Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23]C(OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:42][CH2:43][C:44]([CH3:47])([OH:46])[CH3:45].[OH-].[K+]>O1CCCC1.CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:42][CH2:43][C:44]([OH:46])([CH3:47])[CH3:45])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(O)CCBr
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](SCCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a solution of 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (81.6 mg, 0.140 mmol) and 4-bromo-2-methyl-2-butanol (117 mg, 0.700 mmol) in tetrahydrofuran (1 ml) was added 1M KOH solution in methanol (1 ml), and the mixed solution was stirred at room temperature for 30 minutes, then concentrated under reduced pressure. The residue was diluted with hexane, washed with brine and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane:ethyl acetate=8:1, developed once) to give the title compound as a colorless oil (60.3 mg, 79%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH3:8])[C:6]=1[CH3:7].[OH:16][C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:20]=[CH:21][CH:22]=1.N>O.CC(O)C.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:8][N:5]1[C:6]([CH3:7])=[C:2](/[N:1]=[C:20]2\[CH:21]=[CH:22][C:17](=[O:16])[CH:18]=[C:19]\2[NH:23][C:24](=[O:26])[CH3:25])[C:3](=[O:15])[N:4]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Reactant: CC(=O)Nc1cccc(O)c1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: N
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)NC1=CC(=O)C=C/C1=N\c1c(C)n(C)n(-c2ccccc2)c1=O

Procedure:
10 mmol of 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was dissolved in 30 ml of water. This solution was admixed with 10 mmol of N-(3-hydroxyphenyl)acetamide in solution in 30 ml of 2-propanol, 3 ml of 20% aqueous ammonia and 22 mmol of potassium ferricyanide at a temperature ranging from 5 to 10° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[I:15]I>C(O)C.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[C:7]([NH2:10])=[C:8]([I:15])[CH:9]=1
Reactant: COC(=O)c1ccc(N)c([N+](=O)[O-])c1
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COC(=O)c1cc(I)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 4-amino-3-nitro-benzoic acid methyl ester (4.6 g, 23.45 mmol) in ethanol (120 mL) was added iodine (8.33 g, 32.83 mmol), followed by Ag2SO4 (10.24 g 32.83 mmol). The mixture was stirred overnight at room temperature and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography to give 4.98 g (66%) of 4-amino-3-iodo-5-nitro-benzoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11]C[C:9]2=[O:15])=[O:7])=[CH:4][CH:3]=1.C1(=O)NCCCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C:9]2=[O:15])=[O:7])=[CH:16][CH:17]=1
Reactant: O=C1CCCCCN1C(=O)c1ccc(Cl)cc1
Agent: O=C1CCCCN1
Product: O=C1CCCCN1C(=O)c1ccc(Cl)cc1

Procedure:
Synthesized as for N-(4-chlorobenzoyl)caprolactam (Example XXIX using valerolactam (Aldrich) in place of caprolactam.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:30]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)#[CH:31]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][CH:29]=[C:4]([N:1]3[CH:31]=[C:30]([C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: C#Cc1cccnc1
Reactant: COc1c(NC(=O)c2cccc(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2cccc(-n3cc(-c4cccnc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 16 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-benzamide and 3-ethynyl pyridine in the same manner as Example 15. ESI MS m/z 521 [C26H28N6O4S+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]([CH3:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:14])[CH3:15])[C:9]([CH3:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][N+:6]([O-:25])=[CH:7]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OC(C)C)cc(Br)c2ccncc12
Solvent: ClCCl
Product: Cc1c(OC(C)C)cc(Br)c2cc[n+]([O-])cc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 76.9 %

Procedure:
To a solution of 5-bromo-8-methyl-7-(propan-2-yloxy)isoquinoline (108e, 1.60 g, 5.71 mmol) in DCM (40 mL) was added m-CPBA (1.47 g, 8.56 mmol) and the reaction mixture was stirred at room temperature for 10 hours. The reaction mixture was washed with NaHSO3 (aq., 2×20 mL), 10% aq. NaOH (2×20 mL) and brine (2×10 mL), dried over Na2SO4, and concentrated under vacuum to give 5-bromo-8-methyl-7-(propan-2-yloxy)isoquinoline 2-oxide (108f, 1.3 g, 77%) as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24](F)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH:32]1[C:36]2=[N:37][CH:38]=[CH:39][C:40]([CH2:41][NH2:42])=[C:35]2[CH:34]=[CH:33]1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24]([NH:42][CH2:41][C:40]4[CH:39]=[CH:38][N:37]=[C:36]5[NH:32][CH:33]=[CH:34][C:35]=45)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3F)ccc2C(C)(C)C1
Reactant: NCc1ccnc2[nH]ccc12
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc2C(C)(C)C1
Reaction time: 0.33 h

