Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH3:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:5]3[CH:4]=[CH:3][C:2]([N:28]4[CH2:29][CH2:30][N:26]([CH3:25])[C:27]4=[O:31])=[N:7][C:6]=3[CH3:8])=[O:10])[CH2:12][CH2:13]2)=[N:18][CH:19]=[C:20]([CH3:24])[CH:21]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3C)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)nc3C)CC2)c(C)c1
Yield: 77.4 %

Procedure:
Using (6-bromo-2-methylpyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (234 mg) described in Preparation Example 247 and 1-methylimidazolidin-2-one (72 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (190 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[F:13][CH:14]([F:17])[CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:13][CH:14]([F:17])[CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(O)c(C)c1
Reactant: OCC(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCC(F)F)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
To a stirred solution of methyl 4-hydroxy-3-methylbenzoate (1.5 g, 9.0 mmol), 2,2-difluoroethanol (0.90 g, 10.8 mmol), triphenylphosphine (3.6 g, 13.5 mmol) in THF (40 mL) is added dropwise diethyl azodicarboxylate (4.9 mL, 10.8 mmol, 40% solution in toluene) at 0° C. The mixture is stirred at room temperature for 30 minutes, and then at 60° C. for 2 hours. After cooled to room temperature, the mixture is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (18:1) to give 1.9 g (90% yield) of the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.C(Cl)Cl.[CH2:10]([O:17][C:18](ON1C(=O)CCC1=O)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>CCOC(C)=O.O>[N:1]1([C:18]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:19])[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: C1=CCNCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC=CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1,2,3,6-Tetrahydropyridine (4.90 g, 58.9 mmol), DCM (40 mL), N-(benzyloxycarbonyloxy)succinimide (15.2 g, 61.0 mmol) and triethylamine (10.0 mL, 71.7 mmol) were mixed together and stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc and water. The organic layer was dried, filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel eluting with EtOAc in hexanes (0 to 40%) to give the sub-title compound as clear oil. LCMS calc. for C13H16NO2 (M+H)+: m/z=218.1. Found: 218.0.
Reaction SMILES: [F:1]C1C=CC(OC)=C2C=1N[C@@H](C)CC2.[Br:15][C:16]1[CH:25]=[CH:24][C:23]2[N:22]([C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C@@H:21]([CH3:31])[CH2:20][CH2:19][C:18]=2[C:17]=1[OH:32]>>[Br:15][C:16]1[C:17]([OH:32])=[C:18]2[C:23](=[C:24]([F:1])[CH:25]=1)[N:22]([C:26]([CH:28]1[CH2:30][CH2:29]1)=[O:27])[C@@H:21]([CH3:31])[CH2:20][CH2:19]2
Reactant: C[C@H]1CCc2c(ccc(Br)c2O)N1C(=O)C1CC1
Reactant: COc1ccc(F)c2c1CC[C@H](C)N2
Product: C[C@H]1CCc2c(O)c(Br)cc(F)c2N1C(=O)C1CC1

Procedure:
(S)-(6-Bromo-8-fluoro-5-hydroxy-2-methyl-3,4-dihydroquinolin-1 (2H)-yl)(cyclopropyl)methanone was synthesized from (S)-8-fluoro-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline according to the procedures described above for (2S)-6-bromo-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol (Intermediate 2, Steps 1a, 2a, and 3). MS (ESI, pos. ion) m/z 328, 330 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C:9](=[O:14])[CH2:10][N+:11]([O-])=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>[Pd]>[CH3:1][N:2]([C:9](=[O:14])[CH2:10][NH2:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C(=O)C[N+](=O)[O-])c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Product: CN(C(=O)CN)c1ccccc1
Reaction time: 5 h

