Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][N:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.C([Li])CCC.[C:18]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][N:6]=1)[N:3]=[C:2]([C:18]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:11]=[CH:10]2
Reactant: O=C1CCCC1
Reactant: Clc1cc2ccc(Br)nc2cn1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: OC1(c2ccc3cc(Cl)ncc3n2)CCCC1
Temperature: -78 °C
Reaction time: 6 h

Procedure:
A suspension of 2-bromo-6-chloro-1,7-naphthyridine (300 mg, 1 mmol) in toluene (8 mL) cooled at −78° C. under an atmosphere of nitrogen was treated with n-butyllithium (1.6M solution in hexanes, 2.3 mL, 3.7 mmol) dropwise over 5 minutes. The reaction mixture was stirred at this temperature for 6 hours and then cyclopentanone (0.33 mL, 3.7 mmol) was added slowly as a solution in toluene (1.3 mL). After 15 minutes, the mixture was allowed to warm to room temperature and then quenched with a few drops of saturated aqueous ammonium chloride solution. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 12 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as an orange, waxy solid (65 mg, 20%), which was used in the next step without further purification.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[NH:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[O:16].C([O-])(=O)C.[Na+]>C(O)(=O)C>[OH:8][C:7]1[C:9]([O:10][CH3:11])=[CH:12][C:2](/[CH:1]=[C:20]2/[C:18](=[O:19])[NH:17][C:15](=[O:16])[NH:14]/2)=[CH:3][C:4]=1[O:5][CH3:6]
Reactant: O=C1CNC(=O)N1
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(/C=C2\NC(=O)NC2=O)cc(OC)c1O

Procedure:
In an acetic acid (1.6 mL) solvent, a suspension including syringaldehyde (300 mg, 1.65 mmol), hydantoin (198 mg, 1.98 mmol), and sodium acetate (405 mg, 4.94 mmol) was refluxed for 24 hours, and after cooling, the produced precipitate was filtered. The filtered solid was washed with methylene chloride and a small amount of water. After drying under reduced pressure, a target compound was obtained (192.9 mg, 44.3%).
Reaction SMILES: Cl.[OH:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:31][N:32]([CH3:36])[C:33]([Cl:35])=[O:34].C(N(CC)CC)C.O>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[ClH:35].[CH3:31][N:32]([CH3:36])[C:33](=[O:34])[O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:21](=[O:30])[C:22]4=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]4[C:24]3=[O:25])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CC[C@@H]2c3cccc(O)c3CC[C@@H]21
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)C(=O)Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCN1C(=O)c2ccccc2C1=O
Yield: 65 %

Procedure:
A mixture of 0.12 g (0.28 mol) of rac-N-[4-(cis-1,2,3a, 4,5,9b-hexahydro-6-hydroxy-3H-benzo[e]indol-3-yl)butyl]phthalimide hydrochloride, 0.03 ml (0.34 mmol) of dimethylcarbamoyl chloride, 0.05 ml (0.34 mmol) of triethylamine and 0.042 g (0.34 mmol) of 4-dimethylaminopyridine in 10 ml of toluene was boiled under reflux for 4 hours and then poured into water. The mixture was extracted with toluene, the extracts were dried with sodium sulphate and the solvent was distilled off in a vacuum. The residue was chromatographed over silica gel with methylene chloride/methanol (20:1) and then dissolved in ethanol. The solution was treated with ethanolic HCl and concentrated. The residue was dissolved in methylene chloride, ether was added thereto, the solvent was distilled off and there was obtained 0.11 g (79%) of rac-cis-2,3,3a,4,5,9b-hexahydro-3-(4-phthalimidobutyl)-1H-benzo[e]indol-6-yl dimethylcarbamate hydrochloride as a foam.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:19])[C:6]2[CH:11]=[C:10](/[CH:12]=[CH:13]/[CH2:14][O:15][CH3:16])[CH:9]=[C:8]([CH3:17])[C:7]=2[CH3:18])[CH2:3][CH2:2]1.C>CCOC(C)=O.[Pd]>[CH:1]1([NH:4][C:5](=[O:19])[C:6]2[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[C:8]([CH3:17])[C:7]=2[CH3:18])[CH2:2][CH2:3]1
Reactant: COC/C=C/c1cc(C)c(C)c(C(=O)NC2CC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCCc1cc(C)c(C)c(C(=O)NC2CC2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
N-Cyclopropyl-5-[(1E)-3-methoxy-1-propen-1-yl]-2,3-dimethylbenzamide (1 eq.) from the previous step and 10% w/w palladium over charcoal (0.05 eq.) were suspended in EtOAc (0.2 M). The vessel was then evacuated and purged with H2. Under a balloon-filled H2 atmosphere, the reaction suspension was stirred at RT for 6 h. The reaction suspension was then filtered through a bed of celite and the filtrate concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=2)[S:5][CH:6]=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>N1C=CC=CC=1.CCOC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]([C:7]2[C:8](=[O:14])[N:9]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:22])[C:10](=[O:13])[NH:11][CH:12]=2)[S:5][CH:6]=1
Reactant: Cc1csc(-c2c[nH]c(=O)[nH]c2=O)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1csc(-c2c[nH]c(=O)n(C(=O)c3ccccc3)c2=O)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 54.1 %

