Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]2)=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:25]([O:24][C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]2)=[C:6]([F:8])[CH:7]=1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cn(-c2ccc(N)cc2F)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cn(-c2ccc(NC(=O)OCc3ccccc3)cc2F)cn1
Reaction time: 16 h
Yield: 92.9 %

Procedure:
5-Amino-2-(4-methylimidazol-1-yl)fluorobenzene (50.6 g, 0.265 M) was dissolved in dry dichloromethane (800 ml) under nitrogen, and cooled to −5°. Pyridine (26.1 g, 0.33 M) was added, followed by benzyl chloroformate (49.9 g, 0.292 M) over 30 minutes. The mixture was stirred and the temperature allowed to rise to ambient over 16 hours. Aqueous sodium bicarbonate (5%, 350 ml) was added, the organic layer separated, and the aqueous layer re-extracted with dichloromethane (2×200 ml), and combined organics dried (magnesium sulfate). After filtration and evaporation, the residue was recrystallised from toluene (300 ml) to give title product (80 g).
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([N:14]2[CH2:18][C@@H:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:15]2[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[F:41])=[O:13])=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:40][C:36]1[C:35]([F:41])=[C:34]([C@@H:15]2[C@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:18][N:14]2[C:12]([NH:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:42])=[O:2])=[CH:9][CH:8]=2)=[O:13])[CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)c1ccc(CNC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C[C@@H]1CN(C(=O)NCc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-benzoic acid methyl ester (108.0 mg, 0.18 mmol) in THF/MeOH (0.6 mL/0.2 mL) was added 4 N LiOH (0.2 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 NH2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to 4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-benzoic acid (101.2 mg, 95.9%). FIRMS (ES+) m/z Calcd for C31H29Cl2F2N3O3+H [(M+H): 600.1627; Found: 600.1629.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH:11]([C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH:21]=1)[CH2:19]Cl)([CH3:13])[CH3:12].Cl>C1COCC1.CCCCCC>[CH:11]([C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH2:19][CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH3:10])=[O:8])[CH:21]=1)([CH3:13])[CH3:12]
Reactant: COc1ccc(C(C)C)cc1CCl
Reactant: COC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)CC(=O)CCc1cc(C(C)C)ccc1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 108.5 %

Procedure:
To a stirred suspension of sodium hydride (60% oil suspension, 0.44 g,11 mmol) in THF (25 ml) was added methyl acetoacetate (1.08 ml, 10 mmol) dropwise at 0° C. After 10 min stirring at 0° C., n-buthyllithium (1.31M in hexane, 8 ml, 10.5 mmol) was added to the reaction mixture at 0° C. To this orange color solution was added a solution of 5-isopropyl-2-methoxybenzyl chloride (1.99 9, 10 mmol) in THF (5 ml) at 0° C. After 40 min stirring at 0° C. to room temperature, the reaction mixture was poured into 1N HCl (20 ml) and extracted with ethyl acetate. The extract combined was dried (MgSO4) and concentrated to give 3.02 g of yellow oil, which was purified by column chromatography on silica gel (hexane/ethyl acetate: 10/1 as eluent) to afford 1.55 g (55.8%) of title compound as yellow oil.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[CH2:26][NH:27][NH2:28]>C(O)C>[NH2:10][C:6]1[NH:28][N:27]([CH2:26][C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[F:23])[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1ccccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccccc2F)[nH]1
Reaction time: 2 h

Procedure:
30.2 g of β-amino-β-ethoxyacrylic acid ethyl ester together with 2 g of p-toluenesulphonic acid were dissolved in 300 ml of ethanol and 27.1 g of o-fluorobenzylhydrazine were added under nitrogen. After stirring for 2 hours, the mixture was left to stand overnight and the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 146°, 11 g (27%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]([F:21])([F:20])[S:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([S:12][C:11]([F:21])([F:10])[F:20])[CH:14]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1cccc(SC(F)(F)F)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1Nc1cccc(SC(F)(F)F)c1

Procedure:
In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-(trifluoromethylthio)aniline were reacted to provide 2-chloro-5-fluoro-N4-[3-(trifluoromethylthio)phenyl]-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.13 (bs, 1H), 7.92 (bs, 1H), 7.89-7.84 (m, 1H), 7.48-7.45 (m, 2H), 7.04 (bs, 1H); LCMS: purity: 97%; MS (m/e): 325 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[C:6]([Br:12])[CH:5]=1.[C:14](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:14])=[C:6]([Br:12])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(F)c(O)c(Br)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(F)c(OC)c(Br)c1
Reaction time: 96 h

