Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2cc(Br)ccc2CC12CCC(O)CC2
Temperature: -65 °C
Yield: 221.5 %

Procedure:
6′-Bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (Intermediate 5 Step 1, 6.1 g, 20.8 mmol) was dissolved in THF (220 mL) and cooled to −65° C. Sodium borohydride (0.354 g, 9.36 mmol) was added and the cooling bath was removed. The mixture was allowed to reach 0° C. (approx. 30 min). Water (10 mL) was added, and most of the organic solvent was removed by evaporation. The residue was partitioned between EtOAc (100 mL), and an aq. solution of NaCl (50 mL). The organic phase was dried (MgSO4) and evaporated to give a product which was combined with additional product obtained in a similar way starting from 14.6 g of 6′-bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione. Purification was made by flash chromatography (120 g silica, gradient elution: CH2Cl2 to CH2Cl2/MeOH (90:10)) affording 13.6 g (66% yield) of the title compound. The obtained material consisted of an 80:20 mixture of isomer 1 and isomer 2. Analytical samples of the isomers were isolated by flash chromatography (heptane/EtOAc gradient) to yield:
Reaction SMILES: [OH:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][C:4]=2[CH:3]=1)[NH:11][CH:10]=[C:9]([C:14]#[N:15])[C:8]3=O.P(Cl)(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:23][C:8]1[C:7]2[C:12](=[CH:13][C:4]3[CH:3]=[C:2]([OH:1])[C:18]([O:19][CH3:20])=[CH:17][C:5]=3[CH:6]=2)[N:11]=[CH:10][C:9]=1[C:14]#[N:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2cc3c(=O)c(C#N)c[nH]c3cc2cc1O
Solvent: Cc1ccccc1
Product: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1O
Temperature: 25 °C

Procedure:
A mixture of 3.0 g (11.3 mmol) of 8-hydroxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile and 20.0 mL of phosphorus oxychloride is heated under reflux for 0.5 hour, then is cooled to room temperature. Excess phosphorus oxychloride is evaporated to yield a residue, to which toluene is added and the resulting solution is reduced in vacuo. Toluene is added and evaporated twice more. The resulting residue is cooled with ice bath, neutralized with cold saturated solution of sodium bicarbonate and stirred. The solid was collected by filtration, is washed with cold water and is dried to yield 2.83 g of 4-chloro-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile as a yellow solid. A sample of the material is purified by silica gel chromatography, eluting with 97:3 methylene chloride/methanol to yield a yellow solid, mp.>300° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[NH:7][N:6]=1)=[O:4].C(Cl)Cl.[H-].[Na+].Cl[C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[N:7]([C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:6]=1)=[O:4]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc([N+](=O)[O-])cc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Suspension of 5-nitro-1H-indazole-3-carboxylic acid methyl ester 18AP (7 g, 31.67 mmol) in THF (130 ml) and DCM (15 ml) was added to a NaH (60% in Mineral Oil, 1.61 g, 41.17 mmol) at 0° C. H2 gas was evolved. Chlorotriphenyl methane (8.83 g, 31.67 mmol) was added after stirring for 20 min at 0° C. Reaction mixture was subjected to heat at 60° C. for overnight. It was then cooled to room temperature and concentrated under reduced pressure. Solid was redissolved in DCM and filtered. Filtrate was concentrated under reduced pressure to give desired 5-nitro-1-trityl-1H-indazole-3-carboxylic acid methyl ester 19AP (12.95 g, 88%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[O:16][C:15]([CH3:21])([CH3:20])[CH2:14][C:13]2([CH3:23])[CH3:22]>ClCCl>[C:5]([C:18]1[CH:19]=[C:10]([Br:9])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([CH3:20])([CH3:21])[CH2:14][C:13]2([CH3:23])[CH3:22])(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(Br)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.8 %