Procedure:
5-(4-methyl-1,3-thiazol-2-yl)-2,4(1H,3H)-pyrimidinedione (Prep41, 300 mg, 0.760 mmol) suspended in dry Pyridine (3 ml) was slowly added to a stirring solution of BENZOYL CHLORIDE (0.265 ml, 2.280 mmol) in Pyridine (1 mL) under nitrogen atmosphere. The resulting yellow solution was stirred at rt for 7 hours. Water was added (3 mL) and the mixture was extracted with EtOAc (10 mL). The organic was washed with NH4Cl saturated aqueous solution (2×2 mL) then with NaHCO3 aqueous saturated solution (1×3 mL), dried (Na2SO4, vacuo) to afford a yellow solid that was diluted in EtOAc (20 mL) and washed again with NaHCO3 aqueous saturated solution (2×5 mL), dried (Na2SO4, vacuo) to afford the title compound as a yellow solid (274 mg, 0.411 mmol) used in the next reaction step without further purification.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23]C.C(=O)(O)[O-].[Na+].[OH-].[Na+]>ClCCl>[F:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[C:16]1[C:17]([OH:23])=[CH:18][CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: COc1ccc(F)cc1-c1c(F)c(F)c(F)c(F)c1F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(F)cc1-c1c(F)c(F)c(F)c(F)c1F
Temperature: -78 °C
Reaction time: 3 h
Yield: 81.1 %

Procedure:
A 1.0 M boron tribromide solution in dichloromethane (24 mL, 24 mmol, 2.4 equiv) was added dropwise over 30 minutes, at −78° C., to a solution of compound 2 (3.0 g, 10.2 mmol, 1 equiv) in dichloromethane (100 mL). The reaction was stirred at −78° C. for 3 hours, when 1H NMR indicated that the reaction was complete. The reaction was poured into saturated sodium bicarbonate (200 mL) and the pH was adjusted to 8 with 10% sodium hydroxide. The layers were separated, then the aqueous phase was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified over silica gel (40 g), eluting with a gradient of 0 to 20% ethyl acetate in heptanes to give 2′,3′,4′,5,5′,6′-hexafluoro-[1,1′-biphenyl]-2-ol (3) (2.3 g, 80% yield) as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([CH:14]([C:16]2[C:17]([CH3:28])=[N:18][O:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)[OH:15])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:38]=[CH:39][C:40]([C:24]3[CH:23]=[CH:22][C:21]([C:20]4[O:19][N:18]=[C:17]([CH3:28])[C:16]=4[CH:14]([C:12]4[CH:11]=[CH:10][CH:9]=[C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[N:13]=4)[OH:15])=[CH:26][CH:25]=3)=[CH:41][CH:42]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cccc(Cc2ccccc2)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cccc(Cc5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using (6-benzyl-pyridin-2-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:13][CH2:14][OH:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[Cl-:16].[S:17]([CH2:36][CH2:37][NH:38][C:39](=[O:52])[CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N+:43]([CH3:50])=[C:42]1[CH3:51])[S:18][CH2:19][CH2:20][NH:21][C:22](=[O:35])[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N+:26]([CH3:33])=[C:25]1[CH3:34].[Cl-]>C(O)C.N1CCCCC1>[Cl-:16].[S:17]([CH2:36][CH2:37][NH:38][C:39](=[O:52])[CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N+:43]([CH3:50])=[C:42]1[CH:51]=[CH:9][C:8]1[CH:7]=[CH:6][C:5]([N:4]([CH2:3][CH2:2][OH:1])[CH2:13][CH2:14][OH:15])=[CH:12][CH:11]=1)[S:18][CH2:19][CH2:20][NH:21][C:22](=[O:35])[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N+:26]([CH3:33])=[C:25]1[CH:34]=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:13][CH2:14][OH:15])[CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=1.[Cl-:16]
Reactant: Cc1n(CC(=O)NCCSSCCNC(=O)Cn2c(C)[n+](C)c3ccccc32)c2ccccc2[n+]1C
Reactant: O=Cc1ccc(N(CCO)CCO)cc1
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCNCC1
Product: C[n+]1c(C=Cc2ccc(N(CCO)CCO)cc2)n(CC(=O)NCCSSCCNC(=O)Cn2c(C=Cc3ccc(N(CCO)CCO)cc3)[n+](C)c3ccccc32)c2ccccc21
Yield: 163.3 %

