Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].Br[CH2:11][C:12]#[N:13]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:11][C:12]#[N:13]
Reactant: Oc1cc(F)ccc1F
Reactant: N#CCBr
Product: N#CCOc1cc(F)ccc1F

Procedure:
Analogously to Method F, 2.0 g of 2,5-difluorophenol and 2.1 ml of bromoacetonitrile are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.52 (1:2 EtOAc-heptane); Rt=3.86.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[C:11]([F:12])=[C:10]([O:13]C)[CH:9]=[CH:8][C:7]=1[CH2:15][C:16]([OH:18])=[O:17]>C(Cl)Cl>[F:5][C:6]1[C:11]([F:12])=[C:10]([OH:13])[CH:9]=[CH:8][C:7]=1[CH2:15][C:16]([OH:18])=[O:17]
Reactant: COc1ccc(CC(=O)O)c(F)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)Cc1ccc(O)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of boron tribromide (1M in DCM, 13.4 mL) was added dropwise to suspension of 2-(2,3-difluoro-4-methoxyphenyl)acetic acid (1.18 g) in DCM (5 mL) at −78° C. The reaction was allowed to warm to RT and stirred overnight. The reaction was cooled to −78° C. and a solution of boron tribromide (1M in DCM, 13.4 mL) was added. The reaction was allowed to warm to RT and stirred for 1 h. The reaction was poured onto ice. The resulting aqueous solution was extracted with DCM (5×50 mL). The aqueous phase was then extracted with ethyl acetate (3×100 mL). The organic solutions were combined, washed with brine (50 mL), dried over magnesium sulphate, filtered and evaporated to give the subtitled compound as a tan solid. Yield 1.09 g.
Reaction SMILES: O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+].[Si]([O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(C(C)(C)C)(C)C.Br[C:35]1[C:36]([NH2:41])=[N:37][CH:38]=[CH:39][CH:40]=1>COCCOC.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>[NH2:41][C:36]1[C:35]([C:28]2[CH:27]=[CH:26][C:25]([OH:24])=[CH:30][CH:29]=2)=[CH:40][CH:39]=[CH:38][N:37]=1
Reactant: Nc1ncccc1Br
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncccc1-c1ccc(O)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 86.3 %

Procedure:
A mixture of sodium carbonate decahydrate (86.0 g), tetrakis(triphenylphosphine)palladium(0) (7.76 g), (4-((tert-butyldimethylsilyl)oxy)phenyl)boronic acid (40 g) and 3-bromopyridin-2-amine (26.9 g) in DME (500 mL) and water (50 mL) was stirred at 90° C. for 24 hr. After cooling to room temperature, the aqueous layer was removed. The organic layer was filtered with NH-silica gel cartridge, and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was recrystallized from EtOAc-IPE to give the title compound (25.0 g) as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[O:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1>C1COCC1>[OH:21][C:18]1([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]#[N:9])[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1
Reactant: O=C1CCOCC1
Reactant: N#CCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CC(c1ccccc1)C1(O)CCOCC1
Reaction time: 0.5 h

Procedure:
To benzyl cyanide (1.970 ml, 19.39 mmol) was added THF (100 ml) and the solution cooled to −78° C. n-butyllithium (2.5 M in hexanes, 7.84 ml, 19.59 mmol) was added dropwise over 20 min via syringe pump and the solution stirred 30 min. Tetrahydro-4H-pyran-4-one (1.791 ml, 19.39 mmol) was added over 20 min via syringe pump and the solution stirred for 3 hours. The reaction was quenched by addition of ice-cold satd. NH4Cl and then partitioned between cold satd. NH4Cl and CH2Cl2. The aqueous portion was extracted 2×CH2Cl2, dried (Na2SO4), and concentrated in vacuo. Took up material in CH2Cl2 and allowed to crystallize over the weekend. The crystals were washed with diethyl ether and used without further purification. 3.14 g, 81%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[C:14]#[N:15])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[O:6][C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[C:14]=1[NH2:15])=[O:16])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Cl)cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2ccc(Cl)cc2c1N
Temperature: 0 °C

