Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](/[CH:11]=[N:12]/[OH:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:14]N1C(=O)CCC1=O>CN(C=O)C>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([CH:7]=[CH:6][C:3]=1[C:4]#[N:5])/[C:11](/[Cl:14])=[N:12]/[OH:13]
Reactant: Cc1c(/C=N/O)ccc(C#N)c1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Cc1c(/C(Cl)=N/O)ccc(C#N)c1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(E)-2-chloro-4-((hydroxyimino)methyl)-3-methylbenzonitrile (0.64 g, 3.27 mmol) was dissolved in DMF (20 ml) and cooled to 0° C. N-Chlorosuccinimide (0.48 g, 3.60 mmol) was added and the mixture was allowed to warm at RT. The mixture was stirred overnight at RT and poured into ice water (100 ml), extracted twice with EtOAc, The organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product (0.69 g) was used without purification. 1H-NMR (400 MHz; d6-DMSO): δ 2.42 (s, 3H), 7.64 (d, 1H), 7.92 (d, 1H), 12.77 (s, 1H).
Reaction SMILES: O=C1CCC(=O)N1OC([C:11]1[C:15]2[CH2:16][C:17](=[O:19])[CH2:18][C:14]=2[N:13]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[N:12]=1)=O.[NH4+:30].[OH-].[O:32]1[CH2:37]COCC1>>[O:19]=[C:17]1[CH2:16][C:15]2[C:11]([C:37]([NH2:30])=[O:32])=[N:12][N:13]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[C:14]=2[CH2:18]1
Reactant: [NH4+]
Reactant: C1COCCO1
Reactant: Cc1ccc(S(=O)(=O)n2nc(C(=O)ON3C(=O)CCC3=O)c3c2CC(=O)C3)cc1
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)n2nc(C(N)=O)c3c2CC(=O)C3)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the intermediate from step D above, (380 mg, 0.91 mmol) in 1,4-dioxane (10 mL) was added NH4OH (14.8 N, 10.0 eq, 0.61 mL). A precipitate formed immediately. After stirring at room temperature for 15 minutes the reaction mixture was filtered through a sintered funnel and the precipitate washed with 1,4-dioxane. The filtrate was concentrated in vacuo to give a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O-:9])=[O:8].[CH:19](=O)[CH2:20][CH3:21].[C:23](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:19][CH2:20][CH3:21])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:23])=[O:8]
Reactant: Cc1c(NC2CCOCC2)cc(Br)cc1C(=O)[O-]
Reactant: CC(=O)O
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.3 %

Procedure:
To a stirred solution of 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (1 g, 3.04 mmol) and propionaldehyde (0.354 g, 6.09 mmol) in dichloroethane (10 mL), acetic acid (1.12 g, 18.2 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes. Then sodium triacetoxyborohydride (1.94 g, 9.14 mmol) was added at 0° C. and the reaction mixture stirred at room temperature for 2 h. The solvent was then removed under reduced pressure and water added to the residue. The mixture was extracted with DCM. The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product which was purified by column chromatography to afford methyl 5-bromo-2-methyl-3-(propyl(tetrahydro-2H-pyran-4-yl)amino)benzoate (0.96 g, 85.7%).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrCC[CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].C([O-])([O-])=O.[K+].[K+]>CCN(CC)CC.CN(C=O)C>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:16][CH2:17][N:18]3[C:22](=[O:23])[C:21]4=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]4[C:19]3=[O:28])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2ccccc2)CC1
Yield: 95 %

Procedure:
1-Phenylpiperazine 2 (2.21 g, 7.81 mmol) was reacted with N-(4-bromobutyl)phthalimide (1.26 g, 7.81 mmol) in the presence of K2CO3 (8.0 g) in Et3N (1.0 mL) and DMF (20 mL) to give a yellow solid 3a, 2.70 (95%) (Procedure A). 1H NMR (CDCl3) 1.55-1.82 (m, 4H, CH2CH2), 2.40-2.45 (t, J=7.5 Hz, 2H, NCH2), 2.57-2.61 (t, J=4.8 HZ, 4H, N(CH2)2), 3.17-3.20 (t, J=4.8 Hz, 4H, N(CH2)2), 3.71-3.75 (t, J=6.7 Hz, 2H, NCH2), 6.82-6.94 (3H, Ar—H), 7.23-7.28 (m, 2H, Ar—H), 7.70-7.74 (m, 2H, Ar—H), 7.83-7.86 (m, 2H, Ar—H).
