Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH: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.[Br:14]Br>C(O)(=O)C>[Br:14][C:7]1[CH:6]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: BrBr
Reactant: CCOC(=O)Cc1ccc(O)cc1
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To a solution of ethyl 2-(4-hydroxyphenyl)acetate (Alfa, 2.70 g, 15 mmol) in acetic acid (20 mL) was added drop wise over 15 minutes a solution of bromine (0.773 mL, 15.00 mmol) in acetic acid (15 mL). The mixture was stirred at ambient temperature for 30 minutes and evaporated. Purification by chromatography (silica gel, 10-20% ethyl acetate in hexane) afforded the title compound (3.66 g, 94%).
Reaction SMILES: [CH:1]([P:3](=[O:12])([CH:10]=[CH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[CH3:13][NH2:14].[Cl-].[NH4+]>>[CH3:13][N:14]1[CH2:11][CH2:10][P:3](=[O:12])([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:1][CH2:2]1
Reactant: C=CP(=O)(C=C)c1ccccc1
Reactant: CN
Agent: [Cl-]
Agent: [NH4+]
Product: CN1CCP(=O)(c2ccccc2)CC1
Yield: 98.2 %

Procedure:
A mixture of divinylphenylphosphine oxide (0.40g, 2.24 mmol) and aqueous methylamine (2.6 ml of 1M = 2.7 mmol) was heated under reflux for 30 min. The aqueous solution was cooled, saturated with ammonium chloride, and extracted with chloroform. Bulb to bulb distillation of the product at 140°/0.005 mm gave 1-methyl-4-oxo-4-phenylperhydro-1,4-azaphosphorine (0.46g, 98%), as colourless hydroscopic crystals, m.p. 115°-116°. The m.p. was not raised by recrystallization from anhydrous benzene, cyclohexane (1:3). The purity of this material was confirmed by t.l.c. (chloroform-methanol (3:1)). A freshly dried sample (80°/5 mm over P2O5) gave slightly low carbon and phosphorus values owing to rapid uptake of water prior to analysis (Found: C, 62.6; H, 7.8; P, 14.6. C11H16NOP requires C, 63.2; H, 7.7; P, 14.8%). Mol. wt. (Mass spectrum), 209. Infrared spectrum νmax (Nujol): 2820 (N--CH2), 1590, 1460 (C6H5 --P), 1410, 1380, 1320, 1265, 1170, (P=O), 1110, 1065, 990, 960, 925, 810, 760, 725, 705, 665 cm-1. N.m.r. spectrum (CDCl3): 7.82, dm, 2H (o-aromatic); 7.4-7.7, m, 3H (m- and p-aromatic); 2.6-3.3, m, 4H (methylenes); 2.36, s, 3H (methyl); 1.8-2.5, m, 4H (methylenes). A sample which had been exposed to the atmosphere for a few min showed additional broad absorption bands at 3400 and 1630 cm-1 in the i.r. spectrum, and additional sharp singlets at δ3.06 and 4.62 (exchanged by D2O) in the n.m.r. spectrum.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3([CH2:20][O:21][C:6]=2[CH:5]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19].BrC1C=CC=C2C=1[C:27]1([C:38]3=[CH:39][C:40]4O[CH2:43][O:42][C:41]=4[CH:45]=[C:37]3OC1)C(=O)N2.COC1C=CC(CCl)=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:43][O:42][C:41]1[CH:45]=[CH:37][C:38]([CH2:27][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]3([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][C:6]=4[O:21][CH2:20]3)[C:11]2=[O:19])=[CH:39][CH:40]=1
Reactant: O=C1Nc2ccccc2C12COc1cc(OC(F)(F)F)ccc12
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Agent: COc1ccc(CCl)cc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COc1ccc(CN2C(=O)C3(COc4cc(OC(F)(F)F)ccc43)c3ccccc32)cc1

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using 6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 4-methoxybenzyl chloride to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (91%) as a white solid: mp 82-84° C.; 1H NMR (300 MHz, CDCl3) δ 7.32-6.80 (m, 9H), 6.68 (s, 2H), 5.06 (d, 1H), 5.03 (d, 1H), 4.80 (d, 1H), 4.77 (d, 1H), 3.80 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 171.1, 161.8, 159.4, 150.5, 142.3, 132.0, 129.2, 128.9, 127.7, 124.1, 124.0, 123.7, 122.2, 118.8, 114.4, 114.1, 109.7, 104.3, 80.9, 57.6, 55.4, 43.9; MS (ES+) m/z 442 (M+1).