Procedure:
A stirred, cooled (ice bath) suspension of aluminum chloride (0.99 g, 7.46 mmol) in anhydrous dichloromethane (20 mL) was treated with acetyl chloride (0.58 g, 7.46 mmol). After 5 minutes, a solution of 6-bromo-2,2,4,4-tetramethyl chroman (1 g, 3.73 mmol)in dichloromethane was added. The reaction was allowed to warm to ambient temperature and stirred for 2 h. The reaction mixture was then poured into ice containing 10% hydrochloric acid and extracted with diethyl ether (×2). The combined organic phase was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title compound as a pale yellow oil (0.95 g, 83%). It was used as such for the next step without any characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][C:10]1([CH3:18])[CH2:17][C:15](=O)[CH2:14][C:12](=[O:13])[CH2:11]1>C(O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:15]1[CH2:17][C:10]([CH3:18])([CH3:9])[CH2:11][C:12](=[O:13])[CH:14]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: Nc1ccccc1Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)CC(=O)C=C(Nc2ccccc2Cl)C1

Procedure:
A mixture of 12.75 parts of 2-chloroaniline and 14 parts of dimedone is dissolved in 40 volume parts of ethanol under warming, followed by the addition of 3 drops of glacial acetic acid. The solution is refluxed in a water bath for 2 hours, after which time the ethanol is distilled off and the resulting residue is allowed to cool, whereupon yellow crystals separate. These crystals are collected by filtration, washed with isopropyl ether and recrystallized from acetone. The procedure yields 3-(2-chloroanilino)-5,5-dimethyl-2-cyclohexen-1-one as colorless prisms melting at 150°-152° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]2[S:11][C:12]3[CH2:19][CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:15]=4[C:13]=3[N:14]=2)[CH2:5][CH2:4]1.[C:25](Cl)(=[O:27])[CH3:26].O>N1C=CC=CC=1>[F:24][C:22]1[CH:21]=[CH:20][C:16]2[CH2:17][CH2:18][CH2:19][C:12]3[S:11][C:10]([NH:9][CH:6]4[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:25](=[O:27])[CH3:26])[CH2:4][CH2:5]4)=[N:14][C:13]=3[C:15]=2[CH:23]=1
Reactant: CC(=O)Cl
Reactant: NC[C@H]1CC[C@H](Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NCC1CCC(Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 27.5 %

Procedure:
To a stirred, septum capped solution of trans-N2-[4-(aminomethyl)cyclohexyl]-9-fluoro-5,6-dihydro-4H-benzo-[6,7]cyclohepta-[d][1,3]thiazol-2-amine (0.165 g, 0.394 mmol) in 3.0 ml anhydrous pyridine was added 0.034 ml (0.038 g, 0.48 mmol) acetyl chloride dropwise. Stirring at room temperature was continued for 90 minutes and the solution was then poured into 50 ml water and extracted with EtOAc (2×50 ml). The combined extracts were evaporated to yield 0.126 g of the crude product as a viscous golden oil. The oil was chromatographed on preparative TLC eluting with EtOAc to yield 28% (0.042 g) of the desired product as a white solid: 1H-NMR (CDCl3) δ 1.13 (4H, m), 1.43 (1H, m), 1.80 (2H, m), 1.98 (3H, s), 2.05 (2H, m), 2.21 (2H, m), 2.80 (4H, m), 3.10 (2H, t, J=6.5 Hz), 3.24 (1H, m), 5.00 (1H, d, J=7.8 Hz), 5.75 (1H, m), 6.81 (1H, dt, J=2.8, 8.2 Hz), 7.04 (1H, m), 7.69 (1H, dd, J=2.7, 10.8 Hz); m.p. 88-91° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32]I>CN(C)C=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH3:32])[C:25]([F:26])([F:28])[F:27])=[CH:4][CH:3]=1
Reactant: CI
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C(F)(F)F)c23)c(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(OC)C(F)(F)F)c23)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
To a solution of 1-[9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (100.7 mg, 0.236 mmol) in N,N-dimethylformamide (1.5 mL) was added sodium hydride (14.2 mg, 0.354 mmol) at 0° C. After 30 min, to the mixture was added methyl iodide (73.5 μL, 1.180 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2.5 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless powder (85.5 mg, 0.194 mmol, 82%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(NCC)C.[OH-].[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.O1CCCC1>[C:22]1([C:28]#[C:29][C:2]2[CH:3]=[C:4]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]3)[CH:5]=[N:6][CH:7]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cncc(Br)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCNCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCN(c2cncc(C#Cc3ccccc3)c2)CC1

