Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-:4])(=[O:3])=[O:2]>O>[OH2:2].[S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
An aliquot (1.5 g, 2.2 mmol) of the tosylate anhydrous form 1 salt form of the compound of Formula I prepared above was combined with 9.0 mL of water in a sealed container for 3 days producing a scum-like material. The scum-like material was collected, broken apart, and combined with an additional 15 mL of water, producing a slurry. The slurry was shaken at 25° C. and 350 RPM for six days producing a wet cake. An additional 45 mL of water was added to the wet cake, producing a slurry, which was shaken at 25° C. and 350 RPM for five days. After the shaking period had ended the resulting solids were collected by vacuum filtration and dried under vacuum at room temperature overnight, providing the tosylate hydrate Form I salt form of the compound of Formula I.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1.[N:15]([O-:17])=[O:16].[Na+].[I-].[K+]>C(OCC)(=O)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(F)c2c1C=CCO2
Reactant: O=N[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(F)c2c1C=C([N+](=O)[O-])CO2
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
Into a reactor, equipped with a mechanic stirrer and a reflux condenser, 8-fluoro-2H-chromene-5-carboxylic acid amide (2 g; 10 mmoles), sodium nitrite (1.4 g; 20 mmoles), potassium iodide (0.33 g; 2 mmoles) and ethyl acetate (20 ml) were charged at room temperature and under inert gas. The mixture was heated at 40° C., then Oxistrong 15® (4 ml) was added in 4 hours. At the end of the addition the reaction mixture was kept under stirring for 1.5 hours, then cooled at 20° C. and diluted with ethyl acetate up to complete dissolution (about 150 ml). After washing with a 20% sodium metabisulphite solution, the phases were separated. The organic phase was washed with a saturated sodium chloride solution, dried and the solvent was removed under reduced pressure, obtaining 8-fluoro-3-nitro-2H-chromene-5-carboxylic acid amide (1.8 g; titre 88%; 66% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH:10]2[CH2:15][N:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][CH2:12][N:11]2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:6][CH:5]=1)([O-])=O.CO.[Sn].[OH-].[Na+]>O.C(OCC)(=O)C>[C:16]1([N:14]2[CH2:13][CH2:12][N:11]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:10]([CH2:9][O:8][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:30][CH:29]=3)[CH2:15]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(OCC2CN(c3ccccc3)CCN2Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Agent: [Sn]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Nc1ccc(OCC2CN(c3ccccc3)CCN2Cc2ccccc2)cc1

Procedure:
Dissolve 2-[(4-nitrophenoxy)methyl]-4-phenyl-1-(phenylmethyl)piperazine (7.15 g, 17.7 mmol) in a 1/1 mixture of methanol and ethyl acetate (350 mL) and add tin II chloride dihydrate (20.0 g, 88.6 mmol). Stir the mixture and heat the reaction to reflux. Monitor the progress of the reaction by thin-layer chromatography and add more tin II chloride dihydrate as needed. Upon completion of the reaction, pour reaction mixture into water (200 mL) and add 4N sodium hydroxide to pH=12. Extract with a solution of ethyl acetate/methanol (2/1) (2×200 mL). Wash the combined extracts with water (200 mL) and remove the solvent in vacuo. Flash chromatograph the residue on flash silica gel (250 g) with an ethyl acetate/hexanes [gradient (1/1-1/0)] to give the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.I[C:11]1[CH:12]=[N:13][N:14]([CH3:19])[C:15]=1[C:16]([OH:18])=[O:17]>>[C:8]([C:6]1[N:7]=[C:2]([C:11]2[CH:12]=[N:13][N:14]([CH3:19])[C:15]=2[C:16]([OH:18])=[O:17])[CH:3]=[CH:4][CH:5]=1)#[N:9]
Reactant: N#Cc1cccc(Br)n1
Reactant: Cn1ncc(I)c1C(=O)O
Product: Cn1ncc(-c2cccc(C#N)n2)c1C(=O)O
Yield: 0.5 %