Reaction SMILES: [C:1]([C:4]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[C:7]([OH:8])=[CH:6][C:5]=1[OH:14])(=[O:3])[CH3:2].[OH-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19]>O.ClCCCl>[CH2:19]([C:6]1[C:7]([OH:8])=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=[C:4]([C:1](=[O:3])[CH3:2])[C:5]=1[OH:14])[CH:18]=[CH2:17]
Reactant: CC(=O)c1cc(C(C)=O)c(O)cc1O
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCCl
Product: C=CCc1c(O)c(C(C)=O)cc(C(C)=O)c1O
Temperature: 25 °C

Procedure:
4,6-Diacetylresorcinol (19.4 g; 0.1 mole), sodium hydroxide (8.0 g; 0.2 mole) and allyl bromide (12.1 g; 9 ml; 0.1 mole) in water (160 ml) and 1,2-dichloroethane (150 ml) were stirred at reflux for 3 hours. The mixture was cooled to room temperature, the organic layer was separated and the aqueous layer was extracted with 1,2-dichloroethane (3×50 ml). The combined organic layers were dried (anhydrous sodium sulphate) and evaporated to give 2-allyl-4,6-diacetylresorcinol as a pink oil (9 g; 38%) which rapidly crystallised, m.p. 84°-86° C.
Reaction SMILES: [OH:1][C:2]([C:15]([F:18])([F:17])[F:16])([CH2:5][C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[CH:3]=O.[NH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[N:25]2>>[F:16][C:15]([F:18])([F:17])[C:2]([CH:3]=[N:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[N:25]2)([OH:1])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:14])[CH3:7]
Reactant: Nc1cccc2ncccc12
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccccc1
Product: CC(C)(CC(O)(C=Nc1cccc2ncccc12)C(F)(F)F)c1ccccc1

Procedure:
Analogously to Example 13, 120 mg of 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentanal and 61 mg of 5-aminoquinoline are converted into 95 mg of product.
Reaction SMILES: C([Li])CCC.[CH3:6][CH:7]1[S:11][C:10]2=[CH:12][C:13]3[S:14][C:15]([CH3:18])=[CH:16][C:17]=3[C:9]2=[CH:8]1.[CH2:19]([O:22][C:23]1[C:28]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:27][C:26]([CH3:33])=[CH:25][C:24]=1[Si:34](Cl)([CH2:37][CH3:38])[CH2:35][CH3:36])[CH:20]=[CH2:21]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:19]([O:22][C:23]1[C:28]([C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:27][C:26]([CH3:33])=[CH:25][C:24]=1[Si:34]([C:12]1[C:13]2[S:14][C:15]([CH3:18])=[CH:16][C:17]=2[C:9]2[C:10]=1[S:11][CH:7]([CH3:6])[CH:8]=2)([CH2:35][CH3:36])[CH2:37][CH3:38])[CH:20]=[CH2:21]
Reactant: Cc1cc2c(s1)C=C1SC(C)C=C12
Reactant: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](CC)(CC)C1=C2SC(C)C=C2c2cc(C)sc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
At −78° C., n-butyllithium (1.56 M, 1.69 mL, 2.64 mmol) was added dropwise to a solution of 2,5-dimethylcyclopenta[1,2-b:4,3-b′]dithiophen (0.50 g, 2.42 mmol) in tetrahydrofuran (10 mL) and the mixture was stirred at room temperature for 4 hours. After the reaction mixture was cooled to −78° C., a solution of (2-allyloxy-3-tert-buyl-5-methylphenyl)chlorodiethylsilane (0.72 g, 2.20 mmol) in toluene (3 mL) was added dropwise thereto. The resulting reaction mixture was warmed to room temperature and stirred for 2 hours. After the solvent was distilled off under reduced pressure, toluene was added and the mixture was filtered to remove insoluble substances. The filtrate was concentrated under reduced pressure to quantitatively obtain (2-allyloxy-3-tert-butyl-5-methylphenyl)(2,5-dimethylcyclopenta[1,2-b:4,3-b′]dithiophen-7-yl)diethylsilane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1ccc(Br)cc1