Procedure:
To a solution of (4-chloro-2-cyano-phenoxy)-acetic acid ethyl ester (15.3 g, 64.0 mmol) in DMF (150 mL) was added K2CO3 (14.1 g, 102 mmol). After heating at reflux for 10 h, the reaction mixture was poured into ice water. The crude product was collected by filtration as a brown solid (14.37 g, 92%). 1H NMR (CDCl3): 7.54 (s, 1H), 7.41-7.27 (m, 2H), 4.94 (s, 2H), 4.44 (q, J=7.1 Hz, 2H), 1.44 (t, J=7.1 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH:9](C)[C:8](=S)[NH:7][C:6]=2[CH:14]=1.[C:15]([NH:18][NH2:19])(=O)C>C(O)CCC>[CH:15]1[N:7]2[C:6]3[CH:14]=[CH:2][CH:3]=[CH:4][C:5]=3[N:11]=[CH:10][CH2:9][C:8]2=[N:19][N:18]=1
Reactant: CC(=O)NN
Reactant: CC1CNc2ccc(F)cc2NC1=S
Solvent: CCCCO
Product: C1=Nc2ccccc2-n2cnnc2C1

Procedure:
A solution of 8-fluoro-3-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione (5.0 g, 23.8 mmol) and acetohydrazide (2.64 g, 35.7 mmol) in n-butanol (60 mL) was heated at 130° C. for 15 hours. The mixture was concentrated in vacuo, and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1-2:1) to afford 4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine, 5,6-dihydro-1,4-dimethyl-9-fluoro-as an off-white solid (1.9 g, 34%). LRMS (M+H)+: calcd 232.11. found 232.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH3:11][C@@H:12](O)[CH2:13][CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C@H:12]([CH2:13][CH3:14])[CH3:11])[CH:5]=[O:6]
Reactant: CC[C@@H](C)O
Reactant: O=Cc1ccc(O)c(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@H](C)Oc1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 12.3 %

Procedure:
A solution of 750 mg (5.4 mmol) of 3-fluoro-4-hydroxybenzaldehyde, 403 mg (5.4 mmol) of (R)-(−)-2-butanol and 2 g (7.5 mmol) triphenylphosphine in 10 mL of THF was treated with 1.5 mL of diisopropylazodicarboxylate. The resulting solution was stirred at rt for 14 h, cooled to rt and concentrated. Chromatography on a Biotage 40M cartridge using 4:1 v/v hexanes/Et2O as the eluant afforded 130 mg of the title compound: 1H NMR (500 Mhz) δ 0.99 (t, J=7.6, 3H), 1.35 (d, J=6.2, 3H), 1.58–1.83 (m, 2H), 4.47 (m, 1H), 7.05 (t, J=8.2, 1H), 7.59 (d, J=8.2, 1H), 7.61 (s, 1H), 9.84 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([N:6]1[Si:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][Si:7]1([CH3:14])[CH3:13])([CH3:5])[C:3]#[CH:4].C([Li])CCC.[CH:20](=[O:22])[CH3:21].O>O1CCCC1>[OH:22][CH:20]([C:4]#[C:3][C:2]([N:6]1[Si:7]([CH3:14])([CH3:13])[CH2:8][CH2:9][Si:10]1([CH3:11])[CH3:12])([CH3:1])[CH3:5])[CH3:21]
Reactant: C#CC(C)(C)N1[Si](C)(C)CC[Si]1(C)C
Reactant: CC=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(O)C#CC(C)(C)N1[Si](C)(C)CC[Si]1(C)C
Temperature: -20 °C

Procedure:
1-(1,1-Dimethyl-2-propynyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (1.0 g) in dry tetrahydrofuran (10 ml) was cooled to −50° C. under an atmosphere of nitrogen with stirring and a solution of n-butyl lithium (2.0 ml, 2.5M solution in hexanes) was added dropwise over 2 minutes. The mixture was stirred for 0.25 hour at −50° C., allowed to warm to −20° C. then acetaldehyde (0.22 g) in tetrahydrofuran (2 ml) was added dropwise. The reaction was stirred at −20° C. for 1.5 hours, allowed to warm to ambient temperature over 1 hour and treated with water. The product was extracted with ethyl acetate (three times) and the extracts were combined, washed with water (twice) then dried over magnesium sulphate and evaporated under reduced pressure to give (2-hydroxy-5-methylhex-3-yn-5-yl)- 2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane,1.06 g, as a yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(C)cc2)oc1-c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2nc(CC(=O)O)c(-c3ccco3)o2)cc1
Yield: 55 %

Procedure:
4.0 g of ethyl 2-[2-(4-methylphenyl)-5-(2-furyl)-4-oxazolyl]acetate, 60 ml of methanol, 10 ml of water and 1.5 g of sodium hydroxide are treated in the same manner as described in Example 16. 2.0 g of 2-[2-(4-methylphenyl)-5-(2-furyl)-4-oxazolyl]acetic acid are thereby obtained. Yield: 55.6%
Reaction SMILES: Cl[CH:2]([CH2:6][CH:7]=O)[C:3](=[O:5])[CH3:4].[NH2:9][C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1>C(O)C>[CH3:7][C:6]1[N:9]=[C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]2[C:2]=1[C:3](=[O:5])[CH3:4]
Reactant: Nc1ncccn1
Reactant: CC(=O)C(Cl)CC=O
Solvent: CCO
Product: CC(=O)c1c(C)nc2ncccn12
Temperature: 102.5 °C
Yield: 21.8 %