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([N:11]1[C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:14]([C:22]([O:24]CC)=[O:23])[O:13][C:12]1([CH3:28])[CH3:27])=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.C(O)C>[C:4]([O:8][C:9]([N:11]1[C@@H:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:14]([C:22]([OH:24])=[O:23])[O:13][C:12]1([CH3:28])[CH3:27])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CCOC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccccc2)[C@H](C(=O)O)OC1(C)C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
A solution of 4.62 g of lithium hydroxide hydrate in 80 cm3 of water is added in the course of 10 minutes to a stirred solution of 12.8 g of ethyl (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate in 200 cm3 of ethanol. After stirring for a further 10 minutes, the reaction medium is concentrated to dryness under reduced pressure (2.7kPa) at a temperature in the region of 40° C. The residue obtained is dissolved in 70 cm3 of water and then extracted with 3 times 20 cm3 of isopropyl ether. The aqueous phase is then acidified to a pH in the region of 2.6 by adding approximately 100 cc of 1N aqueous hydrochloric acid solution and thereafter extracting with 3 times 50 cm3 of dichloromethane. The combined organic phases are dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 11.3 g of (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylic acid are thereby obtained in the form of a yellow oil, the characteristics of which are as follows:
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([C:12]1[CH:13]=[C:14]([C:22]([N:24]([CH2:26][C@H:27]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=2)[CH2:28][CH2:29][N:30]2[CH2:33][CH:32]([N:34]3[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]3)[CH2:31]2)[CH3:25])=[O:23])[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)#[N:11]>C(Cl)Cl>[C:10]([C:12]1[CH:13]=[C:14]([C:22]([N:24]([CH2:26][C@H:27]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=2)[CH2:28][CH2:29][N:30]2[CH2:33][CH:32]([N:34]3[CH2:39][CH2:38][CH:37]([F:7])[CH2:36][CH2:35]3)[CH2:31]2)[CH3:25])=[O:23])[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)#[N:11]
Reactant: CN(C[C@@H](CCN1CC(N2CCC(=O)CC2)C1)c1ccc(Cl)c(Cl)c1)C(=O)c1cc(C#N)cc2ccccc12
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CN(C[C@@H](CCN1CC(N2CCC(F)CC2)C1)c1ccc(Cl)c(Cl)c1)C(=O)c1cc(C#N)cc2ccccc12
Temperature: -65 °C
Yield: 20 %

Procedure:
Diethylaminosulfur trifluoride (7 mg, 0.044 mmol) was dissolved in dry CH2Cl2 and cooled with stirring under argon to −65° C. 3-Cyano-N-{(2S)-2-(3,4-dichlorophenyl)-4-[3-(4-oxopiperidin-1-yl)azetidin-1-yl]butyl}-N-methyl-1-naphthamide (Example 26; 40 mg, 0.071 mmol), which was dissolved in dry CH2Cl2 (0.5 mL), was then added. The external cooling was removed and the solution was stirred for 1 h. The reaction mixture was quenched by dropping it to a saturated solution of NaHCO3 aq. (6 mL). The organic solution was washed with water and then dried over MgSO4. The solvent was removed by evaporation and there was obtained 5 mg (12%) of the title compound as an oil. 1H NMR (500 MHz, CD3OD): 1.8-2.6 (cm, 7H), 2.6-3.3 (cm, 7H), 3.4-4.4 (cm, 9H), 5.0-5.3 (cm, 1H), 7.0-8.4 (cm, 7H), 8.4-8.6 (m, 1H), 8.9-9.0 (d, 1H); LCMS: m/z 567 (M+1)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1=[CH:10][C:11]2[C:12]([CH:17]([O:20][Si](C(C)C)(C(C)C)C(C)C)[CH2:18][CH2:19]1)=[N:13][CH:14]=[CH:15][CH:16]=2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1=[CH:10][C:11]2[C:12]([CH:17]([OH:20])[CH2:18][CH2:19]1)=[N:13][CH:14]=[CH:15][CH:16]=2