Product: CCC(NC(=O)Cc1ccc(Br)cc1)C(=O)OCC(C)C

Procedure:
Following General Procedure I' above and using 4-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[C:15]3[CH:16]=[C:17]([C:20]4[O:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH:18]=[CH:19][C:14]=3[O:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[C:15]3[CH:16]=[C:17]([C:20]4[O:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH:18]=[CH:19][C:14]=3[O:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:5]
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(C(=O)O)c(F)c4)c3c2)o1
Reactant: C1CCNC1
Product: Cc1nnc(-c2ccc3occ(-c4ccc(C(=O)N5CCCC5)c(F)c4)c3c2)o1
Yield: 53 %

Procedure:
In the same manner as in Example 117 and using 2-fluoro-4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]benzoic acid instead of 3-[5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazol-2-yl]propionic acid and using pyrrolidine instead of N,O-dimethylhydroxyamine hydrochloride, the title compound (yield 53%) was obtained as colorless crystals.
Reaction SMILES: [ClH:1].[C:2](O)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[ClH:14].[C:2]([Cl:1])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccnc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of nicotinic acid hydrochloride (0.5 g, 3.1 mmol) in CH2Cl2 (200 mL) at room temperature was added oxalyl chloride (0.42 mL, 4.8 mmol) and three drops of DMF. The reaction mixture was stirred at room temperature for 1 h and then concentrated using a rotary evaporator. The resulting residue was re-dissolved in toluene (50 ml), and then again concentrated using a rotary evaporator to afford nicotinic acid chloride hydrochloride (0.5 g, 90%). To a solution of 2′-hydroxyacetophenone (0.38 g, 2.8 mmol) in THF (50 mL) at room temperature was added nicotinic acid chloride hydrochloride (0.5 g, 2.8 mmol) and triethylamine (1.2 mL, 8.6 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (50 mL), extracted with CH2Cl2 (3×100 mL), concentrated using a rotary evaporator. The residue was purified by column chromatography (hexane:ethyl acetate 2:1) to provide the corresponding ester (0.42 g, 62%). A solution of the above ester (0.42 g, 1.73 mmol) in THF (50 mL) was mixed with t-BuOK (0.25 g, 2.25 mmol) and was stirred at room temperature for 16 hours. The reaction was quenched with water (50 mL) and the aqueous was acidified with HCl (0.5 N) to pH=6. The reaction mixture was extract with CH2Cl2 (3×100 mL), concentrated using a rotary evaporator, trituration in hexanes to afford a solid. This solid was collected by filtration and washed with hexanes to provide the diketone (0.3 g, 71%). A solution of the above diketone (0.3 g, 1.25 mmol) in HOAc (50 mL) and HCl (conc., 1 mL) was stirred at reflux for 2 hours. The solvent was removed using a rotary evaporator. The residue was purified by column (hexane:ethyl acetate:MeOH 3:3:1) to provide 2-(pyridin-3-yl)-4H-chromen-4-one as a light yellow solid (0.202 g, 73%); MS (ES) m/z: 224.90 (M+1), 223.92 (M); MP 122.8-124.0° C.
