Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:31]2[CH:36]=[CH:35][C:34](Br)=[CH:33][CH:32]=2)[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])(=[O:21])=[O:20])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:39][C:40]1[CH:45]=[CH:44][C:43](OB(O)O)=[CH:42][CH:41]=1.O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:38])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:31]2[CH:36]=[CH:35][C:34]([C:43]3[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=3)=[CH:33][CH:32]=2)[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])(=[O:21])=[O:20])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN(c2ccc(Br)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN(c2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cs1
Yield: 89.5 %

Procedure:
2-{[4-(2-{(4-Bromophenyl)[(2-nitrophenyl)sulfonyl]amino}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (1.2 g) synthesized in Example 256-1 and 4-fluorophenylboric acid (0.31 g) were dissolved in dioxane (10 mL) and 2 mol/L sodium carbonate (5 mL), tetrakis(triphenylphosphine)palladium (0.11 g) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1 to 2:1) to give the title compound (1.1 g) as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:8]=2[N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[S:6]1(=[O:24])=[O:23].[CH3:25][NH2:26].Cl>>[F:15][C:12]1[CH:13]=[CH:14][C:8]2[N:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[S:6](=[O:24])(=[O:23])[N:5]([CH2:4][CH2:3][CH2:2][NH:26][CH3:25])[CH2:10][C:9]=2[CH:11]=1
Reactant: CN
Reactant: O=S1(=O)N(CCCBr)Cc2cc(F)ccc2N1c1ccccc1F
Agent: Cl
Product: CNCCCN1Cc2cc(F)ccc2N(c2ccccc2F)S1(=O)=O
Yield: 68 %

Procedure:
In an analogous manner to Example 111 step 5, 3-(3-bromopropyl)-6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.1 g, 0.25 mmol) was reacted to methylamine and then treated with HCl to provide 3-[6-fluoro-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine (0.102 g, 68%) as a white solid:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CI.[C:14]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:2]=1[Cl:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(C)nc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
2-Chloro-6-methyl-nicotinic acid (3.58 g, 20.86 mmol) was dissolved in DMF (34 mL). MeI (5.8 mL, 93.88 mmol) and K2CO3(7.78 g, 56.33 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. The reactant was distilled under reduced pressure to remove the solvent and extracted with EtOAc. The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent EtOAc/Hex=1/2) to obtain the title compound (3.68 g, 94%).
Reaction SMILES: [NH:1]1[C@@H:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]2[NH:3][CH:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)=[CH:12][CH:11]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]1[C@@H:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]2[NH:3][CH:2]1[C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][NH2:18])=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C2N[C@@H]3CCCC[C@H]3N2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc(C2N[C@@H]3CCCC[C@H]3N2)cc1

Procedure:
tert-butyl (2-{4-[(3aR,7aR)-octahydro-1H-benzimidazol-2-yl]phenyl}ethyl)carbamate (50 mg, 0.15 mmol) was stirred in a 4:1 mixture of DCM:TFA (1 mL) at ambient temperature for 18 h. The reaction was concentrated in vacuo and the crude product used without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3]1.P(Cl)(Cl)Cl.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[NH2:29])=[CH:24][C:20]=1[C:21](O)=[O:22]>N1C=CC=CC=1>[CH:7]1([N:4]2[CH2:5][CH2:6][CH:2]([NH:1][C:21](=[O:22])[C:20]3[CH:24]=[C:25]([S:28](=[O:30])(=[O:31])[NH2:29])[CH:26]=[CH:27][C:19]=3[O:18][CH3:17])[CH2:3]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)O
Reactant: NC1CCN(C2CCCCC2)C1
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Product: COc1ccc(S(N)(=O)=O)cc1C(=O)NC1CCN(C2CCCCC2)C1
Reaction time: 1 h

Procedure:
To 3.7 g. (0.022 mole) of 3-amino-1-cyclohexylpyrrolidine in 100 ml. of pyridine was added dropwise with cooling 1.1 g. (0.008 mole) of phosphorous trichloride at 20°C. After stirring one hour, 3 g. (0.013 mole) of 2-methoxy-5-sulfamoylbenzoic acid was added and refluxed 6 hrs. The solution was concentrated and the residue partitioned between dilute hydrochloride acid and isopropyl ether. The acid was made basic with ammonium hydroxide and extracted with chloroform which was dried (sodium sulfate) and concentrated. The residue was crystallized from ethyl acetate and recrystallized from isopropyl alcohol. Yield 1 g. (33%); m.p. 184°-187°C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:12]=2)=[CH:4][CH:3]=1.[C:30]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([C:34]1[CH:39]=[CH:38][C:37]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:9][C:10]([C:21]4[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=4)=[C:11]([C:13]4[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=4[Cl:20])[N:12]=3)=[CH:4][CH:3]=2)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: O=[N+]([O-])c1ccc(-c2[nH]c(-c3ccc(Br)cc3)nc2-c2ccc(Cl)cc2Cl)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)cc4Cl)c(-c4ccc([N+](=O)[O-])cc4)[nH]3)cc2)cc1