Reactant: CC(C)[Si](OC1CCC(c2cccc(F)c2F)=Cc2cccnc21)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC1CCC(c2cccc(F)c2F)=Cc2cccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of (E)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-8,9-dihydro-7H-cyclohepta[b]pyridine (1.6072 g, 3.74 mmol) and TBAF (7.48 mL, 7.48 mmol) in THF (10 mL) was stirred at room temperature for 1 hour. LCMS showed no more starting material and conversion of the desired product. The solvent was removed via vacuum. The reaction was purified by flash column eluted with ethyl acetate in hexane from 0 to 35% to 50% to afford the desired product as a white solid (0.825 g, 81%). All analytical data matched that of previously described.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[C-:9]#[N:10].[Na+]>CS(C)=O.CCOC(C)=O>[F:8][C:4]1[N:3]=[C:2]([C:9]#[N:10])[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cccc(F)n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(F)n1
Temperature: 100 °C

Procedure:
2,6 Difluoropyridine (12 g, 100 mmol) was dissolved in DMSO (3 mL) and sodium cyanide (1.3 g, 26 mmol) in DMSO (100 mL) was added dropwise via syringe pump over 16 h. The reaction was then heated at 100° C. for 16 h. The crude mixture was then diluted with EtOAc (500 mL) and washed with a mixture of brine (200 mL) and H2O (500 mL). The organic phase was dried (MgSO4), filtered, and concentrated in vacito. The residue was chromatographed on silica gel eluting with hexanes:EtOAc (4:1) to afford 6-fluoropyridine-2-carbonitrile. MS (ESI) 122.0 (M++H).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:6](=[O:12])[CH2:5][C:4](=O)[CH2:3]1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:22])=[C:19]([SH:21])[CH:20]=1>CS(C)=O>[Br:14][C:15]1[CH:20]=[C:19]2[C:18](=[CH:17][CH:16]=1)[NH:22][C:4]1[CH2:3][CH:2]([CH3:1])[CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:6](=[O:12])[C:5]=1[S:21]2
Reactant: COC(=O)C1C(=O)CC(=O)CC1C
Reactant: Nc1ccc(Br)cc1S
Solvent: CS(C)=O
Product: COC(=O)C1C(=O)C2=C(CC1C)Nc1ccc(Br)cc1S2

Procedure:
A mixture of methyl 6-methyl-2,4-dioxocyclohexane-1-carboxylate, 7a (1.43 g, 7.7 mmole) and 5-bromo-2-aminobenzenethiol, 6 (X=Br, 1.44 g, 7.7 mmole) in DMSO (10 mL) is placed in a preheated heating mantle. The reaction mixture is stirred and refluxed for 0.5 h. Upon cooling, the reaction mixture forms a solid. The crystals are filtered and the remaining mother liquid is poured into cold water, whereupon further precipitation occurs. Each precipitate is separately recrystallized twice from MeOH and proves to be identical. An analytical sample of 4j, (R=Br), mp 186-189° C. occurs as light orange crystals; 0.14 g (13.9%).