Procedure:
To a stirring solution of 4-[bis(2-hydroxyethyl)-amino]benzaldehyde (1.7 g, 8.1 mmol) and 1,1′-{disulfanediylbis[ethane-2,1-diylimino(2-oxoethane-2,1-diyl)]}bis(2,3-dimethyl-1H-benzimidazol-3-ium) chloride (1.2 g, 2 mmol) in 35 ml of ethanol, 0.5 ml of piperidine was added as a catalyst. The reaction mixture was heated to reflux for 7 h. After cooling, the resulting orange solids were collected by filtration and then washed with dichloromethane and methanol. The drying afforded 1.6 g of a orange solid. Analyses were in accordance with the expected structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:14][C:15]1[C:19](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:17][N:16]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:22](=[O:23])/[CH:21]=[CH:20]/[C:19]2[C:15]([CH3:14])=[N:16][O:17][C:18]=2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:7][CH:6]=1)=[O:10])[CH3:13]
Reactant: Cc1noc(-c2ccccc2)c1/C=C/C(=O)O
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(NC(=O)/C=C/c2c(C)noc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.5 %

Procedure:
A mixture of ethyl 4-aminophenylacetate (1.11 g), (E)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenoic acid (0.95 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.75 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.91 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and (E)-N-(4-ethoxycarbonylmethylphenyl)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenamide (1.82 g, yield 97%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 164–165° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Cl:7][C:8]1[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][CH:13]=1>>[Cl:7][C:8]1[CH:13]=[C:12]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: Brc1cccs1
Reactant: OB(O)c1cccc(Cl)c1
Product: Clc1cccc(-c2cccs2)c1

Procedure:
2-Bromothiophene and 3-chlorophenylboronic acid were treated in a manner similar to Reference Example 26-(2) to give 2-(3-chlorophenyl)thiophene as colorless oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17]3[N:18]=[CH:19][C:20](/[CH:23]=[CH:24]/[C:25]([OH:27])=O)=[N:21][CH:22]=3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[O:34][NH2:35].C1C=CC2N(O)N=NC=2C=1.O>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17]3[N:18]=[CH:19][C:20](/[CH:23]=[CH:24]/[C:25]([NH:35][O:34][CH:29]4[CH2:30][CH2:31][CH2:32][CH2:33][O:28]4)=[O:27])=[N:21][CH:22]=3)[CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1cnc(N[C@@H]2CCCN(CCCc3ccccc3)C2)cn1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(/C=C/c1cnc(N[C@@H]2CCCN(CCCc3ccccc3)C2)cn1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 17 h
Yield: 63.2 %

Procedure:
To a mixture of crude (2E)-3-[5-({(3R)-1-[3-phenylpropyl]- 3-piperidinyl}amino)-2-pyrazinyl] acrylic acid (345 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (166 mg), and HOBT in dichloromethane (8.6 mL) was added WSCD (271 mg), which was stirred at room temperature for 17 hours. Water was added to the resultant. The organic layer was extracted and dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel [chromatorexNH, 5 g, hexane:AcOEt=25:75) to give (2E)-3-[5-({(3R)-1-[3-phenylpropyl]-3-piperidinyl}amino)-2-pyrazinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (277 mg) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[N:4][NH:5][C:6]=1[CH:7]([CH3:9])[CH3:8].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][C:22]=1[O:36][CH3:37].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:10]([F:11])([F:13])[F:12])=[N:4][N:5]([CH2:34][C:33]([N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([O:36][CH3:37])[CH:23]=3)[CH2:32][CH2:31]2)=[O:35])[C:6]=1[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)c1[nH]nc(C(F)(F)F)c1Cl
Reactant: COc1cc(N2CCN(C(C)=O)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C(C)C)CC2)ccc1Cl