Procedure:
To a solution of 5.0 g (0.026 moles) N-methyl 2-nitro acetanilide in 250 mL absolute alcohol is added 0.5 g of 10% palladium on activated carbon. The nitro functional group is reduced to amino functionality under catalytic reduction with hydrogen gas in a pressure bottle at 60 PSI using Parr hydrogenation apparatus. The reduction is carried out for five hours by which time the reaction is complete as indicated by no further consumption of H2 gas. The reaction mixture is filtered and the solvent from the filtrate is removed under reduced pressure. To the crude residue a small amount of mixture of ethyl acetate ethanol is added and cooled. The resulting precipitate is filtered and washed with cold ethyl acetate in ethanol solvent and dried to give the desired compound N-methyl 2-amino acetanilide.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(=CC=2)[C:48](=[O:52])N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.COC1C=CC(N=C=S)=CC=1>>[CH3:48][O:52][C:6]1[CH:5]=[CH:4][C:3]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=[CH:2][CH:7]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Agent: COc1ccc(N=C=S)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccc(OC)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 260 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 4-methoxy phenyl isothiocyanate. The compound of example 260 was used directly without isolation for the preparation of compound of example 261.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH:34]1[CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[CH:34]1([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:32])=[O:33])[CH2:37][CH2:36][CH2:35]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)C1CCC1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)C3CCC3)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-bromo-2-(cyclobutylsulfonyl)benzene. MS (ESI): mass calcd. for C20H18FN3O2S, 383.11; m/z found, 384.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.44 (s, 1H), 8.17 (dd, J=7.9, 1.1, 1H), 8.13 (d, J=1.4, 1H), 7.96 (m, 1H), 7.77 (m, 1H), 7.68 (m, 1H), 7.46 (dd, J=7.6, 1.1, 1H), 7.34 (s, 1H), 7.31 (dd, J=6.4, 1.5, 1H), 3.65-3.53 (m, 1H), 2.39-2.26 (m, 2H), 2.08-1.98 (m, 2H), 1.98-1.87 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([C:17]1[CH:30]=[CH:29][C:20]([CH:21]=[C:22]2[O:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1)=[O:16]>[C].[Pd].O1CCCC1>[OH:16][CH:15]([C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[O:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1)[CH2:14][CH2:13][C:3]1[N:4]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:6][C:2]=1[CH3:1]
Reactant: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(C=C2OC(=O)NC2=O)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCC(O)c1ccc(CC2OC(=O)NC2=O)cc1
Yield: 52.8 %

Procedure:
A mixture of 5-[4-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]benzylidene]-2,4-oxazolidinedione (0.75 g), palladium-carbon (5%, 0.75 g) and tetrahydrofuran (THF) (70 ml) was subjected to catalytic hydrogenation at 3 atm and room temperature. After the catalyst was filtered out, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. From the fraction eluted with chloroform-ethyl acetate (1:1, v/v), 5-[4-[1-hydroxy-3-(5-methyl-2-phenyl-4-oxazolyl)propyl]benzyl]-2,4-oxazolidinedione (0.4 g, 53%) was obtained, which was then recrystallized from dichloromethane-methanol-isopropyl ether to yield colorless needles having a melting point of 154°-155° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:31])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([NH:25]C(=O)C)=[CH:18][C:17]=2[O:29][CH3:30])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:32].CO>O>[ClH:32].[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:31])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([NH2:25])=[CH:18][C:17]=2[O:29][CH3:30])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(NC(C)=O)c([N+](=O)[O-])cc1C(=O)NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1cc(N)c([N+](=O)[O-])cc1C(=O)NC1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of N-(1-benzylpiperid-4-yl)-2-methoxy-4-acetamido-5-nitrobenzamide (4.26 g; 0.01 mol) [prepared by the procedure described in Example 1], concentrated hydrochloric acid (5 ml), methanol (40 ml) and water (40 ml) was boiled under reflux for 2 hours. The solvent was removed in vacuo and the solid recrystallized from ethanol to give 3.4 g of N-(1-benzylpiperid-4-yl)-2-methoxy-4-amino-5-nitrobenzamide hydrochloride, m.p. 218°-220° C. (dec).
Reaction SMILES: [OH:1][CH:2]1[CH2:23][CH2:22][C:5]2([C:9](=[O:10])[N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:4][CH:3]1[O:24][CH2:25][C:26]([F:29])([F:28])[F:27].C(O)(C)C>CCCCCCC>[OH:1][C@@H:2]1[CH2:23][CH2:22][C@:5]2([C:9](=[O:10])[N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:4][C@H:3]1[O:24][CH2:25][C:26]([F:29])([F:27])[F:28]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCC(O)C(OCC(F)(F)F)C2
Solvent: CCCCCCC
Solvent: CC(C)O
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CC[C@@]12CC[C@@H](O)[C@H](OCC(F)(F)F)C2
Yield: 28 %