Procedure:
Using 6-bromopicolinonitrile (0.73 g) and 4-iodo-1-methyl-1H-pyrazole-5-carboxylic acid (1 g), the title compound (4.7 mg) was obtained in the form of a colorless solid by the same method as that of (Example 3.22) <Step 1> or a method equivalent thereto.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Cl-].[Cl-].[Al+3].C([O-])(=O)C.[K+]>ClC(Cl)C>[C:16](=[C:17]1[CH:18]=[C:19]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[C:2]([CH3:1])=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:4]3)[CH:20]=[CH:21][CH2:22]1)=[O:23]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C
Reactant: O=C(Cl)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1[nH]c2cccc(C3=CC(=C=O)CC=C3)c2c1C
Yield: 38.7 %

Procedure:
To a solution of ethyl 3-methyl-indole-2-carboxylate (1.5 g, 7.9 mmol) and dichloroethane (20 mL) was added a solution of benzoyl chloride (2.23 g, 15.9 mmol) and dichloroethane (10 mL). Anhydrous aluminum trichloride (2.1 g, 15.8 mmol) was added in one portion and the reaction mixture was heated to reflux for 4 hours. The mixture was then poured over ice and neutralized with potassium acetate. The organic layer was separated, washed with a 5% solution of NaHCO3 and dried over MgSO4. The organic solution was then filtered, concentrated and subjected to silica gel chromatography with ethyl acetate--hexanes mixtures as eluent to provide the title compound (0.94 g). Recrystallization from benzene gave a yellow solid (mp 180-181° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:30][CH3:31])([C:27](O)=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56].[H-].[Na+].Cl>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:25][CH3:26])([C:27]([NH:58][S:55]([CH3:54])(=[O:57])=[O:56])=[O:28])[CH2:30][CH3:31])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Br)ccc12)C(=O)O
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Br)ccc12)C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
A solution of racemic (2′S,3S,4′R)-6-bromo-4′-[5-chloro-2-(1-ethyl-1-hydroxycarbonyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (480 mg, 0.75 mmol) and CDI (242 mg, 1.5 mmol) in DMF (5 mL) was heated at 60° C. for 2 h. Then to this solution was added a mixture of methanesulfonamide (712 mg, 7.5 mmol) and NaH (300 mg, 60%, 7.5 mmol) in DMF (5 mL), which had been stirred at room temperature for 2 h. After the resulting mixture was stirred at room temperature for 1 h, it was poured into water and the aqueous solution was acidified by concentrated HCl solution. After the aqueous phase was extracted with EtOAc twice, the combined organic layers were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (300 mg).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][OH:7])(=[O:3])[CH3:2].N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][Cl:19])=[O:16]>O1CCCC1>[C:15](=[O:16])([O:17][CH2:18][Cl:19])[O:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2]
Reactant: O=C(Cl)OCCl
Reactant: CC(=O)NCCO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)NCCOC(=O)OCCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.4 %

Procedure:
To a mixture of 2-acetylaminoethanol (20.0 g), pyridine (15.3 g) and tetrahydrofuran (100 ml), a solution of chloromethyl chloroformate (25.2 g) in tetrahydrofuran (50 ml) was added dropwise under ice cooling over the period of 30 minutes. After stirring at room temperature for 16 hours, the resulting solid was removed off by filtration and washed with tetrahydrofuran (30 ml). The filtrate and the washing were combined, and concentrated under reduced pressure. To the residue, ethyl acetate (300 ml) and water (100 ml) were added and the organic layer was separated. The aqueous layer was extracted twice with a mixture of ethyl acetate (150 ml) and tetrahydrofuran (50 ml). The organic layers were combined, washed with a saturated sodium chloride aqueous solution (100 ml), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by subjecting to silica gel chromatography (silica gel 240 g, eluent: ethyl acetate-hexane=1:1→ethyl acetate) to obtain [2-(acetylamino)ethyl] chloromethyl carbonate (32.4 g) as a colorless oil.
Reaction SMILES: C(O)(=O)C.[Cl:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=1.[CH2:18]1[C:23](=[O:24])[O:22][CH2:21][C:19]1=O.O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[C:19]1[CH2:21][O:22][C:23](=[O:24])[CH:18]=1
Reactant: ClCCCNCc1ccc(Cl)nc1
Reactant: O=C1COC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: O
Product: O=C1C=C(N(CCCCl)Cc2ccc(Cl)nc2)CO1
Yield: 40.8 %