Procedure:
2-(4-Bromo-phenyl)-4-(2,4-dichloro-phenyl)-5-(4-nitro-phenyl)-1H-imidazole (prepared according to general procedure A) (979 mg, 2 mmol) was treated as described in general procedure G using 4-tert-butylphenylboronic acid (712 mg, 4 mmol) to give 2-(4′-tert-butyl-biphenyl-4-yl)-4-(2,4-dichloro-phenyl)-5-(4-nitro-phenyl)-1 H-imidazole, which was treated as described in general procedure L using 2-(trimethylsilyl)ethoxymethyl chloride (0.7 mL, 4 mmol) to give 2-(4′-tert-butyl-biphenyl-4-yl)-4-(2,4-dichloro-phenyl)-5-(4-nitro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1)(=[S:3])[NH2:2].Cl[CH:17]([CH:20]=O)[CH:18]=[O:19].C(=O)([O-])[O-].[Mg+2]>O1CCOCC1>[CH:18]([C:17]1[S:3][C:1]([CH:4]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]2)=[N:2][CH:20]=1)=[O:19]
Reactant: O=CC(Cl)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)C1
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(C=O)s2)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
tert-Butyl 3-carbamothioylpyrrolidine-1-carboxylate (5 g, 21.71 mmol), 2-chloromalonaldehyde (3.70 g, 34.7 mmol) and magnesium carbonate (1.830 g, 21.71 mmol) were combined in dioxane (100 ml). The mixture was heated to 60° C. for 3 hours, stirred overnight at room temperature and then filtered through a pad of diatomaceous earth, rinsing with dichloromethane. The filtrate was concentrated in vacuo and then purified by normal phase chromatography to provide the title compound.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N+:27]([C:30]1[CH:67]=[CH:66][C:33]([CH2:34][O:35][C:36]([N:38]2[CH2:42][CH2:41][CH2:40][C@H:39]2[C:43]([C:45]2[N:46]=[CH:47][N:48]3[CH:52]=[C:51]([Sn](CCCC)(CCCC)CCCC)[S:50][C:49]=23)=[O:44])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:8]([C:51]3[S:50][C:49]4=[C:45]([C:43]([C@@H:39]5[CH2:40][CH2:41][CH2:42][N:38]5[C:36]([O:35][CH2:34][C:33]5[CH:66]=[CH:67][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=5)=[O:37])=[O:44])[N:46]=[CH:47][N:48]4[CH:52]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)[C@@H]3CCCN3C(=O)OCc3ccc([N+](=O)[O-])cc3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)[C@@H]5CCCN5C(=O)OCc5ccc([N+](=O)[O-])cc5)c4s3)[C@H](C)[C@H]12
Yield: 73.6 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[(2S)-1-(4-nitrobenzyloxycarbonyl)-pyrrolidin-2-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (1.40 g) was prepared in the same manner as in step a) of Example 1, except that 926 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.85 g of 7-[(2S)-1-(4-nitrobenzyloxycarbonyl)-pyrrolidin-2-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: Cl.[CH2:2]([C:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:8][C:7]=2[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=1)[CH3:3].Cl.Br[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:2]([C:4]1[C:12]2[C:7](=[N:8][C:9]([CH:14]3[CH2:15][CH2:16][N:17]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:18][CH2:19]3)=[N:10][C:11]=2[OH:13])[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=1)[CH3:3]
Reactant: Brc1ccncc1
Reactant: CCc1nn(-c2ccccc2)c2nc(C3CCNCC3)[nH]c(=O)c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1nn(-c2ccccc2)c2nc(C3CCN(c4ccncc4)CC3)nc(O)c12
Temperature: 130 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-ethyl-1-phenyl-6-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrochloride (200 mg, 0.56 mmol, 1.00 equiv) in N,N-dimethylformamide (40 mL) at room temperature. To the resulting mixture was then added 4-bromopyridine hydrochloride (131 mg, 0.68 mmol, 1.10 equiv), in portions at room temperature, followed by triethylamine (188 mg, 1.86 mmol, 3.00 equiv), in portions at room temperature. The resulting solution was stirred overnight at 130° C. The resulting mixture was concentrated under vacuum. The resulting residue (150 mg) was purified by Prep-HPLC with the following conditions (Gilson Pre-HPLC): Column, SHISEIDO, CAPCELL PAK C18, 20 mm ID*250 mm, 5 u; mobile phase, methanol/H2O; Detector, UV 254 nm, to yield 3-ethyl-1-phenyl-6-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1.Br[CH2:14][C:15]1[CH:35]=[CH:34][C:18]2/[C:19](=[C:29](/[CH2:32][CH3:33])\[C:30]#[N:31])/[C:20]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=3[O:22][CH2:23][C:17]=2[CH:16]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:20]2=[C:21]([CH:24]=1)[O:22][CH2:23][C:17]1[CH:16]=[C:15]([CH2:14][N:8]3[C:7]4[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=4[N:5]=[C:4]3[CH2:3][O:2][CH3:1])[CH:35]=[CH:34][C:18]=1/[C:19]/2=[C:29](/[CH2:32][CH3:33])\[C:30]#[N:31]
Reactant: COCc1nc2ccccc2[nH]1
Reactant: CC/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: CC/C(C#N)=C1/c2ccc(Cn3c(COC)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 100.3 %

