CH2:39][C:38]1[CH:41]=[C:42]([C:44]([F:46])([F:47])[F:45])[CH:43]=[C:36]([C:35]([F:34])([F:48])[F:49])[CH:37]=1)[CH:13]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@@]2(c3ccccc3)[C@@H](O)C=C[C@@H]1N2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)[C@@H]1C[C@@]2(c3ccccc3)[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C=C[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (94 mg, 60% in oil, 2.45 mmol) was added to a stirred solution of (1R*,2S*,5S*,6R*)-8-benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]oct-3-en-2-ol (Description 5b; 256 mg, 0.6 mmol) and 3,5-bis(trifluoromethyl)benzyl bromide (0.8 ml) in dry THF (3 ml) at room temperature. The reaction mixture was stirred at +50° C. for 30 minutes, then cooled to room temperature and treated with diethyl ether (70 ml). The mixture was washed twice with water, brine. The combined organic extracts were dried (Na2SO4) and concentrated. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-30%) to give the title compound (400 mg, quant.).
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([C:1]1[O:10][N:4]=[C:3]2[C:2]=1[CH:8]=[CH:7][CH:6]=[CH:5]2)(=[O:13])[CH3:12].[N:4]1[O:10][CH:1]=[C:2]2[C:3]=1[CH:5]=[CH:6][CH:7]=[CH:8]2
Reactant: Nc1ccccc1C(=O)O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)c1onc2ccccc12
Product: c1ccc2nocc2c1

Procedure:
reacting a compound of the formula ##STR85## wherein L is a leaving group, with a hydroxylamine hydrochloride to form an isonitrosoacetanilide compound of the formula ##STR86## (2) treating the isonitrosoacetanilide compound of step (1) with acid, followed by addition of ice and purification with alcohol, to obtain an isatin compound of the formula ##STR87## (3) reacting the isatin compound of step (2) with an aqueous basic peroxide to form an anthranilic acid compound of the formula ##STR88## (4) reacting the anthranilic acid compound of step (3) with acetic anhydride to form an acetylanthranil compound of the formula ##STR89## (5) treating the acetylanthranil compound of step (4) with alcohol, followed by acid, to obtain a compound of the formula ##STR90## and (6) reacting the product of step (5) with chloroformamidine hydrochloride to obtain a quinazoline compound of the formula ##STR91##
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][C:33]1([CH3:40])[O:37][C@@H:36]([CH2:38]O)[CH2:35][O:34]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:32][C:33]1([CH3:40])[O:37][C@@H:36]([CH2:38][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:35][O:34]1
Reactant: CC1(C)OC[C@H](CO)O1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](CON2C(=O)c3ccccc3C2=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
A 3-L round-bottomed flask equipped with mechanical stirrer and additional funnel was charged with N-hydroxyphthalimide (68.0 g, 0.416 mol) and tetrahydrofuran (1.2 L) under nitrogen atmosphere. To this solution was added triphenylphosphine (109.2 g, 0.416 mol) and the product of Preparation 1, Step B, (S)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (55.0 g, 0.416 mol). The mixture was cooled to 3° C. to 5° C. and diethyl azodicarboxylate (85.2 mL, 0.541 mol) was added dropwise, while keeping the inner temperature below 15° C. The reaction mixture was warmed to ambient temperature, and stirred for 18 hours. The tetrahydrofuran was evaporated under reduced pressure. To the remaining orange solid was added dichloromethane (0.5 L) and the mixture was stirred for 1 hour. The white solid (Ph3PO) was filtered and washed with dichloromethane (0.1 L). The solvent was removed and ethanol (0.5 L) was added to the resulting solid. The mixture was stirred for 2 hours at 3° C. to 5° C. The white solid was filtered, washed with a small amount of cold ETOH, and dried in vacuum oven at 40° C. to give (R)-2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isoindole-1,3-dione (112.5 g, 97%) as a white solid: 1H NMR (CDCl3): δ 1.33 (s, 3H), 1.99 (s, 3H), 3.96 (m, 1H), 4.15 (m, 2H), 4.30 (m, 1H), 4.48 (m, 1H), 7.59 (m, 2H), 7.84 (m, 2H); MS (APCI+)=278 (M++1).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:8]2[N:9]=[C:10]([S:13][CH3:14])[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>C1COCC1.O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([N:15]2[C:8]3[N:9]=[C:10]([S:13][CH3:14])[N:11]=[CH:12][C:7]=3[CH:6]=[C:5]2[C:3]([OH:4])=[O:2])=[CH:17][CH:18]=1
Reactant: COC(=O)c1cc2cnc(SC)nc2n1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ncc2cc(C(=O)O)n(-c3ccc(F)cc3)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7-(4-fluorophenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester, 23, (3.1 g, 9.7 mmol) in THF (40 mL) is added a solution of NaOH (3.9 g, 97.0 mmol) in water (30 mL). The reaction is allowed to stir for 3 hours at room temperature before the mixture is diluted with H2O and extracted three times with EtOAc. The aqueous phase is acidified slowly to pH 1-2 with conc. HCl and then extracted three times with EtOAc. The combined organic phases are rinsed with brine, dried (MgSO4), filtered, and concentrated in vacuo to afford 2.5 g of the desired product which was used without further purification: 1H NMR (300 MHz, d6-DMSO) δ 9.06 (s, 1H), 7.44 (s, 1H), 7.52 (dd, J=8.2, 5.9 Hz, 2H), 7.38 (t, J=8.7 Hz, 1H), 2.44 (s, 3H); ESI+ MS: m/z (rel intensity) 304.0 (100, M++H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[C:29]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:30]=[CH:31][C:26]([S:23]([N:22]2[CH2:21][CH2:20][S:19][CH:18]2[C:16]([NH:15][CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:17])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Product: O=C(NC(CCN1CCCC1)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method A as outlined in Example 16, starting from 3-({[3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and pyrrolidine, the title compound was obtained in 99.2% purity by HPLC.
Reaction SMILES: [O:1]=[C:2]1[C:5](=O)[C:4]([NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[C:3]1[O:16]CC.[F:19][C:20]([F:27])([C:23]([F:26])([F:25])[F:24])[CH2:21][NH2:22]>C(O)C>[O:1]=[C:2]1[C:3](=[O:16])[C:4]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=2)=[C:5]1[NH:22][CH2:21][C:20]([F:27])([F:19])[C:23]([F:26])([F:25])[F:24]
Reactant: CCOc1c(Nc2ccc(C#N)cc2)c(=O)c1=O
Reactant: NCC(F)(F)C(F)(F)F
Solvent: CCO
Product: N#Cc1ccc(Nc2c(NCC(F)(F)C(F)(F)F)c(=O)c2=O)cc1
Yield: 71 %