Procedure:
Protocol T was followed using 4-Chloro-5-isopropyl-3-trifluoromethyl-1-H-pyrazol, K2CO3, 1-[4-(4-Chloro-3-methoxyphenyl)-piperazine-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=5.5/4.5, Rf=0.52) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3); 7.19–7.22 (d, 2H), 6.42–6.48 (m, 2H), 5.18 (s, 2H), 3.88 (s, 3H), 3.56–3.78 (m, 4H), 3.22–3.44 (m, 4H), 3.04–3.14 (m, 1H), 1.44–1.48 (d, 6H). 13C NMR (400 MHz, CDCl3): 164.2, 154.8, 151, 130, 109.8, 102, 56.2, 54, 50.5, 50, 45.2, 42.6, 26.2, 22.1
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH2:18]Cl)=[CH:13][CH:12]=1.CO.O.C(O)(C)C.[K+].[Br-]>CO>[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH2:18][N:5]2[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]2=[O:9])=[CH:13][CH:12]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: Fc1ccc(SCCl)cc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: O=c1ncc(Cl)cn1CSc1ccc(F)cc1

Procedure:
The title compound was prepared from 5-chloropyrimidin-2-one hydrochloride (10 mmol) and 4-fluoro-1-(chloromethylthio)benzene (10 mmol) in a manner similar to that described in Example 2. The reaction time was 21/2 h. Yield: 1.60 g (59%) of the N- and O-isomers in the ratio 2:1. The N-isomer was isolated by its lower solubility in methanol; m.p. 179° C. (MeOH/H2O/ isoPrOH). 1H NMR (DMSO/d6): δ 5.25 (CH2), 6.9-7.7 (Ph), 8.07 and 8.53 (H-4 and H-6, J 4 Hz). IR (KBr): 1660 cm-1 (CO). (Found: C49.80; H2.54. Calc. for C11H8ClFN2OS: C48.81; H2.98). MS [70 eV, m/z (% rel. int.]): 270/272 (4/2,M), 143/145 (100/32).
Reaction SMILES: BrC1C(CC2(O)C3C(=CC=C(C)C=3)N(CCC(C)C)C2=O)=NC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH2:36][CH2:37][CH3:38])[C:31](=[O:39])[C:30]2=[O:40].[CH3:41][O:42][C:43]1[CH:44]=[CH:45][C:46]([CH3:49])=[N:47][CH:48]=1>>[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH2:36][CH2:37][CH3:38])[C:31](=[O:39])[C:30]2([OH:40])[CH2:49][C:46]1[CH:45]=[CH:44][C:43]([O:42][CH3:41])=[CH:48][N:47]=1
Reactant: COc1ccc(C)nc1
Reactant: CCCN1C(=O)C(=O)c2cc(Cl)ccc21
Agent: Cc1ccc2c(c1)C(O)(Cc1ncccc1Br)C(=O)N2CCC(C)C
Product: CCCN1C(=O)C(O)(Cc2ccc(OC)cn2)c2cc(Cl)ccc21

Procedure:
This compound was prepared in an analogous manner to 3-((3-bromopyridin-2-yl)methyl)-3-hydroxy-1-isopentyl-5-methylindolin-2-one using 5-chloro-1-propylindoline-2,3-dione and 5-methoxy-2-methylpyridine. 1H-NMR δ 8.31 (s, 1H), 7.25 (m, 2H), 7.01 (d, 1H), 6.84 (s, 1H), 6.78 (m, 1H), 4.02 (bs, OH), 3.91 (s, 3H), 3.61 (m, 2H), 3.28 (d, 1H), 3.06 (d, 1H), 1.79 (m, 2H), 0.98 (t, 3H). Calculated mass for C18H19ClN2O3, 346.11. Observed, 347.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=1[C:12]#[C:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[NH4+].[Cl-]>[Zn]>[NH2:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=2[C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:2]([F:1])[CH:23]=1
Reactant: Nc1nccc(Oc2ccc([N+](=O)[O-])cc2F)c1C#Cc1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: Nc1ccc(Oc2ccnc(N)c2C#Cc2ccccn2)c(F)c1
Yield: 78 %