Procedure:
A mixture of 7-[(2-fluoro-pyridine-3-carbonyl)-amino]-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.99 g, 4.98 mmol) and C-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine, dihydrochloride (1.79 g, 8.14 mmol), DIEA (6 mL), and t-butanol (9 mL) in 3 microwave vials was subjected to 170° C., 1200 s of microwave. The combined mixture was concentrated and purified by column chromatography (Biotage, 0 to 7% MeOH with 10% NH4OH in CH2Cl2) to afford the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:30]=[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=1)[C:18]1[O:19][C:20]2[C:25]([C:26](=[O:28])[CH:27]=1)=[CH:24][CH:23]=[C:22]([OH:29])[CH:21]=2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:41][CH:42](Br)[CH3:43]>CN(C)C=O>[Br:41][CH2:42][CH2:43][O:29][C:22]1[CH:21]=[C:20]2[C:25]([C:26](=[O:28])[CH:27]=[C:18]([C:17]3[CH:16]=[C:15]([O:14][CH2:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:32]=[C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:30]=3)[O:19]2)=[CH:24][CH:23]=1
Reactant: CC(Br)Br
Reactant: O=c1cc(-c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)oc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)oc2cc(OCCBr)ccc12
Reaction time: 0.5 h

Procedure:
Potassium carbonate (2.76 g, 20 mmol) was added to a stirred solution of 3′,5′-dibenzyloxy-7-hydroxy-flavone, 22 (2.25 g, 5 mmol) in dry dimethyl formamide (120 mL). After the mixture was stirred for 30 min, dibromo ethane (5 mL, 58 mmol) was added and the resultant was stirred at room temperature for 12 h. Reaction mixture was filtered through celite, concentrated under reduced pressure and extracted with chloroform. The extract was washed with water, dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford 56.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([OH:27])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl.[N:29]([C@H:32]1[CH2:36][C@H:35]([NH2:37])[C@@H:34]([CH3:38])[CH2:33]1)=[N+:30]=[N-:31]>>[N:29]([C@@H:32]1[CH2:36][C@@H:35]([NH:37][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([CH:12]([F:14])[F:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:27])[C@H:34]([CH3:38])[CH2:33]1)=[N+:30]=[N-:31]
Reactant: C[C@H]1C[C@@H](N=[N+]=[N-])C[C@@H]1N
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1C[C@@H](N=[N+]=[N-])C[C@H]1C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and (1S*,2S*,4R*)-4-azido-2-methylcyclopentanamine hydrochloride (example C34) the title compound is obtained as pale yellow foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]=[C:15]([O:25][C@@H:26]4[CH2:30][O:29][C@@H:28]5[C@H:31]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:32][O:33][C@H:27]45)[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:11]3=[CH:10][C:9]=2[Cl:42])=[CH:4][CH:3]=1.[C:43]([CH:45]1[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]1)#[CH:44]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[Si:35]([O:34][C@H:31]1[C@H:28]2[O:29][CH2:30][C@@H:26]([O:25][C:15]3[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:11]4[C:12]([N:14]=3)=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([C:44]#[C:43][CH:45]5[CH2:46][CH2:47][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49][CH2:50]5)=[CH:7][CH:6]=3)=[C:9]([Cl:42])[CH:10]=4)[C@H:27]2[O:33][CH2:32]1)([C:38]([CH3:40])([CH3:41])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(Br)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2ccc(-c3nc4nc(O[C@@H]5CO[C@H]6[C@@H]5OC[C@H]6O[Si](C)(C)C(C)(C)C)n(COCC[Si](C)(C)C)c4cc3Cl)cc2)CC1
Temperature: 25 °C