Reaction SMILES: F[C:2](F)=[C:3](F)F.[K].[CH:8]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([CH3:15])[CH:9]=1.O>CN(C)C=O>[C:13]1([O:14][C:8]2[CH:13]=[CH:12][C:2]([CH3:3])=[CH:10][CH:9]=2)[CH:12]=[CH:11][C:10]([CH3:15])=[CH:9][CH:8]=1
Reactant: Cc1ccc(O)cc1
Reactant: FC(F)=C(F)F
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2ccc(C)cc2)cc1
Reaction time: 2 h

Procedure:
Tetrafluoroethylene tetramer (40 g) was added dropwise to the potassium salt of p-cresol (15 g) stirred in dry dimethyl formamide (100 ml) at 25° C. to 30° C. After addition of the tetramer, the reaction mixture was stirred at 35° C. to 40° C. for two hours. The cooled reaction mixture was poured into water, and worked up as above to give 33 g of the -cresyl ether, C8F15OC6H4CH3, boiling point 104° C. to 106° C. at 12 mm Hg. Elementary analysis, infra-red spectra, mass spectrometry and nuclear magnetic resonance measurements confirmed the identity of the compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([N+:21]([O-])=O)=[CH:19][C:18]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:17][N:16]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>[Pd].CO>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[C:20]([NH2:21])=[CH:19][C:18]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:17][N:16]=2)[CH2:13][CH2:14]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2ncc(S(C)(=O)=O)cc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1CCN(c2ncc(S(C)(=O)=O)cc2N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.03 g (2.48 mmol) of (5′-methanesulfonyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl)-carbamic acid tert-butyl ester and 0.15 g (0.14 mmol) of 10% palladium on carbon in a 1:1 mixture of ethyl acetate:methanol (50 mL) is placed under an atmosphere of hydrogen and stirred overnight at room temperature. The mixture is filtered through diatomaceous earth and the filter pad is washed with methanol. The filtrate is concentrated under reduced pressure to provide 0.980 g (103%) of as a (3′-amino-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl)-carbamic acid tert-butyl ester as a brown resin.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(OC(=O)C1C=CC=CC=1F)C1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][C:10]([F:9])=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C(OCc1ccccc1)c1ccccc1F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1ccc(F)cc1
Reaction time: 18 h

Procedure:
Benzyl alcohol (4.05 mL, 39.1 mmol) was added slowly to a stirring solution of 4-fluorobenzoic acid (5.00 g, 35.7 mmol), 4-(dimethylamino)pyridine (432 mg, 3.53 mmol), and 1,3-dicyclohexylcarbodiimide (8.15 g, 39.5 mmol) in anhydrous CH2Cl2 at room temperature under an argon atmosphere. After 18 h the reaction was worked up according to procedures as outlined for the synthesis of 16. Flash chromatographic purification over silica (10% EtOAc in hexanes) afforded 17 as a clear, colorless liquid (7.75 g, 94%). 1H-NMR (500 MHz, CDCl3) δ 5.35 (s, 2H), 7.06-14 (m, 2H), 7.32-7.41 (m, 3H), 7.41-7.47 (m, 2H), 8.06-8.12 (m, 2H); 13C-NMR (125 MHz, CDCl3) δ 66.84, 115.5 (d, JC-F=22.0 Hz), 126.4 (d, JC-F=2.9 Hz), 128.2, 128.3, 128.6, 132.3 (d, JC-F=9.6 Hz), 135.9, 165.5, 165.8 (d, JC-F=253 Hz); GC-MS 230 m/z [M]+, C14H11OF2 requires 230.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]([C:11]1([CH3:26])[CH2:16][CH2:15][C:14]2[C:17]([CH3:25])=[C:18]([O:23][CH3:24])[C:19]([CH3:22])=[C:20]([CH3:21])[C:13]=2[O:12]1)C(OCC)=O)C.[OH-].[K+]>C(O)CO.O>[CH3:24][O:23][C:18]1[C:19]([CH3:22])=[C:20]([CH3:21])[C:13]2[O:12][C:11]([CH3:26])([CH2:5][C:4]([OH:27])=[O:3])[CH2:16][CH2:15][C:14]=2[C:17]=1[CH3:25]
Reactant: CCOC(=O)C(C(=O)OCC)C1(C)CCc2c(C)c(OC)c(C)c(C)c2O1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)O)O2
Yield: 75.9 %

Procedure:
A mixture of 1.29 g (3.41 mmoles) of rac.-3,4-dihydro-2,5,7,8-tetramethyl-6-methoxy-2H-1-benzopyran-2-ylpropanedioic acid diethyl ester, 1.68 g of potassium hydroxide, and 75 ml of 9:1 parts by volume ethylene glycol-water mixture was stirred and refluxed for 6 hours. The resulting mixture was poured on ice and extracted with ether (the ether extract was discarded). The aqueous solution was acidified with 3N HCl and the precipitated acid was extracted 3 times with ether. The combined ether extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by preparative thick layer chromatography gave 0.72 g (75.9%) of rac.-3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetic acid, as a colorless solid, mp 96°-98° C. Dimethylation using the procedure of example 14 gives rac.-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetic acid which can be converted to alpha-tocopherol as described in Helv. Chim. Acta. 59, 290 (1976).