Procedure:
6 g (24.09 mmol) of the product obtained in step 1 were dissolved in 60 ml of acetone, 10.13 g (2.270 mmol) of potassium carbonate and 6.84 g (48.18 mmol) of iodomethane were added, and the mixture was stirred for 4 days. Then is was filtered and evaporated. The resulting product (5.8 g) was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[N:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:21])=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:21])=[N:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2ccc(OC)nc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2ccc(OC)nc2c1Cl
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 6-methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester (110.0 g, 407.67 mmol, 1.0 eq) in phosphorus oxychloride (650 mL) is refluxed for 4 hours. Then the reaction mixture is cooled to room temperature and the solvent is evaporated. The residue is poured into ice water and the resulting mixture is basified with 25% ammonium hydroxide to pH=8-9 and extracted with ethyl acetate (3×500 mL). The combined organic layers are dried over sodium sulfate, filtered and evaporated to give a brown solid as crude product, which is then purified by column chromatography (silica gel, eluent: ethyl acetate:petroleum ether, 1:4, v/v) to afford 4-chloro-6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester as a light yellow solid (78 g, 62% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([S:6][C:7]3[CH:8]=[C:9]([C:17]([OH:19])=O)[CH:10]=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O.CN(C)C=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([S:6][C:7]3[CH:8]=[C:9]([C:17]([Cl:22])=[O:19])[CH:10]=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1ccc2sc3cc(C(=O)O)ccc3c(=O)c2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1ccc2sc3cc(C(=O)Cl)ccc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
The 7-methyl-9-oxothioxanthene-3-carboxylic acid (MTA), 50.0 g (0.185 mol), was dissolved in 350 ml of toluene and 415 ml (5.69 mol) of thionyl chloride using an overhead stirrer in a 2 liter 3-neck round bottom flask. N,N-Dimethylformamide (DMF), 2 ml, was added and the reaction was brought to reflux for 2 hours. After this time, the mixture was stirred at room temperature for 16 hours. The solvent was removed under vacuum and the product was azeotroped with 3×350 ml of toluene to remove the excess thionyl chloride. The product was recrystallized from 800 ml of chloroform and the resulting solid was placed in a vacuum oven for 16 hours at 45° C. to complete removal of solvent. The isolated product weighed 45.31 g (85% yield) and nuclear magnetic resonance spectroscopy (NMR) confirmed the desired structure. This product was used for the preparation of a photoreactive monomer as described in Example 2.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20]>OS(O)(=O)=O>[Br:8][C:18]1[CH:17]=[C:13]([CH:12]=[C:11]([N+:19]([O-:21])=[O:20])[C:10]=1[F:9])[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(Br)c(F)c([N+](=O)[O-])c1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
NBS (47.9 g, 0.268 mol) was added portion-wise to a solution of 4-fluoro-3-nitro-benzoic acid (41.5 g, 0.224 mol) in conc. H2SO4 (0.35 L). The reaction mixture was stirred for 5 h at 65° C. and then poured into ice-water (1.5 L). The precipitate was filtered off, washed twice with water (300 mL) and dried to give the title compound as a white solid. 1H-NMR (300 MHz, CDCl3): δ (ppm) 10.7 (s, br, 1H), 8.76 (m, 1H), 8.62 (m, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([Sn](C)(C)C)[N:10]=1.[Br:15]C1SC=C(Br)N=1.C1(S)C=CC=CC=1.[OH-].[Na+]>C(O)C.O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([Br:15])[N:10]=1
Reactant: C[Sn](C)(C)c1csc(-c2cccs2)n1
Reactant: Brc1csc(Br)n1
Agent: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Brc1csc(-c2cccs2)n1
Temperature: 45 °C
Yield: 84 %

Procedure:
Synthesis of 2-Thiophenyl-4-(trimethylstannyl)thiazole 381 as illustrated in FIG. 53. 2,4-Dibromothiazole (358; 1.0 equiv) was dissolved in ethanol (0.1 M) and treated with thiophenol (3.0 equiv) and solid sodium hydroxide (3.0 equiv). The reaction mixture was heated at 45° C. for 4 h, upon which completion of the reaction was indicated by TLC. The mixture was poured into water and extracted with ether (2×). Drying (MgSO4) and evaporation of the solvents gave 2-thiophenyl-4-bromothiazole 380, which was isolated after flash column chromatography (silica gel, 5% EtOAc in hexanes) in 84% yield.
Reaction SMILES: C[C:2]([C:4]([C:14]([CH3:16])=[O:15])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[Cl:13])=O.C1(C)C=CC(S([CH2:26][N+:27]#[C-])(=O)=O)=CC=1.C[O-].[Na+].O>CO>[CH3:16][C:14]([C:4]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=2[Cl:13])=[CH:26][NH:27][CH:2]=1)=[O:15]
Reactant: CC(=O)C(=Cc1cccc(Cl)c1Cl)C(C)=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)c1c[nH]cc1-c1cccc(Cl)c1Cl
Yield: 50 %

