Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:34])=[C:12]([C:29](OCC)=[O:30])[C:13](=[O:28])[N:14]3[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:37][CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1>>[F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:34])=[C:12]([C:29]([NH:37][CH2:38][C:39]4[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=4)=[O:30])[C:13](=[O:28])[N:14]3[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Reactant: NCc1cccnc1
Product: CS(=O)(=O)c1ccc(Cn2c(=O)c(C(=O)NCc3cccnc3)c(O)c3ncc(Cc4ccc(F)cc4)cc32)cc1

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-1-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-(aminomethyl)pyridine employing methods similar to those described in Example 5 and was obtained as a white solid; 1H NMR (CDCl3) δ 10.82 (1H, br t, J=6 Hz), 8.79 (1H, s), 8.67 (1H, d, J=5 Hz), 8.61 (1H, s), 8.44 (1H, d, J=8 Hz), 7.90 (1H, m), 7.86 (2H, d, J=8.2 Hz), 7.22 (2H, d, J=8.2 Hz), 7.07 (1H, s), 7.00 (4H, m), 5.44 (2H, br), 4.83 (2H, d, J=6 Hz), 4.05 (2H, s), 3.04 (3H, s); ES+ MS: 573 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.Cl[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][CH3:23]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][OH:13])=[N:8][C:7]([S:18][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][CH3:23])=[N:6][C:5]=2[N:19]=1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: CCC(Cl)c1ccccc1
Product: CCC(Sc1nc(N[C@@H](CO)CC(C)C)c2sc(N)nc2n1)c1ccccc1
Yield: 31 %

Procedure:
The title compound was synthesized as a mixture of two diastereomers by general method A from the reaction of (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (30 mg, 100 μmol) with (1-chloropropyl)benzene (15.5 μL, 100 μmol) to give 13 mg (31% yield) as an oil.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[S:15]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=1)(=[O:17])=[O:16].[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[F:25][C:20]1[CH:19]=[C:18]([S:15]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([F:26])[CH:32]=2)=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=3)(=[O:17])=[O:16])[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: OB(O)c1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc2c(Br)c(S(=O)(=O)c3ccc(F)c(F)c3)cnc2c1
Product: O=[N+]([O-])c1ccc2c(-c3cccc(F)c3)c(S(=O)(=O)c3ccc(F)c(F)c3)cnc2c1
Yield: 56.7 %