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[C:14]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:15]=3[S:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[O:12])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:14]2[C:13]([C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:4]#[C:3][CH2:2][O:1][S:40]([CH3:39])(=[O:42])=[O:41])=[CH:10][CH:9]=3)=[O:12])=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[S:16][C:15]=2[CH:26]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(C#CCO)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(C#CCOS(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product from Step 2 (195 mg, 0.46 mmol) was dissolved in 3 mL of methylene chloride and treated with 127 mL of triethylamine and methanesulfonyl chloride (53 mL, 0.68 mmol) and stirred 30 minutes at room temperature. The reaction was concentrated and extracted into ethyl acetate. The combined organic layers was washed with brine and dried over anhydrous magnesium sulfate. After filtration, concentration the title compound (205 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[CH2:17]([N:24]([CH:29]([CH3:31])[CH3:30])[C:25](=[O:28])[CH:26]=[CH2:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:27][CH2:26][C:25]([N:24]([CH:29]([CH3:30])[CH3:31])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:28])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: C=CC(=O)N(Cc1ccccc1)C(C)C
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)N(Cc1ccccc1)C(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (1.19 g, 5 mmole), N-benzyl-N-isopropyl-2-propenamide (1.0 g, 5 mmole) (prepared from acryloyl chloride and benzylisopropylamine), and triethylamine (0.05 ml) in methanol was stirred for 60 hours at room temperature. The reaction mixture was concentrated in vacuo to an oil. Chromatography on silica gel gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[CH3:19][C:17]1[CH:18]=[C:2]2[C:3]([C:4](=[O:5])[N:6]([CH:7]3[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]3=[O:14])[CH:20]=[N:1]2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(C(=O)NC2CCC(=O)NC2=O)c(N)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Product: Cc1ccc2c(=O)n(C3CCC(=O)NC3=O)cnc2c1
Yield: 223.4 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-4-methyl-benzamide (1.0 g, 3.8 mmol) and trimethyl orthoformate (10 mL) and p-toluene sulfonic acid (250 mg) was heated to 160° C. in a microwave oven for 30 minutes. The suspension was filtered and washed with methanol (20 mL), water (20 mL) and methanol (20 mL) to give 3-(7-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as an off-white solid (880 mg, 85% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 20/80 CF3CN/0.1% H3PO4, 5.14 min (97.1%); mp: 313-315° C.; 1H NMR (DMSO-d6) δ 2.11-2.18 (m, 1H, CHH), 2.48 (s, 3H, CH), 2.61-2.74 (m, 2H, 2CHH), 2.82-2.92 (m, 1H, CHH), 5.46 (br, 1H. NCH), 7.41 (dd, J=1, 8 Hz, 1H, Ar), 7.53 (s, 1H, Ar), 8.03 (d, J=8 Hz, 1H, Ar), 8.33 (s, 1H, CH), 11.15 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.23, 22.51, 30.91, 56.74, 118.95, 125.93, 126.74, 128.66, 145.27, 147.35, 147.59, 159.54, 169.88, 172.44; LCMS: MH=272; Anal Calcd for C14H13N3O3+0.1H2O: C, 61.58; H, 4.87; N, 15.39. Found: C, 61.41; H, 4.87; N, 15.15.