Procedure:
With stirring, 20 g of 1,1-di(methylcarbonyl)-2-(2,3-dichlorophenyl)ethene are added at 0° C. to 65 g of a 23.2% by weight solution of (p-tolylsulfonyl)methyl isocyanide prepared according to Example P1 (a). Then 28.1 g of a 30 % solution of sodium methylate in methanol are added dropwise over 3 hours. The mixture is stirred for 60 minutes at a temperature of +10° C. and then 170 ml of water are added dropwise and the product is subsequently isolated by filtration. The filter residue is recrystallised from a 1:1 mixture of methanol/ethanol and dried under vacuum, affording 8.3 g (50% of theory) of 4-methylcarbonyl-3-(2,3-dichlorophenyl)pyrrole which melts at 192°-194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH:13][CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH3:12]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:13]([CH2:11][CH3:12])[CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=1)([OH:20])[C:16]([F:17])([F:19])[F:18])=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1Cl

Procedure:
Prepared similarly to Example 1 from 2-chlorobenzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].Br[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[F:22]>CN(C=O)C>[F:22][C:14]1[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=1[CH:4]([C:3]([O:10][CH3:11])=[O:9])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1ccc(Br)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
To a suspension of sodium hydride (NaH, 60%, 0.40 g, 10.0 mmol) in dry DMF (10 mL) under ice cooling was added dimethyl malonate (1.04 mL, 9.1 mmol) dropwise followed by a solution of 1-bromo-2-fluoro-4-nitrobenzene (1.00 g, 4.55 mmol) in dry DMF (3 mL) under an argon atmosphere. The resulting mixture was stirred at 70° C. overnight and then allowed to cool to 21° C. The reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate (2×50 mL). The organic layer was dried over MgSO4, concentrated and the residue was purified with silica gel column chromatography (hexane:ethyl acetate, 2:1) to give Dimethyl 2-(2-fluoro-4-nitrophenyl)malonate (86) (0.90 g, 73%) as a light yellowish solid: 1H NMR δ 8.07 (dd, 1H, J=8.6, 2.2 Hz), 7.98 (dd, 1H, J=9.3, 2.2 Hz), 7.74 (dd, 1H, J=8.6, 7.1 Hz), 5.08 (s, 1H), 3.81 (s, 6H).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][C@H:21]([CH2:23]O)[N:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:19][C@H:18]1[CH3:32])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:22][C@H:21]([CH2:23][F:7])[N:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:19][C@H:18]1[CH3:32])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CO)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](CF)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a stirred solution of diethylaminosulfur trifluoride (0.32 mL, 0.393 g, 2.44 mmol) in DCM (2 mL) at −78° C. under nitrogen was added a solution of (2R,5R)-4-benzyl-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.651 g, 2.03 mmol) in DCM (6 mL). Mixture was stirred at −78° C. for 0.5 h then at 20° C. for 3 h. Mixture was poured into saturated aqueous sodium hydrogen carbonate (100 mL) and ice (20 g) then extracted with DCM (3×50 mL). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-40% Et2O in 40-60 petroleum ether) gave the title compound (0.393 g) as an oil. MS: [M+H]+=323.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[O:4][CH2:5][CH2:6]Br.[C:13]1([N:19]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:20](=O)[CH2:21][CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[O:4][CH2:5][CH2:6][N:27]1[CH2:28][CH2:29][CH:24]([N:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:20][CH2:21][CH3:22])[CH2:25][CH2:26]1
Reactant: Cc1cccc(C)c1OCCBr
Reactant: CCC(=O)N(c1ccccc1)C1CCNCC1
Product: CCCN(c1ccccc1)C1CCN(CCOc2c(C)cccc2C)CC1
Yield: 79.7 %