Procedure:
4-(3,4-Dioxo-2-ethoxy-cyclobut-1-enylamino)-benzonitrile (1 g, 4.1 mmol) and 2,2,3,3,3-pentafluoropropylamine (3 mL) in ethanol were refluxed for 24 hours. The reaction mixture was filtered and the resulting solid was triturated with diethyl ether to give 1.0 g (71%) of 4-[3,4-dioxo-2-(2,2,3,3,3-pentafluoro-propylamino)-cyclobut-1-enylamino]-benzonitrile as a yellow solid: mp 272°-275° C. (dec); 1H NMR (DMSO-d6): δ10.15 (br s, 1H), 8.19 (br s, 1H), 7.81 (d, 2H), 7.79 (d, 2H), 4.54 (dt, 2H). IR (KBr): 3185, 2239, 1804, 1672, 1608, 1565, 1548 cm-1 ; MS (m/z) 346 ([M+H]+).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH3:3].Cl.Cl.N[OH:14].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].Cl[C:33](Cl)(Cl)[CH:34]([OH:36])O>O.C(O)C>[CH3:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:9][CH:10]=1)[NH:8][C:33](=[O:14])[C:34]2=[O:36])[CH3:3]
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: NO
Reactant: CC(C)c1ccc(N)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)c1ccc2c(c1)C(=O)C(=O)N2
Temperature: 80 °C

Procedure:
4-(1-Methylethyl)-aniline (6.75 g) was dissolved in water (30 ml) containing concentrated hydrochloric acid (4.4 ml). Hydroxylamine hydrochloride (16.9 g) in water (48 ml) and sodium sulphate decahydrate (100 g) in water (120 ml) were added, followed by chloral hydrate (16.5 g) in ethanol (180 ml). The reaction mixture was heated under reflux for 3 hours, then poured into water. The solid isonitroso-acetanilide intermediate was collected by filtration, washed and dried. This material was cooled in an ice-salt bath and concentrated sulphuric acid (48 ml) was added dropwise with stirring. After addition was complete the mixture was warmed to 80° C. for 20 minutes and then poured onto crushed ice. The resulting red solid was collected by filtration, washed, dried and then recrystallised from toluene-light petroleum to give the title compound, m.p. 127°-129° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>CN(C=O)C.CCOC(C)=O>[CH2:22]([O:24][C:25](=[O:30])[C:26]([O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15])[CH:9]=1)([CH3:28])[CH3:27])[CH3:23]
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 70 °C
Reaction time: 0.12 h

Procedure:
To a solution of (3-Hydroxy-phenyl)-carbamic acid tert-butyl ester (2.4 g, 11.4 mmol) in 5 ml of dry DMF, anhydrous potassium carbonate (7.9 g, 57.416 mmol) was added. The mixture stirred for 5-10 minutes, added ethyl-2-bromo-isobutyrate (4.5 g, 22.9 mmol). The resulting mixture was heated at 70° C. for 12 hours. Upon completion (˜25 h), the solution was diluted with EtOAc (25 ml) and washed with saturated NH4Cl (5 ml). The aqueous layer was then extracted for two additional times with EtOAc (10 ml) and the combined organic fractions were washed with brine (2×5 ml). The solution was then dried over Na2SO4 and concentrated to give brown oil. Purification on silica gel (hexanes/acetone) yielded 1.8 g (49%). 1H-NMR (400 MHz, CDCl3): δ 1H NMR (400 MHz, CDCl3): 1.26 (t, J=7.2 Hz, 3H), 1.50 (s, 9H), 1.59 (s, 6H), 6.43 (s, 1H), 6.47-6.50 (m, 1H), 6.96 (t, J=8.4 Hz, 2H), 7.11 (t, J=8.0, 1H).