Procedure:
A mixture of 1-(5-bromo-3-pyridyl)-4-tert-butoxycarbonylhomopiperazine (3.5 g, 9.8 mmol), phenylacetylene (2.0 g, 19.6 mmol), tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.086 mmol), diethylamine (1.4 g, 19.6 mmol) and tetrahydrofuran (50 ml) was refluxed for 5 hours. Aqueous sodium hydroxide (75 ml, 1M) was added. The mixture was extracted twice with ethyl acetate. The mixture was purified by chromatography on silica gel using ethyl acetate:petroleum (1:1) as solvent. Yield 0.54 g, 7.3%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21]S(C)(=O)=O)[CH:18]=[CH:17][C:16]=2[Cl:26])[C:10](=[O:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>C(O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:16]=2[Cl:26])[C:10](=[O:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(OS(C)(=O)=O)ccc2Cl)C(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(O)ccc2Cl)C(=O)C1

Procedure:
A solution of product from step C (3.88 g, 9.65 mmol) and potassium t-butoxide (2.16 g, 19.3 mmol) in ethanol (100 mL) and H2O (5 ml) was heated at reflux for 3 hours. The reaction was concentrated in vacuo and the residue was partitioned between EtOAc and sat. NH4Cl. The organic layer was washed with H2O and brine, dried over magnesium sulfate, and concentrated in vacuo to give title product which was sufficiently pure for use in the next step.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:15])[C:4](=[O:14])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[N:7]=1.[OH-:16].[Na+].Cl>O1CCOCC1>[OH:16][C:2]1[N:3]([CH3:15])[C:4](=[O:14])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[N:7]=1
Reactant: [OH-]
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1c(O)nc(-c2ccncn2)cc1=O
Temperature: 85 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (20 g, 90 mmol) in 1,4-dioxane (200 ml) was added 5N aqueous solution of sodium hydroxide (100 ml) at room temperature. The resulting mixture was heated to 85° C. and stirred for 18 hours. After cooling to room temperature, the reaction mixture was neutralized by the addition of 1N aqueous hydrochloric acid. The resulting solid was collected by filtration and washed by ethyl acetate. 2-Hydroxy-1-methyl-1H-[4,4′]bipyrimidinyl-6-one was then isolated as a white solid (14.5 g, 71 mmol, 79%).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[NH2:16][OH:17]>C(O)C>[OH:17][NH:16][C:1](=[NH:2])[N:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCN(C#N)CC1
Reactant: NO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Temperature: 0 °C
Yield: 83.8 %

Procedure:
1,1-Dimethylethyl 4-cyanopiperazine-1-carboxylate (10 g, 47.1 mmol) was taken into ethanol (100 mL) and the resulting solution was cooled to 0° C. Hydroxylamine (50% aqueous solution, 3.5 mL, 56.5 mmol) was added and the mixture was allowed to warm to room temperature then stirred an additional hour. The mixture was then concentrated in vacuo to a paste and suspended in 1:1 ethyl ether/hexane (100 mL) and the solid product collected by filtration. The solid was washed with an additional portion of ethyl ether/hexane then dried to give 1,1-dimethylethyl 4-[(hydroxyamino)(imino)methyl]piperazine-1-carboxylate (9.64 g, 83% yield) as a white solid. 1H-NMR (400 MHz, DMSO-d6): 8.34 (s, 1H), 5.19 (s, 2H), 3.30 (tr, 4H), 2.91 (tr, 4H), 1.39 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])(=[S:3])[NH2:2].CO[CH:16](OC)[CH2:17]Cl.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[S:3]1[CH:17]=[CH:16][N:2]=[C:1]1[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cccc(C(N)=S)c1
Reactant: COC(CCl)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: COC(=O)c1cccc(-c2nccs2)c1
Temperature: 100 °C
Yield: 76 %