Reaction SMILES: [H-].[Na+].[CH3:3][OH:4].Cl[C:6]1[N:7]=[C:8]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH:27]2[C:32](=[O:41])[NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=2)[C:9]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[CH:13]=[CH:12][C:10]=2[N:11]=1>O1CCCC1.O>[CH3:3][O:4][C:6]1[N:7]=[C:8]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH:27]2[C:32](=[O:41])[NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=2)[C:9]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: CO
Reactant: COc1ccc(-c2ccc3nc(Cl)nc(N4CCNCC4C(=O)Nc4cccc(C)c4)c3n2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(N2CCNCC2C(=O)Nc2cccc(C)c2)c2nc(-c3ccc(OC)c(OC)c3)ccc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.5 %

Procedure:
24 mg (0.6 mmole) of 60% by weight NaH in mineral oil was suspended in dry tetrahydrofuran (3 ml) under a N2 atmosphere followed by the addition of methanol (0.4 mmole). The mixture was stirred at room temperature for 15 minutes, and 2-chloro-4-[(N-3-methyl-phenylcarbamoyl)-piperazin-1-yl]-6-(3,4-dimethoxy phenyl)-pyrido[3,2-d]pyrimidine (104 mg, 0.2 mmole) was added. The solution was heated at reflux under N2 for 1 hour and diluted with water. The crude product was extracted from the reaction mixture with ethyl acetate and the organic layer was washed with brine, dried over MgSO4 and evaporated to dryness under reduced pressure. Preparative thin layer chromatography on silica, using a n-hexane/ethyl acetate mixture in a ratio of 1:5 as eluent, afforded the pure title compound (52 mg, yield 51%) which was characterized by its mass spectrum as follows: MS (m/z): 515 ([M+H]+, 100).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH2:13][NH:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C(N(CC)CC)C.[C:26](=[S:28])=[S:27].[C:29]1([CH2:34]Cl)[S:33][CH:32]=[CH:31][CH:30]=1>CO>[CH3:1][N:2]1[C:14]2[CH2:13][N:12]([C:26]([S:28][CH2:34][C:29]3[S:33][CH:32]=[CH:31][CH:30]=3)=[S:27])[CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: COC(=O)C1Cc2c(n(C)c3ccccc23)CN1
Reactant: S=C=S
Reactant: ClCc1cccs1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C1Cc2c(n(C)c3ccccc23)CN1C(=S)SCc1cccs1
Yield: 50.1 %

Procedure:
In the same manner as described in Example 53, methyl (3RS)-9-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (421 mg), triethylamine (365 mg), carbon disulfide (137 mg), methanol (20 ml) and 2-thenyl chloride (238 mg) are reacted and treated. The product is recrystallized from methanol to give the title compound (360 mg, 57.6%) as colorless prisms, m.p. 139°-140° C.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][C:3]=1[CH:8]=[O:9].[OH:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.O.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>[Br:7][C:6]1[C:2]([C:14]2[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=2)=[C:3]([CH:8]=[O:9])[S:4][CH:5]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: O=Cc1scc(Br)c1Br
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: O=Cc1scc(Br)c1-c1ccc(O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
A mixture of 3,4-dibromothiophene-2-carbaldehyde (see Intermediate 1 (see Example 15 for Intermediate synthesis)) (2.0 g, 7.5 mmol), 4-hydroxyphenylboronic acid (Scheme II, 8A, X1=4-hydroxyphenyl) (1.0 g, 7.5 mmol), Na2CO3 (1.6 g, 15 mmol), and Pd(PPh3)4 (431 mg, 0.37 mmol) in toluene/EtOH/H2O (30 mL, 5:3:2) was heated to 80° C. and stirred overnight under nitrogen. When TLC indicated that the starting material was consumed, the mixture was diluted with water, neutralized to pH=4-5 with HCl (1M), extracted with EtOAc, concentrated, and purified by column chromatography (PE:EtOAc=20:1) to give 4-bromo-3-(4-hydroxyphenyl)thiophene-2-carbaldehyde (Scheme II, 8, X1=4-hydroxyphenyl) (350 mg, yield 17%) as a white solid. 1H NMR (DMSO-d6 400 MHz): δ9.90 (s, 1H), 9.53 (s, 1H), 8.33 (s, 1H), 7.33 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H).