Procedure:
rac-(5R,7R,8R)-8-hydroxy-7-(2,2,2-trifluoroethoxy)-2-(4-(trifluoromethoxy)phenyl)-2-azaspiro[4.5]decan-1-one (25 mg, obtained in example 6) was subjected to resolution by preparative HPLC (Chiralpack AD, 30% isopropanol in heptane) to provide (5R,7R,8R)-8-hydroxy-7-(2,2,2-trifluoro-ethoxy)-2-(4-trifluoromethoxy-phenyl)-2-aza-spiro[4.5]decan-1-one (7 mg), MS (ESI): 428.2 (MH+),
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(N(CC)C(C)C)(C)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29]>ClCCl.C(OCC)(=O)C>[C:14]([O:13][C:11]([N:8]1[CH2:7][CH2:6][CH:5]([NH:4][CH2:1][CH:2]=[CH:3][C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=2)=[O:29])[CH2:10][CH2:9]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: C=CCNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(NCC=CC(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.1 %

Procedure:
A portion of the crude 4-(allylamino)-1-(tert-butoxycarbonyl)piperidine (400 mg, 1.66 mmol) was dissolved in 10 mL of dichloromethane and treated with N,N-diisopropylethylamine (0.700 mL, 519 mg, 4.0 mmol) and 4-nitrobenzyl chloroformate (392 mg, 1.82 mmol). After stirring 3 h at RT, the mixture was diluted with 30 mL of ethyl acetate and washed with 15 mL each of 2 N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate, and evaporated. The residue was purified by flash column chromatography on silica gel, eluting with 30% ethyl acetate in hexane, to give 572 mg of the title compound as a colorless syrup. 1H NMR (400 MHz, CDCl3): δ8.22 (d, 2H, J=8 Hz), 7.50 (d, 2H, J=8 Hz), 5.80 (ddt, 1H, J=17, 10, 5 Hz), 5.23 (s, 2H), 5.18-5.09 (m, 2H), 4.27-4.08 (m, 3H), 3.89-3.79 (m, 2H), 2.79-2.66 (m, 2H), 1.74-1.52 (m, 4H), 1.46 (s, 9H). Mass spectrum (ESI): m/z=420 (M+1, 27%), 437 (M+1+NH3, 100%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]([C:12](OCC)=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]>>[NH2:1][C:2]1[S:3][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([OH:13])[N:4]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: NC(N)=S
Product: CCOC(=O)c1sc(N)nc1O

Procedure:
Prepared according to literature procedure (Baldwin, J. J., et al. J. Med. Chem. 1980, 23, 65-70.) from thiourea and diethyl bromomalonate. MS m/z 189 (m+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[CH2:35][C:36]1[CH:47]=[CH:46][C:39]([C:40]([O:42][CH2:43][CH:44]=[CH2:45])=[O:41])=[CH:38][CH:37]=1.[C:48]([OH:51])(=[S:50])[CH3:49]>C1COCC1.O>[C:48]([S:50][CH2:35][C:36]1[CH:47]=[CH:46][C:39]([C:40]([O:42][CH2:43][CH:44]=[CH2:45])=[O:41])=[CH:38][CH:37]=1)(=[O:51])[CH3:49]
Reactant: C=CCOC(=O)c1ccc(CO)cc1
Reactant: CC(O)=S
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)c1ccc(CSC(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
25.7 g (98 mmol) of triphenylphosphine and 100 ml of THF are introduced into a round-bottomed flask and 19.8 g (98 mmol) of diisopropyl azodicarboxylate, dissolved in 150 ml of THF, are added dropwise at 0° C. The mixture is stirred for one hour at 0° C. and a mixture of 9.4 g (49 mmol) of allyl 4-hydroxymethylbenzoate and 7 ml (98 mmol) of thioacetic acid is then added. The mixture is stirred at room temperature for four hours, the reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of dichloromethane and hexane (60:40). 12.2 g (100%) of the expected product are obtained in the form of an oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[O:19][C:18](=[O:20])[CH2:17][C:16](=[O:21])[CH2:15]2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]2[N:35]=[C:36]([CH:38]=O)[N:37]=[C:30]2[N:29]=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[O:19][C:18](=[O:20])[C:17]([CH2:38][C:36]3[N:37]=[C:30]4[N:29]=[C:28]([CH3:27])[CH:33]=[C:32]([CH3:34])[N:31]4[N:35]=3)=[C:16]([OH:21])[CH2:15]2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1O
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Product: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(O)c(C(C)(C)C)c4)(C4CCCC4)OC3=O)nc2n1