Procedure:
3-Chloro-2,5-pentanedione (2) (106 mL, 119 g, 887 mmol, 1.2 eq) was dissolved in 650 mL of anhydrous ethanol. 2-Aminopyrimidine (1) (71.5 g×97%=69.36 g, 729 mmol) was added to above stirred solution. The resulting mixture was refluxed for 40 h at an oil bath temperature of 100-105° C. The black reaction mixture was cooled and concentrated under reduced pressure. The residue was treated with saturated sodium bicarbonate solution (˜500 mL) in portions, and swelled the flask to mix well. The mixture was extracted with dichloromethane (×6). The extracts were washed with sodium bicarbonate solution and brine. The organic phase was dried and concentrated. The residue was purified by flash chromatography on a silica gel column (7×30 cm) by gradient elution using n-hexane-ethyl acetate (3:1, 2:1, 1:1, 1:2 and 0:1) and then dichloromethane-methanol (30:1, 20:1, 10:1 and 5:1). The product fractions were collected (TLC, Rf 0.36, 100% ethyl acetate) and concentrated providing a light black solid. Other fractions contained products were collected and re-purified again by the same way. 27.84 g (21.8%) of the final product was obtained. Portion of the product was re-crystallized from small amount of acetonitrile to give red to light brown crystals 4, m.p. 255.6-256.6° C. 1H NMR (CDCl3) δ 2.65 (s, 3H, 3-COCH3), 2.86 (s, 3H, 2-CH3), 7.04-7.12 (m, 1H, 6-H), 7.70-7.74 (m, 1H), 9.96-10.00 (m, 1H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1.[Si:17]([O:24][C@H:25]1[CH2:34][C:33]([CH3:36])([CH3:35])[CH2:32][C:31]2[N:30]=[C:29]([CH:37]([CH3:39])[CH3:38])[C:28]([CH:40]=[O:41])=[C:27]([I:42])[C:26]1=2)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[Si:17]([O:24][C@H:25]1[CH2:34][C:33]([CH3:35])([CH3:36])[CH2:32][C:31]2[N:30]=[C:29]([CH:37]([CH3:38])[CH3:39])[C:28]([C@H:40]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=3)[OH:41])=[C:27]([I:42])[C:26]1=2)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(C(F)(F)F)cn1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reaction time: 1 h

Procedure:
1.23 ml of a 2.5 M solution of n-butyllithium in toluene are added dropwise to a solution of 695 mg 2-bromo-5-trifluoromethylpyridine in 10 ml toluene at −80° C. The mixture is stirred for 1 hour and then a solution of 600 mg (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde in 1 ml toluene is added dropwise. After stirring the mixture for 1 hour at −80° C. the reaction is quenched by addition of a saturated aqueous ammonium chloride solution. The phases are separated and the aqueous phase is extracted for three times with ethylacetate. The combined organic phases are dried with magnesium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (pentane/diethylether 100:0 to 70:30).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][N:4]1[C:16]([S:18][CH3:19])=[S:17].[C:20](OC(=O)C)(=[O:22])[CH3:21].Cl>N1C=CC=CC=1>[C:20]([O:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][N:4]1[C:16]([S:18][CH3:19])=[S:17])(=[O:22])[CH3:21]
Reactant: CSC(=S)N1Cc2[nH]c3ccccc3c2C[C@H]1CO
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CSC(=S)N1Cc2[nH]c3ccccc3c2C[C@H]1COC(C)=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 95 %