Procedure:
4.26 ml (74.4 mmol) of acetic acid are added to 16.30 g (74.4 mmol) of 3-chloro-N-[(6-chloropyridin-3-yl)methyl]propan-1-amine (IVa-1 cf. also B. Latli et al. J. Med. Chem. 1999, 42, 2227-2234) in 300 ml of benzene, and the mixture is stirred at room temperature for 30 minutes. 9.68 g (96.7 mmol) of tetronic acid and 128 mg of 4-toluenesulphonic acid are then added, and the mixture is heated under reflux on a water separator for 2 hours. The reaction mixture is concentrated under reduced pressure, the residue is then taken up in the solvent mixture dichloromethane:methanol (95:5) and the mixture is washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated sodium chloride solution and dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl acetate gives 9.15 g (33% of theory) of 4-[(3-chloropropyl)[(6-chloropyridin-3-yl)methyl]amino]furan-2(5H)-one.
Reaction SMILES: COC(C1SC([C:22]([F:25])([F:24])[F:23])=C(C#N)C=1C1C=CC(C(C)(C)C)=CC=1)=O.[CH2:26]([O:28][C:29]([C:31]1[S:32][C:33](I)=[C:34]([C:50]#[N:51])[C:35]=1[C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[S:48][CH3:49])=[CH:38][CH:37]=1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1[S:32][C:33]([C:22]([F:25])([F:24])[F:23])=[C:34]([C:50]#[N:51])[C:35]=1[C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[S:48][CH3:49])=[CH:38][CH:37]=1)=[O:30])[CH3:27]
Reactant: COC(=O)c1sc(C(F)(F)F)c(C#N)c1-c1ccc(C(C)(C)C)cc1
Reactant: CCOC(=O)c1sc(I)c(C#N)c1-c1ccc(-c2ccccc2SC)cc1
Product: CCOC(=O)c1sc(C(F)(F)F)c(C#N)c1-c1ccc(-c2ccccc2SC)cc1

Procedure:
Using a method substantially in accordance with the method of 3-(4-tert-butyl-phenyl)-4-cyano-5-trifluoromethyl-thiophene-2-carboxylic acid methyl ester starting with the compound, 4-cyano-5-iodo-3-(2′-methylsulfanyl-biphenyl-4-yl)-thiophene-2-carboxylic acid ethyl ester gives the title compound: 1H NMR (400 MHz, CDCl3) δ 7.82-7.47 (m, 8H), 4.27 (q, 2H, J=7.2 Hz), 2.38 (s, 3H), 1.22 (t, 3H, J=7.3 Hz).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:76][CH:77]1[CH2:82][CH2:81][N:80]([CH2:83][CH3:84])[CH2:79][CH2:78]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26]([NH:76][CH:77]5[CH2:82][CH2:81][N:80]([CH2:83][CH3:84])[CH2:79][CH2:78]5)=[O:28])=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN1CCC(N)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)O)cc3F)ncc21
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CCC(NC(=O)c2cc(F)c(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)cc2F)CC1
Reaction time: 0.17 h
Yield: 70.2 %

Procedure:
To a mixture of 0.0606 g (0.134 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-benzoic acid (I-232) and 4 mL of dimethylformamide was added 0.0292 g (0.216 mmole) of 1-hydroxybenzotriazole, 0.0784 g (0.207 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1083 g (0.804 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0256 g (0.20 mmole) of 4-amino-1-ethylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.053 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethyl-piperidin-4-yl)-2,5-difluoro-benzamide (I-234) as a white solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([NH2:35])=[N:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[CH:23][CH:22]=3)[N:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:36]([O:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][C:51](Cl)=[O:52])=[CH:46][CH:45]=1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]([NH:35][C:51](=[O:52])[CH2:50][C:47]3[CH:46]=[CH:45][C:44]([O:43][Si:36]([C:39]([CH3:41])([CH3:40])[CH3:42])([CH3:37])[CH3:38])=[CH:49][CH:48]=3)=[N:17][CH:18]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:29])[CH3:30])=[CH:25][CH:26]=3)[N:20]=2)=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 81.1 %