Procedure:
Using 2-(methoxymethyl)-1H-benzo[d]imidazole (61 mg, 0.376 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]butanenitrile (140 mg, 0.376 mmol) obtained in Reference Example 8, and in the same manner as in Reference Example 1A, the title compound (171 mg, 100%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:15][CH3:16])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:28][CH2:29][CH:30]=[C:31]1[C:37]2[CH:38]=[CH:39][CH:40]=[N:41][C:36]=2[CH2:35][O:34][C:33]2[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:15][CH3:16])[CH:9]2[CH2:14][CH2:13][N:12]([CH2:28][CH2:29][CH:30]=[C:31]3[C:37]4[CH:38]=[CH:39][CH:40]=[N:41][C:36]=4[CH2:35][O:34][C:33]4[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]3=4)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CCN(c1ccc(Cl)cc1)C1CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: CCN(c1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 80 °C
Reaction time: 14 h
Yield: 33.8 %

Procedure:
To a solution of the (4-chloro-phenyl)-ethyl-piperidin-4-yl-amine (0.150 g, 0.63 mmol) in isopropanol was added 2,6-lutidine (0.24 mL, 2.1 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.221 g, 0.6 mmol), added in portions over 1 h. The solution was then stirred at 80° C. for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanol/85% methylene chloride) to yield the title compound (0.108 g, 34%). 1H-NMR (CDCl3): δ 1.12 (t, 3H), 1.57 (s, 6H), 2.67-2.80 (m, 4H), 2.00 (m, 2H), 2.34-2.41 (m, 2H), 2.43-2.54 (m, 2H), 2.88 (d, 2H), 3.22 (q, 2H), 3.37-3.51 (m, 1H), 5.28 (bs, 2H), 6.12 (t, 1H), 6.60 (d, 2H), 6.80 (d, 1H), 7.13 (d, 2H), 7.21-7.30 (m, 2H), 7.45 (s, 1H), 7.56 (d, 1H), 8.48 (dd, 1H). ESI-MS m/z: 532 (M+1), retention time 2.47.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH2:61])=[N:58][C:57]=1[CH3:62])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH:64]1([C:69](Cl)=[O:70])[CH2:68][CH2:67][CH2:66][CH2:65]1>>[CH3:1][O:2][C:3](=[O:63])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61][C:69]([CH:64]2[CH2:68][CH2:67][CH2:66][CH2:65]2)=[O:70])=[N:58][C:57]=1[CH3:62])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: O=C(Cl)C1CCCC1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(=O)C2CCCC2)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(S)-7-(2-amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (30 mg) was reacted with cyclopentanecarbonyl chloride according to General Procedure F to furnish (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-7-[2-(cyclopentanecarbonyl-amino)-4-methyl-thiazole-5-sulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester. This ester (25 mg), upon hydrolysis according to General Procedure B, gave the title compound (21 mg). LCMS (m/z): 1009.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4](P(OCC)(OCC)=O)[CH3:5].[H-].[Na+].[C:17]([O:21][C:22]([C:24]1[S:25][C:26]([CH:29]=O)=[CH:27][CH:28]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[C:17]([O:21][C:22]([C:24]1[S:25][C:26](/[CH:29]=[C:4](/[C:3]([O:2][CH3:1])=[O:14])\[CH3:5])=[CH:27][CH:28]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOP(=O)(OCC)C(C)C(=O)OC
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C(C)=C/c1ccc(C(=O)OC(C)(C)C)s1
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
2-(Diethylphosphono)propanoic acid methyl ester (23.0 g, 0.103 mol) was dissolved in tetrahydrofuran (150 mL), 60% sodium hydride (2.4 g, 0.06 mol) was added at 0° C., and the mixture was stirred for 30 minutes. To the reaction mixture was added a solution of 5-formyl-2-thiophenecarboxylic acid tert-butyl ester obtained in Example 1, step 2 (11.0 g, 0.052 mol) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was partitioned between ethyl acetate and 1N-hydrochloric acid solution, and washed successively with water and brine. After drying over anhydrous magnesium sulfate, the residue was purified by silica gel column chromatography to give the title compound (13.1 g, 0.047 mol, 90%).
Reaction SMILES: [CH:1]([C:4]([CH:15]([CH3:17])[CH3:16])=[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[O:6][CH3:7])([CH3:3])[CH3:2].[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl.C(N(CC)CC)C>[C:18]([O:14][C:10]1[CH:9]=[C:8]([C:5]([O:6][CH3:7])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:15]([CH3:17])[CH3:16])[CH:13]=[CH:12][CH:11]=1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=C(C(C)C)C(C)C)c1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=C(C(C)C)C(C)C)c1cccc(OC(=O)C(C)(C)C)c1
Reaction time: 3 h