Procedure:
The title compound was prepared by coupling 6-[2-(3-tert-Butyl-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione from Example A(2), to 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (described in Step 3 of example B(75)) using the Me2NHBH3 method described in the synthesis of Example B(31) 1H NMR (CDCl3): δ 1.37 (s, 9H), 1.43-1.86 (br m, 8H), 1.93-2.05 (m, 2H), 2.37 (m, 1H), 2.53-2.79 (m, 10), 3.49 (s, 2H), 4.06 (d, J=15.4 Hz, 1H), 4.11 (d, J=15.4 Hz, 1H), 6.58 (d, J=8.1 Hz 1H)), 6.81-6.84 (m, 2H), 7.00 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[N:7]=[C:8]([NH:29]C(=O)OC(C)(C)C)[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)[CH2:14][CH2:15][CH3:16])=[CH:11]2.[OH:38][C@H:39]1[CH2:43][CH2:42][N:41]([C:44]([C:46]2[CH:51]=[CH:50][C:49](B3OC(C)(C)C(C)(C)O3)=[CH:48][CH:47]=2)=[O:45])[CH2:40]1.CC1(C)C(C)(C)OB(C2C=CC(C(O)=O)=CC=2)O1.N1CC[C@H](O)C1>>[NH2:29][C:8]1[CH2:9][C:10]([C:12]([N:13]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:14][CH2:15][CH3:16])=[O:28])=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:49]3[CH:48]=[CH:47][C:46]([C:44]([N:41]4[CH2:42][CH2:43][C@H:39]([OH:38])[CH2:40]4)=[O:45])=[CH:51][CH:50]=3)=[CH:37][C:6]=2[N:7]=1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CC[C@H](O)C3)cc2)OC1(C)C
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Agent: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Agent: O[C@H]1CCNC1
Product: CCCN(CCCO)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CC[C@H](O)C4)cc3)cc2N=C(N)C1

Procedure:
The title compound was prepared by the procedure as described in Example 124 (Step F) using tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate and (S)-(3-hydroxypyrrolidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone that was prepared by the procedure as described in Example 101 (Step H) using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and (S)-pyrrolidin-3-ol. MS APCI (+) m/z 705 (M+1) detected.
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Cl:24][CH2:25][CH2:26][CH2:27]Br.O.O.O.O.O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.CCOC(C)=O.[Cl-].[Na+].O.O.[I-].[Na+]>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][CH2:27][CH2:26][CH2:25][Cl:24])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: ClCCCBr
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCCCCl)o1
Reaction time: 12 h
Yield: 69.1 %