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](/[C:15](/[CH2:19][CH3:20])=[CH:16]/[C:17]#[CH:18])[CH:10]=1)(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>C1COCC1>[CH2:19](/[C:15](/[C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=1)=[CH:16]\[C:17]#[CH:18])[CH3:20]
Reactant: C#C/C=C(\CC)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: C#C/C=C(\CC)c1cccc(O)c1
Reaction time: 0.5 h

Procedure:
1 g (3.5 mmol) of tert-butyl-[3-((E)-1-ethylbut-1-en-3-ynyl)phenoxy]dimethylsilane is dissolved in 50 ml of THF, and 3.8 ml (38 mmol) of a 1.0 M solution of tetrabutylammonium fluoride are added drop by drop. The mixture is stirred for 30 minutes, then treated with a saturated solution of ammonium chloride and extracted with ethyl acetate. A yellow oil is obtained (m=690 mg; Y=100%).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][OH:20])[C:12](=[O:21])[N:11]([CH3:22])[C:10]=3[N:9]=[C:8]2[C:23](=[O:35])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][OH:20])[C:12](=[O:21])[N:11]([CH3:22])[C:10]=3[N:9]=[C:8]2[CH:23]([OH:35])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:32])([F:33])[F:34])[CH:25]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(=O)n(CCCO)c(=O)c2c1nc(C(=O)c1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1c(=O)n(CCCO)c(=O)c2c1nc(C(O)c1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 22.9 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)benzoyl)-1H-purine-2,6(3H,7H)-dione (50 mg, 0.081 mmol, example 91) in methanol (3 mL) was added sodium borohydride (10 mg, 0.263 mmol) at 0° C. under nitrogen. The reaction was stirred at 0° C. for 2 h. The reaction was quenched and partitioned with ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by preparative HPLC to give 7-(4-chlorobenzyl)-8-(hydroxy(3-(trifluoromethoxy)phenyl)methyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (10 mg, 22.9%) as white solid. 1H-NMR (CDCl3) δ 7.36-7.31(t, 1H), 7.23-7.14(m, 5H), 6.94-6.92(d, 2H), 5.87-5.85(d, 1H), 5.60-5.56(d, 1H), 5.39-5.35(d, 1H), 4.20-4.17(t, 2H), 3.65-3.63(s, 4H), 3.54-3.51(m, 2H), 3.31(s, 1H), 1.91-1.88(t, 2H). LCMS retention time 2.605 min; LCMS MH+ 539.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]([C:10]1[S:11][C:12]([S:34][CH3:35])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([O:31][CH3:32])=[CH:26][C:25]=3[NH2:33])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[Br:37][CH2:38][C:39](Br)=[O:40].CCN(CC)CC.CCOC(C)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]([C:10]1[S:11][C:12]([S:34][CH3:35])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:25]([NH:33][C:39](=[O:40])[CH2:38][Br:37])=[CH:26][C:27]([O:31][CH3:32])=[CH:28][C:29]=3[CH3:30])[CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH:14]=1)=[NH:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(N)c1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(NC(=O)CBr)c1
Yield: 68.7 %

Procedure:
Following the procedure described for Example 234, step a, reaction of {[4-(6′-amino-4′-methoxy-2′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (204 mg, 0.37 mmol, as prepared in Example 198, step e), bromoacetyl bromide (39 μL, 0.45 mmol), and Et3N (77 μL, 0.56 mmol) in DCM (5 mL) afforded 170 mg (69%) of the title compound as a yellow foamy solid after chromatography (PTLC, 50% EtOAc in hexanes, 4×1000μ SiO2 plate). 1H-NMR (CDCl3; 400 MHz): δ 8.02–8.05 (m, 1H), 7.91 (s, 1H), 7.87 (t, 1H, J=1.6 Hz), 7.73 (br s, 1H), 7.63–7.67 (m, 2H), 7.45–7.49 (m, 1H), 6.69 (d, 1H, J=2.1 Hz), 3.85 (s, 3H), 3.69 and 3.74 (AB quartet, 2H, J=14.1 Hz), 2.59 (s, 3H), 2.00 (s, 3H), 1.52 (s, 9H). ESI-MS (m/z): Calcd. for C27H30BrN3O6S3: 668.0 (M+H); found: 669.6, 667.6, 570.0, 568.0 (M−Boc).