Procedure:
Preparation H11, Step 3: A solution of 0.6 g (0.003 mol) of methyl 3-carbamothioylbenzoate in 6 ml of acetic acid was charged with 1.15 g (0.009 mol) of chloroacetaldehyde dimethyl acetal and a catalytic amount of PTSA. The RM was heated to 100° C. over night. Acetic acid was removed under vacuum and the crude product was purified by 60-120 silica gel column using 5% of ethyl acetate in pet ether as eluent to provide methyl 3-(thiazol-2-yl)benzoate (0.5 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1B(O)O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:25]4[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=4[CH3:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C)c(B(O)O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cc(C)ccc4C)c3O2)cc1
Yield: 80.7 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (2,5-dimethylphenyl)boronic acid (0.294 g, 1.96 mmol) generally according to the procedure described for Intermediate 184 provided 0.430 g (81%) of (±)-[7-(2,5-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.43 (silica, ethyl acetate:hexanes 1:4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([C:19]4[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=4)[C:22](O)=[O:23])[C:11]3=[O:28])[CH2:9]2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:60]1[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([C:19]4[CH:27]=[CH:26][CH:25]=[C:21]([C:22]([N:60]5[CH2:65][CH2:64][O:63][CH2:62][CH2:61]5)=[O:23])[CH:20]=4)[C:11]3=[O:28])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1cccc(N2C(=O)[C@@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cccc(N2C(=O)[C@@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 60.3 %

Procedure:
A mixture of (1S,2S) and (1R,2R)-3-(2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)benzoic acid (117 mg, 0.3 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU)(145 mg, 0.45 mmol), N,N-Diisopropylethylamine (DIPEA) (154 μL, 0.9 mmol) and morpholine (79 μL, 0.9 mmol) in DMF (2 mL) was stirred at room temperature for 14 hours. Purification by preparative HPLC gave desired product as a white solid (83 mg, 60%). LC/MS m/e calcd. for C27H23ClN2O3: 458, observed (M+H)+: 459.2 1H NMR (400 MHz, MeOD-d4) δppm 2.23-2.31 (m, 2 H) 3.28-3.32 (m, 1 H) 3.77 (br. s., 8 H) 6.16 (d, J=7.58 Hz, 1 H) 6.81 (t, J=7.58 Hz, 1 H) 6.93 (d, J=7.83 Hz, 1 H) 7.11-7.19 (m, 1 H) 7.26-7.33 (m, 2 H) 7.33-7.38 (m, 2 H) 7.56 (d, J=7.58 Hz, 1 H) 7.60-7.67 (m, 2 H) 7.68-7.76 (m, 1 H).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[NH:17][C:16]([CH:18]=[C:19]4[N:54]=[C:22]([C:23]([CH:35]([CH2:45][CH2:46][O:47][P:48]([O:52]C)([O:50]C)=[O:49])[CH2:36][CH2:37][O:38][P:39]([O:43]C)([O:41]C)=[O:40])=[C:24]5[NH:34][C:27](=[CH:28][C:29]6[CH:30]=[CH:31][C:32]=2[N:33]=6)[CH:26]=[CH:25]5)[CH:21]=[CH:20]4)=[CH:15][CH:14]=3)=[CH:8][CH:7]=1)([OH:3])=[O:2].[Si](Br)(C)(C)C>C(Cl)Cl>[C:1]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:13]3[NH:17][C:16]([CH:18]=[C:19]4[N:54]=[C:22]([C:23]([CH:35]([CH2:36][CH2:37][O:38][P:39]([OH:43])([OH:41])=[O:40])[CH2:45][CH2:46][O:47][P:48]([OH:52])([OH:50])=[O:49])=[C:24]5[NH:34][C:27](=[CH:28][C:29]6[CH:30]=[CH:31][C:32]=2[N:33]=6)[CH:26]=[CH:25]5)[CH:21]=[CH:20]4)=[CH:15][CH:14]=3)=[CH:10][CH:11]=1)([OH:3])=[O:2]
Reactant: COP(=O)(OC)OCCC(CCOP(=O)(OC)OC)c1c2nc(cc3ccc([nH]3)c(-c3ccc(OCC(=O)O)cc3)c3nc(cc4ccc1[nH]4)C=C3)C=C2
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=C(O)COc1ccc(-c2c3nc(cc4ccc([nH]4)c(C(CCOP(=O)(O)O)CCOP(=O)(O)O)c4nc(cc5ccc2[nH]5)C=C4)C=C3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
A sample of thoroughly dried 13a (11.8 mg, 0.015 mmol) was dissolved in dry CH2Cl2 (2.0 mL) and then treated with TMS-Br (100 μL, 0.760 mmol). The reaction mixture was stirred at room temperature for 3 h under argon. The solvents were evaporated at reduced pressure. The residue was dissolved in MeOH (3.0 mL). The solution was stirred for 1 h at room temperature. The volatile components were evaporated. The solid residue was dissolved in ˜0.2 mL aqueous NaOH (15 wt %), and the sample was diluted to ˜3 mL with water. The sample was chromatographed (silica C-18, water/MeOH, 0→50%) to afford a dark red solid (8.2 mg, 76%): 1H NMR 6 (D2O) 3.61 (m, 4H), 3.95 (m, 2H), 4.33 (m, 2H), 5.04 (s, 2H), 5.89 (m, 1H), 7.57 (d, J=7.8 Hz, 2H), 7.94-7.97 (m, 2H), 8.91 (m, 2H), 9.28-9.34 (m, 2H), 9.78-9.82 (m, 2H), 10.24-10.33 (m, 4H); ESI-MS obsd (+) 362.1 (M+2H)2+, 723.1 (M+H)+, 745.1 (M+Na)+ (−) 721.1 (M−H)−, calcd 722.15 (M, M=C33H32N4O11P2); λabs 402, 506 nm; λem (λexc 402 nm) 628, 688 nm; HPLC (20% B, 1.5 mL/min, tR=2.22 min).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH3:7])=[O:3].[O:8]([C:18]1[CH:29]=[CH:28][C:21]2[C:22]([CH3:27])=[CH:23][C:24](=[O:26])[O:25][C:20]=2[CH:19]=1)[C@@H:9]1[S:17][CH2:16][C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]1[OH:11]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH2:5]([O:4][C:2]([O:11][C@@H:10]1[C@@H:12]([O:13][C:2]([O:4][CH2:5][CH2:6][CH3:7])=[O:3])[C@H:14]([O:15][C:2]([O:4][CH2:5][CH2:6][CH3:7])=[O:3])[CH2:16][S:17][C@H:9]1[O:8][C:18]1[CH:29]=[CH:28][C:21]2[C:22]([CH3:27])=[CH:23][C:24](=[O:26])[O:25][C:20]=2[CH:19]=1)=[O:3])[CH2:6][CH3:7]
Reactant: CCCOC(=O)Cl
Reactant: Cc1cc(=O)oc2cc(O[C@@H]3SC[C@@H](O)[C@H](O)[C@H]3O)ccc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCOC(=O)O[C@@H]1[C@@H](OC(=O)OCCC)[C@H](OC(=O)OCCC)CS[C@H]1Oc1ccc2c(C)cc(=O)oc2c1
Reaction time: 1 h