Procedure:
0.88 g of methyl (3S)-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline-2-carbodithioate is dissolved in 10 ml of pyridine. 0.43 ml of acetic anhydride is added to the solution, and the mixture is stirred at room temperature for 13 hours. After the reaction, the mixture is poured into 10% hydrochloric acid and then extracted with ethyl acetate. The extract is washed with water, dried and then evaporated to remove the solvent, whereby 0.95 g of methyl (3S)-3-acetoxymethyl-1,2,3,4-tetrahydro-β-carboline-2-carbodithioate is obtained as white powder. Yield: 95%
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8]O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:41])C(=O)C1>C(Cl)Cl>[CH2:1]([O:3][CH2:4][O:5][C:6]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][Br:41])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOCOc1c(C)cccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOCOc1c(C)cccc1CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
To a stirred solution of 2-(ethoxymethoxy)-3-methylbenzyl alcohol (Ib) (2.67 g, 13.6 mmol) and triphenylphosphine (5.35 g, 20.4 mmol) in CH2Cl2 (70 mL) was added NBS (3.63 g, 20.4 mmol) at RT. The reaction was stirred at RT for 2 h, and quenched with water (15 mL). The product was extracted with CH2Cl2 (3×30 mL). The combined organic extracts were washed with water (30 mL), brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (hexane/ethyl acetate=10:1, v/v) yielded the compound IIb as a colorless oil (1.56 g, 77%).
Reaction SMILES: [S-][C:2]#[N:3].[K+].F.[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1>>[C:14]1([C:2]#[N:3])[C:15]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: N#C[S-]
Reactant: c1ccc2ccccc2c1
Agent: F
Agent: [K+]
Product: N#Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
At a temperature and in the manner as described in Example 1, 39 g of potassium thiocyanate (0.4 mol) are introduced into 0.3 l of 98% hydrofluoric acid, 42 g of naphthalene (0.33 mol) are added and the mixture is agitated for 2 days at room temperature. After work-up, 54 g of crude α-thionaphthoic acid amide (0.32 mol) having a melting point of 119° C are obtained. A sample recrystallized from xylene has a melting point of 122° - 125° C. By alkaline splitting of the product, pure α-naphthonitrile may be obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:15](=[O:16])[CH2:14][C:12](=[O:13])[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30]1([CH2:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:1]([N:8]1[C:15](=[O:16])[CH:14]([C:37](=[O:38])[CH2:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:12](=[O:13])[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(=O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)C1C(=O)N(Cc2ccccc2)C(=O)N(Cc2ccccc2)C1=O
Temperature: 0 °C
Yield: 88.8 %

Procedure:
To a solution of 1,3-dibenzyl barbituric acid 192 mg (0.623 mmol) in dry dichloromethane 2.0 mL under nitrogen atmosphere, added was pyridine 1.0 mL (12 mmol) and stirred at 0° C. Added was phenylacetyl chloride 96 mg (0.623 mmol, 1.00 equivalent) in dichloromethane 1.0 mL to the solution slowly during a period of 20 minutes, then stirred at room temperature for 3 hours. Added was dichloromethane 40 mL and washed the organic layer with 2 M hydrochloric acid and saturated brine, and dried over sodium sulfate. Purified was the crude product 273 mg, after removal of the solvent under the reduced pressure, by column chromatography (silica gel, eluted with dichloromethane). It obtained 1,3-dibenzyl-5-(phenylacetyl)barbituric acid 236 mg as colorless viscous oil at first (88.7% yield) and it gradually turned white plates.
Reaction SMILES: C(OC([C@@H:11]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:12]([C@H:21]1[CH2:25][C@@H:24]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH2:23][N:22]1C(OC(C)(C)C)=O)[O:13][Si](C(C)(C)C)(C)C)=O)C1C=CC=CC=1.[C:46]([NH:49][C@:50]1([C@@H:105]([CH2:107][CH3:108])[CH3:106])[CH2:54][CH2:53][N:52]([C@@H:55]([CH2:96][CH2:97][C:98]2[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=2)[C:56]([NH:58][C@@H](CC2C=C(F)C=C(F)C=2)[C@@H]([C@H]2C[C@H](OC3C=CC=CN=3)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)O)=[O:57])[C:51]1=[O:104])(=[O:48])[CH3:47].OOS([O-])=O.[K+]>CO.O>[C:46]([NH:49][C@:50]1([C@@H:105]([CH2:107][CH3:108])[CH3:106])[CH2:54][CH2:53][N:52]([C@@H:55]([CH2:96][CH2:97][C:98]2[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=2)[C:56]([NH:58][C@@H:11]([CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:12]([OH:13])[C@H:21]2[CH2:25][C@@H:24]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])[CH2:23][NH:22]2)=[O:57])[C:51]1=[O:104])(=[O:48])[CH3:47]
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@H](Oc3ccccn3)CN2C(c2ccccc2)c2ccccc2)C1=O
Reactant: CCCS(=O)(=O)[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCS(=O)(=O)[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@H](CCc2ccccc2)N2CC[C@](NC(C)=O)([C@H](C)CC)C2=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Step 22 (D): (2R,4R)-tert-butyl 2-((1S,2S)-2-(benzyloxycarbonyl)-1-(tert-butyldimethylsilyloxy)-3-phenylpropyl)-4-(propylsulfonyl)pyrrolidine-1-carboxylate. A solution of 130 mg (0.2 mmol) of the compound of step 22 (C) dissolved in 2 mL of methanol was treated with a solution of 240 mg (0.4 mmol) of oxone dissolved in 0.4 mL of water. After stirring at rt for 30 min, the reaction solution was partitioned between ethyl acetate and water, the organic layer was concentrated, and the crude product was purified by chromatography eluting with a gradient of 20 to 80% ethyl acetate in hexanes to provide 86 mg (64%) of the desired sulfone and 37 mg (28%) of the sulfoxide intermediate as a lower-eluting compound. 1H NMR (500 MHz, CDCl3) δ 0.06 (s, 3 H) 0.11 (s, 3 H) 0.96 (s, 9 H) 1.07 (t, J=7.32 Hz, 3 H) 1.47 (s, 9 H) 1.87 (dd, J=13.43, 6.71 Hz, 3 H) 2.03 (s, 1 H) 2.26 (t, J=12.21 Hz, 1 H) 2.38 (s, 1 H) 2.68 (s, 1 H) 2.90 (s, 2 H) 3.46 (m, 2 H) 3.75 (s, 1 H) 4.09 (m, 2 H) 4.26 (d, J=7.02 Hz, 1 H) 4.77 (m, 1 H) 4.95 (m, 1 H) 7.18 (m, 10 H) MS (ESI) (M+H−Boc)+=575.25
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7]Br)=[N:4][CH:3]=1.[P:9]([O:16]CC)([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>C1(C)C=CC=CC=1>[CH2:11]([O:10][P:9]([CH2:7][C:5]1[S:6][C:2]([Br:1])=[CH:3][N:4]=1)(=[O:16])[O:13][CH2:14][CH3:15])[CH3:12]
Reactant: CCOP(OCC)OCC
Reactant: BrCc1ncc(Br)s1
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ncc(Br)s1)OCC
Temperature: 25 °C