Procedure:
To a round bottom flask fitted with a reflux condenser under a nitrogen atmosphere was added 5-(4-bromophenyl)-2-(((3R,3aR,6R,6aS)-6-((tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (436 mg, 0.625 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (157 mg, 0.750 mmol), CuI (9.5 mg, 0.049 mmol), and Pd(PPh3)2Cl2 (70 mg, 0.100 mmol). Then triethylamine (4.0 mL) was added. The reaction mixture was cooled to −78°, evacuated and placed under an inert nitrogen atmosphere. Then the mixture was warmed to room temperature, and heated to 50° C. for 17 h. The mixture was allowed to cool to room temperature, and then filtered through Celite™ and rinsed with ethyl acetate until the filtrate was colorless. The filtrate was concentrated under reduced pressure. Flash silica gel chromatography of the resulting residue utilizing a Biotage™ 50 G SNAP cartridge and employing a linear gradient: 0-30% EtOAc in 1:1 Hexane/DCM over 20 column volumes afforded the desired product as a clear, colorless oil following concentration under reduced pressure. LC-MS: calculated for C42H61ClN4O7Si2 824.38, observed m/e: 825.60 (M+H)+ (Rt 3.32/4 min)
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C@@H:8]2[CH2:11][CH2:10][C@H:9]2[C:12]([OH:14])=O)=O)=[CH:4][CH:3]=1.[NH:17]([CH2:19][CH:20]([OH:23])[CH2:21][CH3:22])[NH2:18].C1(C)C=CC=CC=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[CH:8]3[CH:9]([C:12](=[O:14])[N:17]([CH2:19][CH:20]([OH:23])[CH2:21][CH3:22])[N:18]=2)[CH2:10][CH2:11]3)=[CH:15][CH:16]=1
Reactant: CCC(O)CNN
Reactant: O=C(O)[C@@H]1CC[C@H]1C(=O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(O)CN1N=C(c2ccc(Cl)cc2)C2CCC2C1=O
Temperature: 25 °C

Procedure:
Into a flask equipped with a stirrer, heating mantle and Dean - Stark water separator is charged 7.2 g (0.30 mole) of a mixture of cis-and trans-2-p-chlorobenzoylcyclobutane carboxylic acid, 3.5 g (0.033 mole) of 1-hydrazino-2-butanol and 100 ml. of toluene. The mixture is stirred and refluxed until the water layer in the Dean-Stark tube remains constant (ca. 5hr). The solvent is removed in vacuo on a rotary evaporator, and the residue is dissolved in hot diethyl ether and allowed to cool to room temperature. The resultant solid is filtered off and yields 2-(p-chlorophenyl)-4-(2-hydroxybutyl) 3,4-diazabicyclo [4.2.0]-oct-2-ene-5-one(isomer B;m.p. 133°-135°). The filtrate is further concentrated to give Isomer A (m.p. 115.5°-119° C).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:9].[OH:16][C:17]1[C:22]2[N:23]=[C:24]([NH:26][C:27](=[O:29])[CH3:28])[S:25][C:21]=2[CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:11]([NH:10][C:8](=[O:9])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:16][C:17]1[C:22]2[N:23]=[C:24]([NH:26][C:27](=[O:29])[CH3:28])[S:25][C:21]=2[CH:20]=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCNC(=O)NCCCCCBr
Reactant: CC(=O)Nc1nc2c(O)cccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCNC(=O)NCCCCCOc1cccc2sc(NC(C)=O)nc12
Temperature: 60 °C
Reaction time: 6 h
Yield: 40.6 %