Procedure:
The title compound was prepared from the reduction of 4-(2-fluoro-4-nitrophenoxy)-3-(2-(pyridin-2-yl)ethynyl)pyridin-2-amine (35 mg, 0.10 mmol) using zinc dust (65 mg, 1.0 mmol) and NH4Cl (53 mg, 1.0 mmol) in the same manner as Step C of Example 11. This gave the title compound (25 mg, 78%) as brown oil. MS(ESI+): m/z 321.25 (M+H)+.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:49])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:19][S:20]([CH2:23][CH:24]=C)(=[O:22])=[O:21])=[O:18])[CH:15]=2)[C:10]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:9]1[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[C:37]([C:42]1[S:46][C:45]([CH3:47])=[N:44][C:43]=1[CH3:48])[CH:36]=[CH:35]2)[CH2:2][CH:3]=C.N#N>ClCCCl.CC(C)OC1C(C=[Ru](Cl)([P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)Cl)=CC=CC=1>[CH:26]1([C:10]2[C:11]3[CH:12]=[CH:13][C:14]4[C:17](=[O:18])[NH:19][S:20](=[O:22])(=[O:21])[CH2:23][CH:24]=[CH:3][CH2:2][CH2:1][NH:5][C:6](=[O:49])[CH2:7][N:8]([C:16]=3[CH:15]=4)[C:9]=2[C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]=[C:37]([C:42]2[S:46][C:45]([CH3:47])=[N:44][C:43]=2[CH3:48])[CH:36]=[CH:35]3)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C=CCCNC(=O)Cn1c(-c2ccc3nc(-c4sc(C)nc4C)ccc3c2)c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)CC=C)cc21
Agent: CC(C)Oc1ccccc1C=[Ru](Cl)(Cl)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Agent: N#N
Solvent: ClCCCl
Product: Cc1nc(C)c(-c2ccc3cc(-c4c(C5CCCCC5)c5ccc6cc5n4CC(=O)NCCC=CCS(=O)(=O)NC6=O)ccc3n2)s1
Temperature: 80 °C

Procedure:
A solution of intermediate 17-5 (260 mg, 0.373 mmol) in DCE (400 mL) was bubbled through with N2 during 2 h. Hoveyda-Grubbs 1st generation catalyst (45 mg, 0.2 eq) was next added and the reaction mixture was heated at 80° C. under N2 overnight. The reaction mixture was then concentrated under reduced pressure and purified by flash chromatography (CH2Cl2/methanol 95:5) to give the desired product 18 as a gray powder after recrystallization from CH2Cl2/isopropyl ether; m/z=668 (M+H+), NMR (DMSO-d6): δ (ppm) 1.20-1.30 (m, 3H), 1.63-1.93 (m, 9H), 2.34 (m, 2H), 2.66 (m, 1H), 2.67 (s, 3H), 2.73 (s, 3H), 3.23 (m, 2H), 4.50 (s, 2H), 5.64 (m, 2H), 7.45 (m, 1H), 7.73-8.12 (m, 6H), 8.47 (broad s, 1H, NHCO), 8.54 (d, J=8.4 Hz, 1H), 11.47 (broad s, 1H, NHSO2).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:8]3=[CH:9][CH:10]=2)[O:5][C:4](=[O:17])[CH:3]=1.CC(O)=O.Cl[CH2:23][C:24](=O)[CH3:25]>C1(C)C=CC=CC=1.CCO.O>[CH3:16][C:12]1[C:8]2[CH:9]=[CH:10][C:11]3[C:2]4[O:1][CH:23]=[C:24]([CH3:25])[C:3]=4[C:4](=[O:17])[O:5][C:6]=3[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc2c1ccc1c(O)cc(=O)oc12
Reactant: CC(=O)CCl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cccc2c1ccc1c3occ(C)c3c(=O)oc21
Yield: 60.2 %

Procedure:
To a solution of 7 (50 mg, 0.22 mmol) in toluene (8 mL) was added a mixture of HOAc (66 mg, 1.1 mmol) and NH4OAc (80 mg, 1.1 mmol) in EtOH (2 mL) and chloroacetone (103 mg, 1.1 mmol). The mixture was refluxed 24 h. After cooling, the mixture was diluted with H2O and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by column chromatography to give 1 (35 mg, 60%) as a white solid. The spectroscopic data of synthetic compound 1 were identical with those of the natural product 1.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[Cl:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[O:9][CH2:10][CH2:11][OH:12].C(N(CC)CC)C>C(#N)C>[Cl:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[O:9][CH2:10][CH2:11][O:12][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: OCCOc1ccccc1Cl
Reactant: NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NS(=O)(=O)OCCOc1ccccc1Cl
Yield: 58 %

Procedure:
The title compound was obtained using the following procedure: The sulfamoyl chloride solution prepared in (a) was reacted as in Example 4 with 17.3 g (0.100 mole) of 2-(2-chlorophenoxy)ethanol and 40.4 g (0.400 mole) of triethylamine in 100 ml of acetonitrile followed by extraction, washing and concentration procedures of Example 4 through the first evaporation. The viscous, oily residue was partitioned between 500 ml of water and 500 ml of ethyl ether. The organic layer was washed with four 300 ml portions of water (pH of wash finally neutral to pH paper), dried over magnesium sulfate and the solvent evaporated under reduced pressure to give a white solid. The solid was recrystallized from ethyl ether-petroleum ether (bp 30°-60° C.) to give 14.5 g (58%) of title compound as white solid, mp 84.5°-86° C.