Procedure:
A solution of 100 mg (0.8.10−3 mol) of 4-dimethylaminopyridine in 12 ml of pyridine is prepared and 2.1 ml (18.7.10−3 mol) of propyl chloroformate are added at 0° C., followed by 1 g (3.1.10−3 mol) of 4-methyl-2-oxo-2H-1-benzopyran-7-yl 5-thio-β-D-xylopyranoside. The reaction mixture is stirred for 1 hour, a further 1 ml (8.9.10−3 mol) of propyl chloroformate is then added and stirring is continued for 1 hour. The mixture is then hydrolyzed in ice water and extracted with ethyl acetate. The organic phase is washed with dilute hydrochloric acid solution and then with water, dried and finally concentrated under reduced pressure. The residue is purified by chromatography on silica gel using a toluene/ethyl acetate mixture (4/1; v/v) as the eluent. The pure product fraction is crystallized from an ethyl acetate/ diethyl ether mixture to give 1.13 g of the expected product in the form of a fine and light white solid (yield=63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]=O)=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[N:18]([NH2:19])[CH:17]=[N:16][N:15]=1.C([O-])(=O)C.[Na+].C(O)(=O)C>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:11]=[N:19][N:18]3[CH:17]=[N:16][N:15]=[C:14]3[N:13]=2)=[CH:5][CH:4]=1
Reactant: Nc1nncn1N
Reactant: COc1ccc(C(=O)C=O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2cnn3cnnc3n2)cc1

Procedure:
A solution of 9.1 g. of p-methoxyphenylglyoxal, 6.7 g. of 3,4-diamino-4H-1,2,4-triazole and 4.1 g. of sodium acetate in 90 ml. of 67% acetic acid is heated on a steam bath for 1/2 hour. Water is added and heating is continued until crystals separate. The mixture is cooled and filtered. The precipitate is washed with water, ethanol and then hexane giving the desired product as yellow plates, m.p. 282.5°-284.5° C.