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[H-].[Na+].[CH2:16]([CH2:26]S([O-])(=O)=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=C.O>CS(C)=O>[CH2:24]([N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:26]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: C=CCCCCCCCCCS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.1 %

Procedure:
Theobromine (3.45 g, 19.2 mmol) was added to a suspension (30 ml) of sodium hydride (461 mg, 19.2 mmol) in dimethylsulfoxide. After 15 minutes, the 9-decenylmesylate (2.25 g, 11 mmol) was added and the reaction stirred for 18 hours at 25° C., then for 40 minutes at 100° C. The mixture was then poured into water (100 ml) and extracted with three 50 ml aliquots of dichloromethane. The combined organic portions were washed with saturated salt solution (60 ml) and dried over magnesium sulfate. Evaporating the solvent under vacuum left a white solid residue. Recrystallization of the residue in ether produced 3.40 g of 1-(9-decenyl)-3,7-dimethylxanthine (56% yield).
Reaction SMILES: [CH3:1][C:2]1C(C)=C(C)[SiH](C)[SiH-](C)(C)C=1.[Na+].[C:14]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:16])[CH3:15].C([CH:27]1[CH:53]=[C:52]([CH3:54])[CH2:51][CH:50]([CH3:55])[CH2:49][CH:48]([O:56][CH3:57])[CH:47]2[O:58][C:43]([OH:62])([CH:44]([CH3:61])[CH2:45][CH:46]2[O:59][CH3:60])[C:42](=[O:63])[C:41](=[O:64])[N:40]2[CH:35]([CH2:36][CH2:37][CH2:38][CH2:39]2)[C:34](=[O:65])[O:33][CH:32]([C:66]([CH3:77])=[CH:67][CH:68]2[CH2:73][CH2:72][C:71](=[O:74])[CH:70]([O:75][CH3:76])[CH2:69]2)[CH:31]([CH3:78])[CH:30]([O:79][Si:80]([C:83]([CH3:86])([CH3:85])[CH3:84])([CH3:82])[CH3:81])[CH2:29][C:28]1=[O:87])C>O1CCCC1>[CH2:1]([CH:37]1[CH2:36][CH:35]2[N:40]([C:41](=[O:64])[C:42](=[O:63])[C:43]3([OH:62])[O:58][CH:47]([CH:48]([O:56][CH3:57])[CH2:49][CH:50]([CH3:55])[CH2:51][C:52]([CH3:54])=[CH:53][CH2:27][C:28](=[O:87])[CH2:29][CH:30]([O:79][Si:80]([C:83]([CH3:84])([CH3:85])[CH3:86])([CH3:82])[CH3:81])[CH:31]([CH3:78])[CH:32]([C:66]([CH3:77])=[CH:67][CH:68]4[CH2:73][CH2:72][C:71]([OH:74])([CH2:15][C:14]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[O:16])[CH:70]([O:75][CH3:76])[CH2:69]4)[O:33][C:34]2=[O:65])[CH:46]([O:59][CH3:60])[CH2:45][CH:44]3[CH3:61])[CH2:39][CH2:38]1)[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reactant: CC1=C[SiH-](C)(C)[SiH](C)C(C)=C1C
Reactant: CC(=O)OCc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC1CCN2C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CCC(=O)CC(O[Si](C)(C)C(C)(C)C)C(C)C(C(C)=CC4CCC(O)(CC(=O)OCc5ccccc5)C(OC)C4)OC(=O)C2C1)C(OC)CC3C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 49 %

Procedure:
A solution of 20 mL of a 1.0 M solution of sodium hexamethyldisilamide in tetrahydrofuran was cooled to -78° C. in an ice bath under nitrogen. Then a solution of 3.00 g (20 mmole) of benzyl acetate in 10 mL of dry THF was added and the solution was stirred at 0° C. under nitrogen. After 15 min., 4.5 g (5 mmole) of 17-ethyl-1-hydroxy-12-[2'-(4"-oxo-3"-methoxycyclohexyl)-1'-methylvinyl]-14-t-butyldimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10, 16-tetraone (Example 9) in 10 mL of dry tetrahydrofuran was added dropwise over 5 minutes and the solution was stirred at -78° C. under nitrogen. After 3 h, the reaction was quenched by addition of 2 mL of glacial acetic acid in 10 mL of dry tetrahydrofuran. Diethylether was added and the mixture was partitioned between ether and water and the aqueous layer was washed with ether. The organic fraction was sequentially washed with saturated KHCO3 solution and brine, dried over MgSO4, filtered and concentrated. The oily residue was purified by flash chromatography (silica gel, 6 cm×20 cm) using ethyl acetate-hexane to afford 2.58 g (49%) of the title compound as a colorless foam; MS (FAB) 1060 (M+Li).