Procedure:
Using the procedure described in Example I and starting from 12.7 g (2,6-dimethylphenoxyethyl) bromide and 12.8 g 4-(N'-phenyl-N'-propionylamino)-piperidine, 16.1 g of the title product are obtained melting at 82° after recrystallization from hexane. Mixing the compound with 4-(N'-phenyl-N'-propionylamino)-piperidine depresses the melting point.
Reaction SMILES: [O:1]=[C:2]1[O:3][CH2:4][CH2:5]/[C:6]/1=[CH:7]/[C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[S:21](Cl)(=[O:23])=[O:22].[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[CH2:33][O:32][B:31]([OH:34])[C:30]=2[CH:35]=1.N1C=CC=CC=1>O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>[F:17][C:16]([F:19])([F:18])[C:15]([NH:14][C:12]1[CH:11]=[CH:10][C:9]([S:21](=[O:23])(=[O:22])[NH:25][C:26]2[CH:27]=[CH:28][C:29]3[CH2:33][O:32][B:31]([OH:34])[C:30]=3[CH:35]=2)=[C:8](/[CH:7]=[C:6]2\[C:2](=[O:1])[O:3][CH2:4][CH2:5]\2)[CH:13]=1)=[O:20]
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: O=C1OCC/C1=C/c1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Cl
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: c1ccncc1
Product: O=C1OCC/C1=C/c1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
The crude intermediate (Z)-2-((2-oxodihydrofuran-3(2H)-ylidene)methyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (2.85 g, 10 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (1.5 g, 10 mmol) was suspended in CAN (50 ml), followed by the addition of pyridine (3 ml) dropwise. After stirred at rt for 3 hrs, the mixture was poured into ice-H2O and extracted with EtOAc, washed with H2O, brine, dried over MgSO4, filtered, concentrated in reduced pressure to dryness. The crude product was treated with DCM to give (Z)-2,2,2-trifluoro-N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-3-((2-oxodihydrofuran-3(2H)-ylidene)methyl)phenyl)acetamide as a solid (3.4 g). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.63 (s, 1H), 10.34 (s, 1H), 9.18 (s, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 7.87 (dd, J=8.4, 1.6 Hz, 1H), 7.82 (t, J=2.8 Hz, 1H), 7.34 (d, J=1.6 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.07 (dd, J=8.4, 1.6 Hz, 1H), 4.85 (s, 2H), 4.28 (t, J=7.2 Hz, 2H), 2.88 (dt, J=2.8, 7.2 Hz, 2H). MS (ESI) m/z=495 (M−1).
Reaction SMILES: [NH2:1][C:2]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)=[S:3].Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O>[N:4]1([C:2]2[S:3][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:1]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: NC(=S)N1CCOCC1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(N2CCOCC2)n1
Yield: 55.2 %

Procedure:
A mixture of 1.85 g (12.7 mmol) of 4-((amino)thiocarbonyl)morpholine, 1.59 ml (12.7 mmol) of ethyl bromopyruvate, and excess MgSO4 in 50 ml of acetone was heated at reflux for 2 h. The resulting mixture was allowed to cool, filtered, and concentrated in vacuo. The residue was taken up in chloroform, washed with aqueous NaHCO3, dried over Na2SO4, and concentrated. Silica gel chromatography using 1% methanol in chloroform provided 1.7 g (55%) of the desired compound, Rf 0.70 (ethyl acetate). Mass spectrum: (M+H)+ =243.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35]([N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:36])[CH3:39]
Reactant: CCOC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: CCOC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A138) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[C:14](Br)=[CH:13][C:12]([Cl:16])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:21]=1)#[CH:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[C:14]([C:19]#[C:18][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:21]=2)=[CH:13][C:12]([Cl:16])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1ncc(Cl)cc1Br
Reactant: C#Cc1cccc(S(=O)(=O)CCC)c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)c1cccc(C#Cc2cc(Cl)cnc2OCC(=O)OC(C)(C)C)c1
Temperature: 90 °C

Procedure:
A mixture of tert-butyl[(3-bromo-5-chloropyridin-2-yl)oxy]acetate (Intermediate 182; 160 mg; 0.50 mmol), 1-ethynyl-3-(propane-1-sulfonyl)-benzene (Intermediate 42; 155 mg; 0.74 mmol), bis(triphenylphosphine)palladium (II) chloride (10 mg; 0.01 mmol) and triphenylphosphine (26 mg; 0.10 mmol) is treated with cuprous iodide (3 mg; 0.01 mmol) and TEA (1.10 ml) and heated at 90° C. in a sealed vessel for 15 hours. The mixture was diluted with EtOAc and washed with a saturated NH4Cl solution and brine. The organic phase was dried over MgSO4, concentrated to dryness under reduced pressure affording a sticky solid, which was purified by column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc, affording the title compound as a yellow sticky solid
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:9][S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:9][S:8][C:7]=1[N:18]1[C:22](=[O:23])[C:21]2[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:24])=[O:5])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)csc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccccc2Cl)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(2-chlorophenyl)-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 8, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization from petroleum ether affords the desired product.