Procedure:
5-Bromo-2-(bromomethyl)-1,3-thiazole (1.02 g, 3.97 mmol) and triethyl phosphite (1.389 mL, 7.94 mmol) were combined in toluene (8 mL) and stirred at reflux overnight. The reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-5% methanol in ethyl acetate) to afford diethyl[(5-bromo-1,3-thiazol-2-yl)methyl]phosphonate as a yellow oil. MS ESI calc'd. for C8H14BrNO3PS [M+H]+ 314, 316. found 314, 316. 1H NMR (500 MHz, CDCl3) δ 7.59 (s, 1H), 4.17-4.09 (m, 4H), 3.57 (d, J=21.2 Hz, 2H), 1.32 (t, J=7.1 Hz, 6H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:20]=[C:17]3[CH:16]=[CH:15][C:14]([CH3:13])=[CH:19][N:18]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(N)nc1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2cn3cc(C)ccc3n2)cc1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
To a magnetically stirred solution of 2-bromo-1-(4-methoxy-phenyl)-ethanone (3.0 g, 13.09 mmol) and 5-methyl-pyridin-2-ylamine (1.42 g, 13.09 mmol) in EtOH (30 mL) under Ar atmosphere was added sodium carbonate (2.77 g, 26.18 mmol). The reaction mixture was refluxed for 4 h. The mixture was cooled to room temperature and concentrated in vacuo. Water (60 mL) was added, and the aqueous phase was extracted with dichloromethane (100 mL). The combined organic layers were washed with water (100 mL), dried (MgSO4), and concentrated in vacuo to provide the title compound (2.8 g, 90%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.27 (s, 3H), 3.82 (s, 3H), 6.95 (m, 3H), 7.48 (d, J=8.8 Hz, 1H), 7.65 (s, 1H), 7.85 (m, 3H).
Reaction SMILES: C[O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][N:9]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[C:8]=12.[I-].[Na+].Cl[Si](C)(C)C>C(#N)C>[O:2]=[C:3]1[C:8]2[N:9]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[CH:5][NH:4]1
Reactant: COc1nccc2c(-c3ccccc3)nn(Cc3ccc(S(N)(=O)=O)cc3)c12
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(Cn2nc(-c3ccccc3)c3cc[nH]c(=O)c32)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of 4-((7-methoxy-3-phenyl-1H-pyrazolo[3,4-c]pyridin-1-yl)methyl)benzenesulfonamide (155 mg) in acetonitrile (30 mL) were added sodium iodide (118 mg) and chloro(trimethyl)silane (342 mg), and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate). To the obtained residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate and hexane to give the title compound (147 mg).