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:38][CH:39]([CH3:56])[CH2:40][C@@H:41]([B:43]1[O:47][C@@H:46]2[CH2:48][C@@H:49]3[CH2:52][C@H:51]([C@:45]2([CH3:55])[O:44]1)[C:50]3([CH3:54])[CH3:53])[NH2:42].FC(F)(F)C([O-])=O.CCN(C(C)C)C(C)C>CN(C)C=O>[F:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:42][C@H:41]([B:43]1[O:47][C@H:46]2[CH2:48][C@H:49]3[CH2:52][C@@H:51]([C@@:45]2([CH3:55])[O:44]1)[C:50]3([CH3:53])[CH3:54])[CH2:40][CH:39]([CH3:56])[CH3:38])=[O:10])=[O:5]
Reactant: CC(C)C[C@H](N)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reactant: O=C(O)CNC(=O)c1cccc(F)c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)CNC(=O)c1cccc(F)c1F)B1O[C@H]2C[C@H]3C[C@H](C3(C)C)[C@@]2(C)O1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of [(2,3-difluorobenzoyl)amino]acetic acid (0.205 g, 0.95 mmol) in dimethylformamide (10 mL) were added TBTU (0.337 g, 1.0 mmol) and (1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butan-1-amine as its trifluoroacetate salt (0.362 g, 0.95 mmol). The mixture was allowed to cool to 0° C. and DIEA (0.498 mL, 2.9 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water (100 mL) and the product partitioned into DCM. The organic layer was dried over sodium sulfate and the solvent removed to give 2,3-difluoro-N-[2-({(1R)-3-methyl-1-[(3aR,4R,6R,7aS)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-2-oxoethyl]benzamide.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:16]=[CH:15][C:10]2[NH:11][C:12](=[S:14])[S:13][C:9]=2[CH:8]=1)[CH3:6])C.[OH-].[Na+].CC(O)=O>C1COCC1.O>[S:14]=[C:12]1[NH:11][C:10]2[CH:15]=[CH:16][C:7]([CH:5]([CH3:6])[C:4]([OH:17])=[O:3])=[CH:8][C:9]=2[S:13]1
Reactant: CCOC(=O)C(C)c1ccc2[nH]c(=S)sc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc2[nH]c(=S)sc2c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 2-(2-Thioxo-2,3-dihydro-benzothiazol-6-yl)-propionic acid ethyl ester (587 mg) in THF (4 mL) and H2O (4 mL) was added NaOH (229 mg) at room temperature. After stirred for 14 h at room temperature, the reaction mixture was acidified with AcOH (pH=4) and diluted with water. The resulting mixture extracted with dichloromethane and the combined organic layer was dried magnesium sulfate, filtered and concentrated in vacuo. (511 mg, 97%, pale yellow solid)