Procedure:
A mixture of 1-(5-bromopentyl)-3-n-pentylurea (100 mg, 0.37 mmol), commercial N-(4-hydroxybenzo[d]thiazol-2-yl)acetamide (100 mg, 0.48 mmol), and K2CO3 (67 mg, 0.48 mmol) in DMF (5 mL) was heated at 60° C. After 6 h, the reaction mixture was cooled to rt, diluted with water (25 mL), and extracted into EtOAc (3×10 mL). The combined organic extracts were washed with water (2×5 mL), brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The residue thus obtained was purified by silica gel column chromatography to give 31 (61 mg, 40%), mp 61.6-61.8° C. TLC:EtOAc/hexane (3:2), Rf˜0.40; 1H NMR (300 MHz) δ 7.39 (dd, J=0.9, 7.3 Hz, 1H), 7.20 (dd, J=7.8, 7.3 Hz, 1H), 6.86 (dd, J=0.9, 7.8 Hz, 1H), 4.42 (br s, —NH, 2H), 4.17 (t, J=5.4 Hz, 2H), 3.19-3.30 (m, 4H), 2.33 (s, 3H), 1.82-1.98 (m, 2H), 1.64-1.80 (m, 4H), 1.42-1.60 (m, 2H), 1.24-1.40 (m, 4H), 0.88 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz) δ 170.16, 159.91, 158.94, 151.37, 139.10, 133.67, 124.40, 113.94, 108.68, 68.21, 40.64, 39.98, 30.27, 29.30, 28.33, 26.54, 23.25, 22.64, 22.33, 14.26. HRMS (ESI-neg) calcd for C20H29N4O3S [M−1]− 405.1960, found 405.1938.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:19]([CH3:20])[O:18][C:17](=[O:21])[CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1>[C:22]([O:1][CH:2]([C:15]1[CH:19]([CH3:20])[O:18][C:17](=[O:21])[CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCC(O)C1=CC(=O)OC1C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCC(OC(C)=O)C1=CC(=O)OC1C

Procedure:
4-(1-Hydroxytridecyl)-5-methyl-2(5H)-furanone (Compound 3, 329 mg, 1.11 mmol), acetic anhydride (453 mg, 4.45 mmol), triethylamine (227 mg, 2.22 mmol) and 4-dimethylaminopyridine (2 mg, 0.02 mmol ) were stirred at room temperature under argon for 3 hours in anhydrous THF (30 mL). The crude reaction mixture was concentrated and the residue was taken up in diethyl ether and washed with a 10% aqueous HCl solution, a saturated solution of sodium bicarbonate, H20 and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by flash chromatography on silica using 20% ethyl acetate/hexane to give the title compound.
Reaction SMILES: [O:1]1C(=O)C[CH2:3][C:2]1=O.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:22](=[S:23])[N:21]([C:24]3[CH:25]=[C:26]([CH3:32])[C:27]([C:30]#[N:31])=[N:28][CH:29]=3)[C:20](=[O:33])[C:16]32[CH2:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:1][CH2:2][CH2:3][O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:22](=[S:23])[N:21]([C:24]3[CH:25]=[C:26]([CH3:32])[C:27]([C:30]#[N:31])=[N:28][CH:29]=3)[C:20](=[O:33])[C:16]32[CH2:19][CH2:18][CH2:17]3)=[CH:13][CH:14]=1
Reactant: Cc1cc(N2C(=O)C3(CCC3)N(c3ccc(O)cc3)C2=S)cnc1C#N
Reactant: O=C1CCC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N2C(=O)C3(CCC3)N(c3ccc(OCCO)cc3)C2=S)cnc1C#N
Temperature: 85 °C
Yield: 70.8 %

Procedure:
Dihydrofuran-2,5-dione (604 mg, 6.87 mmol) in DMF (5 mL) was added to a mixture of 5-(5-(4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methylpicolinonitrile (500 mg, 1.37 mmol) and potassium carbonate (378 mg, 2.74 mmol) in DMF (10 mL) and the resulting mixture was heated to 85° C. overnight. The mixture was cooled to room temperature and partitioned between water and EtOAc. The aqueous was extracted further with EtOAc (2×) and the combined organics were washed with water, then brine. The organics were dried over sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (50 to 100% EtOAc/hexanes) afforded 396 mg of 5-(5-(4-(2-hydroxyethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methylpicolinonitrile as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.71 (d, 1H), 8.14 (d, 1H), 7.33 (d, 2H), 7.13 (d, 2H), 4.92 (t, 1H), 4.11-4.05 (m, 2H), 3.78-3.73 (m, 2H), 2.63-2.5 (m, 5H), 2.49-2.37 (m, 2H), 2.00-1.90 (m, 1H), 1.56-1.51 (m, 1H). LCMS [M+1]+ 409.0.
Reaction SMILES: Cl.[C:2]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:5])[NH:3][NH2:4].[C:13]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)(=O)[CH3:14].C(O)C>O>[N:19]1[CH:20]=[CH:21][C:16]([C:13](=[N:4][NH:3][C:2]([O:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:5])[CH3:14])=[CH:17][CH:18]=1
Reactant: CC(=O)c1ccncc1
Reactant: NNC(=O)Oc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(=NNC(=O)Oc1ccccc1)c1ccncc1
Yield: 53.9 %