Procedure:
To a vigorously stirred suspension of 5-(tetradecyloxy)furan-2-carboxylic acid (0.650 g, 2.0 mmol) in 10 mL of N,N-dimethylformamide was added 3-chlorobromopropane (0.618 mL, 6.0 mmol), tetrabutylammonium hydroxide pentahydrate (0.734 g, 4.2 mmol) and sodium iodide (˜20 mg). The suspension appeared to go into solution briefly, and then a very finely dispersed white precipitate was observed. The reaction was allowed to stir for 12 hrs. The suspension was then diluted with EtOAc (100 mL), brine (50 mL) and water (50 mL). The phases were separated and the organic phase was washed with water (50 mL) and brine (50 mL). The organic phase was then dried and concentrated to yield 0.554 g of the title compound. This material was used in the subsequent step without further purification.
Reaction SMILES: [C:1]1([CH:7]([SiH2:14][CH2:15][CH2:16][P:17]([O:20][C@@H:21]2[C@@H:25]([CH2:26][O:27][C:28]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[O:24][C@@H:23]([N:51]3[C:68]4[N:67]=[CH:66][N:65]=[C:55]([NH:56][C:57](=[O:64])[C:58]5[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=5)[C:54]=4[N:53]=[CH:52]3)[CH2:22]2)(=O)[OH:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:69]([NH:72][CH:73]([CH3:75])[CH3:74])([CH3:71])[CH3:70].BrC1C=C(Br)C=C(Br)C=1OP(OC1C(Br)=CC(Br)=CC=1Br)(OC1C(Br)=CC(Br)=CC=1Br)(Cl)Cl>C(#N)C>[C:1]1([CH:7]([SiH2:14][CH2:15][CH2:16][PH:17]([O:20][C@@H:21]2[C@@H:25]([CH2:26][O:27][C:28]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[O:24][C@@H:23]([N:51]3[C:68]4[N:67]=[CH:66][N:65]=[C:55]([NH:56][C:57](=[O:64])[C:58]5[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=5)[C:54]=4[N:53]=[CH:52]3)[CH2:22]2)([N:72]([CH:73]([CH3:75])[CH3:74])[CH:69]([CH3:71])[CH3:70])[OH:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)NC(C)C
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)C[C@@H]2OP(=O)(O)CC[SiH2]C(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: ClP(Cl)(Oc1c(Br)cc(Br)cc1Br)(Oc1c(Br)cc(Br)cc1Br)Oc1c(Br)cc(Br)cc1Br
Solvent: CC#N
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)C[C@@H]2O[PH](O)(CC[SiH2]C(c2ccccc2)c2ccccc2)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 3 h

Procedure:
A 250 mL two necked flask equipped with a magnetic stirrer, a gas inlet for argon, and a septum is assembled under an argon atmosphere. All glassware are dried at 120° C. for 1 hour. The flask is charged with N6-Benzoyl-5′-O-(4,4′dimethoxytrityl)-2′-deoxyadenosine- 3′-O-(2-diphenylmethylsilylethylphosphonate) (0.015 mole) and diisopropylamine (0.12 mole). Anhydrous acetonitrile (200 mL) is added. To this stirred mixture under argon at room temperature is added tris(2,4,6-tribromophenoxy)dichlorophosphorane (0.225 mole). After stirring for three hours, the reaction mixture is filtered, and concentrated under reduced pressure. The crude product is purified by flash chromatography using silica gel to afford the desired product. Triethylamine (1%) is used throughout the purification.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH:23]([CH3:28])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.[NH4+].[OH-]>CCCCCC.CCOCC>[CH2:14]([N:21]1[CH2:26][CH2:25][C:24]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)([OH:27])[CH:23]([CH3:28])[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: Cl
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1CN(Cc2ccccc2)CCC1(O)c1ccc(F)cc1
Temperature: -50 °C
Reaction time: 0.67 h
Yield: 84.2 %

Procedure:
To a solution of n-butyllithium (1-2 equivalents, preferably 1.1 equivalents) (1.6 M in hexane, 8.6 ml, 13.76 mmol) in Et2O (10.32 mL) was added a solution of 1-bromo-4-fluorobenzene (2.21 g, 12.63 mmol) in Et2O (5 ml) at about −50° C. After the reaction mixture was stirred at about −50° C. for about 40 min, a solution of 1-benzyl-3-methylpiperidin-4-one (2.00 g, 9.84 mmol) in Et2O (7 mL) was added dropwise. The mixture was allowed to warm up to about −20° C. to 0° C. (preferably −10° C.). 1M hydrochloric acid (20 mL) was added and the organic phase was discarded. Et2O (20 mL) was added to the aqueous solution and aqueous NH4OH was added to the solution until pH>9. The organic layer was separated and the aqueous layer was extracted with DCM (20 mL), The combined organic portions were washed with brine (2×10 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 1-benzyl-4-(4-fluorophenyl)-3-methylpiperidin-4-ol (2.48 g, 84%) as an oil which was used in subsequent reactions without further purification. RP-HPLC (Table 1, Method a) Rt 1.63 min; m/z: (M+H)+ 300.