Procedure:
Under an argon atmosphere, to a mixture of 3,5-bis[4-(tert-butyldimethylsilyloxy)phenyl]pyrazin-2-amine (7j) (591 mg, 1.16 mmol) and 4-(dimethylamino)pyridine (15.7 mg, 129 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 15 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=4/1) to give Compound 11j (714 mg, 945 μmol, 81.1%) as a yellow foamy solid. Rf=0.37 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.14 (s, 6H), 0.19 (s, 6H), 0.20 (s, 6H), 0.92 (s, 9H), 0.95 (s, 18H), 3.47 (s, 2H), 6.71-6.78 (2AA′BB′, 4H), 6.94-7.02 (AA′BB′, 2H), 7.03-7.13 (AA′BB′, 2H), 7.57-7.63 (AA′BB′, 2H), 8.03-8.10 (AA′BB′, 2H), 8.91 (s, 1H), 10.49 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.5 (6C), 17.9 (3C), 25.5 (9C), 41.7, 119.3 (2C), 119.5 (2C), 120.3 (2C), 127.9, 128.1 (2C), 128.9, 129.3 (2C), 130.4 (2C), 130.7, 136.9, 142.4, 147.2, 147.8, 153.8, 155.7, 156.7, 169.3; IR (KBr, cm−1) 523, 637, 677, 710, 781, 804, 839, 914, 1009, 1078, 1105, 1169, 1258, 1362, 1402, 1416, 1441, 1472, 1510, 1605, 1667, 2857, 2886, 2928, 2955, 3036, 3221; HRMS (ESP) m/z 778.3853 ([M+Na]+, C42H61N3NaO4Si3+ requires 778.3862).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[C:5]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:4]=2[C:3]=1[F:23].[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCCCCC>[CH:24]1([S:27]([N:11]2[C:5]3[C:6]4[O:10][CH:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]([F:23])[C:4]=3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:12]2=[O:22])(=[O:29])=[O:28])[CH2:26][CH2:25]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: O=c1[nH]c2c3ocnc3c(F)c(F)c2n1-c1ccc(I)cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=c1n(-c2ccc(I)cc2F)c2c(F)c(F)c3ncoc3c2n1S(=O)(=O)C1CC1
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
TEA (78 mg, 0.55 mmol) and DMAP (10 mg) were added to a solution of 4,5-difluoro-6-(2-fluoro-4-iodo-phenyl)-6,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazol-7-one (I-15a: 80 mg, 0.178 mmol) in dry DCM (5 mL) at 0° C. and the resulting mixture was stirred for 15 minutes. This was followed by the addition of cyclopropanesulfonyl chloride (39 mg, 0.27 mmol) and stirring was continued for a further 3 hours at room temperature. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to afford the crude product. Purification by column chromatography on silica gel (20-30% ethyl acetate in hexane) afforded 65 mg of the product (65% yield). H1NMR (CDCl3, 300 MHz): δ 8.14 (s, 1H), 7.72-7.65 (m, 2H), 7.28-7.24 (m, 1H), 3.35-3.25 (m, 1H), 1.75-1.60 (m, 2H), 1.35-1.25 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([SH:11])[C:5](=[O:10])[N:6]([CH2:8][CH3:9])[CH:7]=1.Cl[CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].C(N(C(C)C)CC)(C)C.O>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([S:11][CH2:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[C:5](=[O:10])[N:6]([CH2:8][CH3:9])[CH:7]=1
Reactant: O=C(CCl)Nc1ccccc1
Reactant: CCn1cc(Cl)nc(S)c1=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1cc(Cl)nc(SCC(=O)Nc2ccccc2)c1=O
Yield: 50 %