Procedure:
A solution of 5.66 gm (0.03 mole) of phenyl carbazate hydrochloride, 3.63 gm (0.03 mole) of 4-acetylpyridine and 50 ml of ethanol is refluxed 2 hr. The solution is cooled and evaporated to dryness in vacuo to give an oil. The oil is triturated with ethyl acetate-methanol to afford a solid. The solid is dissolved in 50 ml of water and treated with 50 ml water containing 5 gm sodium carbonate. A gummy solid separates which solidifies on standing. The crude product is collected and crystallized from ethyl acetate-Skellysolve B to yield 4.13 gm (54%) of the title compound having a melting point of 120.4° C. (decomp.).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[C:26]([Br:28])[S:27][C:21]=2[N:20]=[C:19]1[CH:29]([NH:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH2:30][CH3:31])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[C:26]([Br:28])[S:27][C:21]=2[N:20]=[C:19]1[CH:29]([N:32]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:30][CH3:31])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCC(NCCN(C)C)c1nc2sc(Br)cc2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(c1nc2sc(Br)cc2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzoyl chloride (19 mg, 0.085 mmol, 1 equiv) in dichloromethane (1 mL) was added to a solution of 3-benzyl-6-bromo-2-(1-{[2-(dimethylamino)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one (2-8, 38 mg, 0.085 mmol, 1 equiv) and N,N-diisopropylethylamine (11 mg, 0.085 mmol, 1 equiv) in dichloromethane (5 mL), and the resulting reaction mixture was stirred under ambient conditions for 1 h. The reaction mixture was washed with saturated aqueous NaHCO3 solution, and brine, then dried (MgSO4) and concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide N-[1-(3-benzyl-6-bromo-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]bromo-N-[2-(dimethylamino)ethyl]benzamide (2-10) as a colorless foam. 1H NMR (500 MHz, CDCl3) δ 7.55 (m, 3H), 7.31 (m, 5H), 7.14 (m, 2H), 6.04 (d, J=15.4 Hz, 1H), 5.92 (m, 1H), 5.12 (d, J=15.4 Hz, 1H), 3.37 (m, 2H), 2.05 (m, 4 H), 1.83 (m, 6H), 0.65 (m, 3H).
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([C:9]([F:21])([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([I:22])[C:3]=1[NH2:4].[N+:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30])([O-:25])=[O:24]>>[I:1][C:2]1[CH:8]=[C:7]([C:9]([F:21])([C:14]([F:19])([F:20])[C:15]([F:16])([F:17])[F:18])[C:10]([F:11])([F:12])[F:13])[CH:6]=[C:5]([I:22])[C:3]=1[NH:4][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=1
Reactant: Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1I
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Product: O=C(Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1I)c1cccc([N+](=O)[O-])c1

Procedure:
According to the method of 4-3 of Example 4, a target compound was prepared from 2,6-diiodo-4-(perfluorobutan-2-yl)aniline and 3-nitrobenzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH:27]=[O:28])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[O-:29][Mn](=O)(=O)=O.[K+].[OH-].[K+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[C:27]([OH:29])=[O:28])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)cn(C)c34)no2)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 55 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To a solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole-3-carbaldehyde (D61) (1.4 g) in THF (20 mL) was added KMnO4 (1.1 g) and aqueous KOH (10 mL). The reaction mixture was stirred at 55° C. overnight. After cooled to room temperature, the mixture was diluted with THF (30 mL), and filtered. The filtrate was concentrated and the aqueous suspension was acidified with aqueous HCl (2 M) to pH 5-6. The resulting white solid was collected, washed with water, dried in vacuo to give the crude compound, which was purified by column chromatography (10% ethyl acetate in hexane) to afford 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole-3-carboxylic acid (D95) as a white solid (1.3 g). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 3.74 (3H, s), 4.88 (1H, m), 7.35 (1H, dd), 7.45 (1H, d), 7.53 (1H, dd), 8.12 (1H, d), 8.14 (1H, d), 8.20 (1H, d), 8.32 (1H, dd), 12.15 (1H, s). MS (ES): C21H18ClN3O4 requires 411. found 412.1 (M+H+).