Procedure:
Alkene 1b (2 g, 8.6 mmol) was dissolved in 50 mL of dry CH2Cl2 with 2.4 mL of anhydrous triethylamine. The flask was purged with argon and cooled in an ice bath. Pivaloyl chloride (1.6 g, 2 eq.) was added dropwise over one hour. The cooling bath was removed and stirring continued for 3 hours at room temperature. The solution was washed with aq. K2CO3 and then water, dried over MgSO4 and evaporated. The residue was purified by column chromatography on silica gel, eluting with 5% triethylamine in hexane yielding 1.95 g of dioxetane 1e: 1H NMR (CDCl3) δ 7.34-6.98 (m, 4H), 3.198 (s, 3H), 2.47 (sept, 1H), 2.33 (sept, 1H), 1.36 (s, 9H), 1.24 (d, 6H, J=6.9 Hz), 0.92 (d, 6H, J=6.9 Hz).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1.[CH2:50]([SH:54])[CH2:51][CH2:52][CH3:53].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:50]([S:54][C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:22][N:23]=[N:24][N:25]=3)=[CH:13][CH:14]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1)[CH2:51][CH2:52][CH3:53]
Reactant: CCCCS
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCSc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 55 %

Procedure:
A mixture of 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.5 g), butylmercaptan (0.1 ml) and potassium carbonate (0.13 g) in acetonitrile (10 ml) was heated under reflux for 3 hours with stirring. The insoluble material was removed from the reaction mixture by filtration and the filtrate was concentrated to dryness. The resulting residue was dissolved in methanol (15 ml) and then 1N hydrochloric acid (1.5 ml) was added to the solution, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless powders (0.2 g, 55%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 100 °C
Yield: 86.4 %

Procedure:
Combine [2-(4-Hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.0 g, 4.2 mmol), 4-fluoronitrobenzene (0.6 g, 4.2 mmol), cesium carbonate (2.7 g, 8.4 mmol), and N,N-dimethylformamide (35 mL), stir and heat at 100° C. for 18 hours. Cool to room temperature and evaporate on a rotary evaporator to yield the crude product (9.5 g). The crude product is purified by flash column chromatography on silica gel eluting with (10% conc. ammonium hydroxide in ethanol) and chloroform to yield {2-[4-(4-nitro-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.3 g): 1H NMR (CDCl3, 300.00 MHz): 8.23 (d, 2H, J=9.2 Hz), 7.32-7.25 (m, 2H), 7.10-7.00 (m, 4H), 4.63 (s, 1H), 3.43 (m, 2H), 2.86 (t, 2H, J=7.0 Hz), 1.48 (s, 9H). Step 3 {2-[4-(4-Amino-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[C:7]([CH:8]=O)[C:6]([OH:11])=[CH:5][CH:4]=1.[NH:12]1[C:19](=O)[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[S:14].CS(O)(=O)=O>C(O)CCC>[CH2:2]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:19]3[NH:12][C:13](=[S:14])[NH:15][C:16](=[O:17])[C:18]=3[CH2:8][C:7]=2[CH:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=C1CC(=O)NC(=S)N1
Reactant: O=Cc1cc(CO)ccc1O
Agent: CS(=O)(=O)O
Solvent: CCCCO
Product: CCCCOCc1ccc2c(c1)Cc1c([nH]c(=S)[nH]c1=O)O2
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxymethyl-salicylaldehyde (5.8 g.) and 2-thiobarbituric acid (6 g.) in n-butanol (100 ml.) add methanesulfonic acid (10 ml.) and heat to reflux, with stirring, for 1 hour. Cool, filter and wash the solid with ethanol and ether to yield 7-n-butyloxymethyl-(1H,3H,5H)-(1)-benzopyrano-(2,3-d)-pyrimidine-4-one-2-thione.