Procedure:
200 mg (1.05 mM) of 5-chloro-1-ethyl-3-mercaptopyrazin-2(1H)-one, 178 mg (1 mM) of 2-chloro-N-phenylacetamide and 135.6 mg (1.05 mM) of diisopropylethylamine in 5 ml of tetrahydrofurane were stirred overnight at room temperature. Water was added and the precipitate was filtered and washed with water, to give 170 mg of 2-[(6-chloro-4-ethyl-3-oxo-3,4-dihydropyrazin-2-yl)thio]-N-phenylacetamide. Yield: 50%.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[CH:43]=[C:44]([CH3:47])[CH:45]=[CH:46][C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: Cc1ccc(F)c(B(O)O)c1
Product: Cc1ccc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@@H](F)CO3)c(N)s2)c1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-5-methylphenyl)boronic acid gave 274. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 7.90 (d, J=7.4 Hz, 1H), 7.82 (s, 1H), 7.41 (br, 2H), 7.24 (d, J=8.8 Hz, 2H), 5.09-4.68 (m, 2H), 4.22-3.97 (m, 2H), 3.74 (s, 3H), 2.36 (s, 3H), 2.23-2.12 (m, 1H), 1.88-1.73 (m, 2H), 1.68-1.63 (m, 3H). LCMS (ES+) m/z 463 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:5][C:6]1[CH:22]=[CH:21][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.N1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:5][C:6]1[CH:22]=[CH:21][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:38](=[O:40])[CH3:39])=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(O)cc1)O2)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OC(C)=O)cc1)O2)NC(=O)OC(C)(C)C
Reaction time: 2.5 h

Procedure:
To a solution of (S)-2-tert-Butoxycarbonylamino-3-[(S)-2-(4-hydroxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-propionic acid methyl ester (240 mg) in DCM (10 mL) was added pyridine at 0° C. To this mixture was added acetic anhydride. The mixture was stirred for 2-3 h. After completion of the reaction, the mixture was diluted with DCM (50 mL) and was washed with water, 1N HCl and brine solution. The organic layer was dried and concentrated to get the desired product as a white solid (208 mg). LCMS (m/z): 473
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:9])[C:6](Cl)=[O:7])(=[O:3])[CH3:2].[C:10]1([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12][CH:11]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:4][CH:5]([CH3:9])[C:6](=[O:7])[C:11]1[CH2:12][CH2:13][CH2:14][C:10]=1[N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)(=[O:3])[CH3:2]
Reactant: C1=C(N2CCCC2)CCC1
Reactant: CC(=O)OC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)OC(C)C(=O)C1=C(N2CCCC2)CCC1
Yield: 95.2 %

Procedure:
Add dropwise a solution of 1-chloro-1-oxopropan-2-yl acetate (600 g, 3.98 mol) in toluene (1200 mL) to a solution of 1-cyclopent-1-enyl-pyrrolidine (546.7 g, 3.98 mol) and triethyl amine (483.9 g, 4.78 mol) in toluene (2400 mL). Reflux the mixture for overnight. Filter the mixture and concentrate the filtration to give crude 1-oxo-1-(2-(pyrrolidin-1-yl)cyclopent-1-enyl)propan-2-yl acetate (952 g), which is used in next step without further purification. 1H NMR (CDCl3, 400 MHz): δ 5.27 (m, 1H), 3.56 (m, 2H), 3.16 (m, 2H), 2.83 (m, 1H), 2.58 (m, 3H), 2.10 (s, 3H), 1.93 (m, 2H), 1.82 (m, 4H), 1.36 (d, J=7.2, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[CH:9][CH2:10]CCC.BrC1C=NC=CC=1C=O>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[CH:9][CH3:10]
Reactant: CCCCC=Cc1ccncc1Br
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=Cc1ccncc1Br
Agent: [Br-]
Product: CC=Cc1ccncc1Br

Procedure:
Following the general method as outlined in Intermediate 12, starting from 3-bromo-4-pyridinecarboxaldehyde (Aldrich) and ethyltriphenylphosphonium bromide, the title compound (mixture of cis and trans isomers) was obtained as a colorless liquid after purification by flash column chromatography, eluting with cyclohexane containing increasing amounts of EtOAc.