Procedure:
The title compound was prepared applying the procedure described in Example 7 from 4-Bromo-3-(3,4-difluoro-benzenesulfonyl)-7-nitro-quinoline (0.53 g, 1.23 mmol) and 3-fluorophenylboronic acid (0.21 g, 1.5 mmol). The crude product was purified by column chromatography on silica gel (Kieselgel 60, eluent: chloroform) and crystallized from methanol to obtain 0.31 g of the title compound in 57% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[N:9]=2)[CH:5]=[CH:4][C:3]=1[OH:17].Br[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C@H:28]([C@H:32]([CH3:37])[C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:26]2.C([O-])([O-])=O.[Cs+].[Cs+]>O.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[N:9]=2)[CH:5]=[CH:4][C:3]=1[O:17][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C@H:28]([C@H:32]([CH3:37])[C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:26]2
Reactant: Cc1cc(-c2nc(C(F)(F)F)ns2)ccc1O
Reactant: COC(=O)[C@@H](C)[C@@H]1CCc2cc(OCCCBr)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H](C)[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc(C(F)(F)F)ns4)cc3C)ccc21
Temperature: 40 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
2-Methyl-4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]phenol (57.7 mg, 0.22 mmol), methyl (2S)-2-[(1S)-5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]propanoate (Example 234) (72.0 mg, 0.21 mmol), Cs2CO3 (82.5 mg, 0.25 mmol), and water (3 drops) were combined in DMF (4 mL) and stirred at 40° C. for 16 h. The reaction mixture was concentrated under reduced pressure, water was added and the aqueous phase was extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v)=1:20) gave 70 mg (64%) of the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.07 (d, 3H), 1.90 (m, 1H), 2.17 (m, 1H), 2.29 (s, 3H), 2.34 (m, 2H), 2.77-2.91 (m, 3H), 3.50 (m, 1H), 3.71 (s, 3H), 4.17 (t, 2H), 4.25 (t, 2H), 6.70 (d, 1H), 6.78 (s, 1H), 6.92 (d, 1H), 6.99 (d, 1H), 7.79 (m, 2H).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]=[CH2:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:31][CH2:32][CH:33]=[CH2:34]>CN(C=O)C.CCOC(C)=O>[CH2:34]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=[CH2:27])[CH2:33][CH:32]=[CH2:31]
Reactant: C=CCCBr
Reactant: C=Cc1ccccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCCn1c(-c2ccccc2C=C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 0.3M solution of methyl 3-cyclohexyl-2-(2-vinylphenyl)-1H-indole-6-carboxylate in dry DMF, 60% NaH (1.5 eq) in mineral oil was added at 0° C.; after stirring for 45 min at RT, 4-bromobut-1-ene (1.5 eq) was added and the suspension was stirred for 5 h at 40° C. and then 1 day at RT (NaH and 4-bromobut-1-ene were added several times). The mixture was diluted with EtOAc, washed with 1N HCl, water and brine, dried (Na2SO4) and concentrated in vacuo to give, after chromatography (PE/EtOAc 95:5), the title compound (60%) along with recovered starting material (40%); MS (ES+) m/z 414 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[C:34](=[O:40])[CH2:33][CH2:32][CH2:31]2.C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:29]=[C:30]5[C:35](=[CH:36][C:37]=4[O:38][CH3:39])[C:34](=[O:40])[CH2:33][CH2:32][CH2:31]5)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc2c(cc1OCCCCl)CCCC2=O
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc2c(cc1OCCCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2=O
Yield: 117.4 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (0.78 g, 3.6 mmol), K2CO3 (0.60 g, 4.1 mmol). Kl (100 mg), 6-(3-chloropropoxy)-7-methoxy-1-tetralone (0.87 g, 3.2 mmol), and acetonitrile (50 ml) was stirred at reflux under nitrogen for 17 hours. The cooled reaction was poured into 100 ml of water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried with MgSO4 and concentrated to yield 1.7 g of a brown oil. The oil was purified by preparative HPLC (Waters Associates Prep LC/SYSTEM 500) to afford 1.0 g of a light brown solid. This was combined with an additional sample (2,3 g total) and recrystallization from ethanol yielded 1.7 g. A subsequent recrystallization from ethanol gave 1.25 g (36%) of 6-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-7-methoxy-1-as a beige powder, m.p.=129°-130° C. ANALYSIS: Calculated for C20H24FN2O4: 69.01%C 6.46%H 6.19%N Found: 68.77%C 6.43%H 6.16%N
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:16])[C:9]([CH2:12][C:13]([OH:15])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:29]([NH2:32])[CH2:30][CH3:31]>C(Cl)(Cl)Cl>[CH2:29]([NH:32][C:13](=[O:15])[CH2:12][C:9]1[C:8](=[O:16])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)[CH2:30][CH3:31]
Reactant: CCCN
Reactant: Cc1cccc2ncc(CC(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCNC(=O)Cc1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
A mixture containing 2.18 g (0.01 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-acetic acid and 1.55 ml (0.011 mol) of triethylamine in 60 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 0.945 g (0.01 mol) of methyl chloroformate in 5 ml of chloroform is dropped to the above mixture at -12° C. during 7 minutes. After stirring for 5 minutes, 0.65 g (0.011 mol) of propylamine dissolved in 10 ml of chloroform is dropped to the above solution at -15° C. during 10 minutes. The reaction mixture is stirred at -15° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 40 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 40 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated. Alter thoroughly triturating the residue with cold ethyl acetate, 0.8 g (30.9%) of the named compound is obtained, m.p.: 96°-98° C. after recrystallization from ethyl acetate.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:19]O>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:19])=[O:12])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)CCCc1ccc(I)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(p-iodophenyl)-butyric acid (45.0 g, 0.155 mol) in methanol (1.3 L), was added sulfuric acid (concentrated, 8.4 mL) dropwise and it was stirred at room temperature under nitrogen for 3 hours. The reaction mixture was concentrated on a rota-vapor, the residue was then partitioned between ethyl acetate (700 mL) and saturated sodium bicarbonate aqueous solution (500 mL). The organic phase was separated, washed with brine (2×200 mL), then dried over Na2SO4 and filtered. Evaporation of solvent gave the titled compound as an oil that was used in step B without further purification.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:13]([C:14](OCC)=[O:15])=[C:12]([CH3:19])[C:11]2[C:6](=[CH:7][C:8]([C:20]([F:23])([F:22])[F:21])=[CH:9][N:10]=2)[N:5]=1)[CH3:2].C[Al](C)C.[F:28][C:29]1[CH:30]=[C:31]([CH2:35][NH2:36])[CH:32]=[CH:33][CH:34]=1>C1(C)C=CC=CC=1.O>[CH2:1]([S:3][C:4]1[C:13]([C:14]([NH:36][CH2:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([F:28])[CH:30]=2)=[O:15])=[C:12]([CH3:19])[C:11]2[C:6](=[CH:7][C:8]([C:20]([F:23])([F:21])[F:22])=[CH:9][N:10]=2)[N:5]=1)[CH3:2]
Reactant: NCc1cccc(F)c1
Reactant: CCOC(=O)c1c(SCC)nc2cc(C(F)(F)F)cnc2c1C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CCSc1nc2cc(C(F)(F)F)cnc2c(C)c1C(=O)NCc1cccc(F)c1
Temperature: 110 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
To a solution of ethyl 2-(ethylthio)-4-methyl-7-(trifluoromethyl)-1,5-naphthyridine-3-carboxylate (0.20 g, 0.58 mmol, 1 eq.) in toluene (6 ml) were added Me3Al(2M solution in toluene, 1.16 ml, 2.32 mmol, 4 eq.) and (3-fluorophenyl)methanamine (0.27 ml, 2.32 mmol, 4 eq.) at RT. The reaction mixture was stirred at 110° C. for 16 h. Afterwards the mixture was diluted with water (50 ml) and was extracted with EtOAc (3×40 ml). The combined organic layers were washed with a 0.5 M aq. HCl (60 ml), brine (60 ml), dried over anhydrous Na2SO4 and evaporated to provide the crude product, which was purified by CC (EtOAc/hexane 1:4) to yield 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-7-(trifluoromethyl)-[1,5]naphthyridine-3-carboxylic acid amide (example 1) (0.14 g, 0.33 mmol, 57%). MS m/z [M+H]+ 424.1.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([CH3:11])[N:5]=[C:4]([NH2:12])[N:3]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(O)CCC>[CH2:13]([N:20]1[C:2]2[N:3]=[C:4]([NH2:12])[N:5]=[C:6]([CH3:11])[C:7]=2[CH2:8][CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(N)nc(Cl)c1CCCl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc2c1CCN2Cc1ccccc1

Procedure:
Thus, for example, J. Med. Chem. 2000, 43, 3837-3851 describes the cyclization of 4-chloro-5-(2-chloroethyl)-6-methylpyrimidine-2-amine with benzylamine in the presence of triethylamine and n-butanol to give 7-benzyl-4-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-2-amine.
Reaction SMILES: [O:1]=O.[CH3:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=C)=[CH:8][C:7]=1[OH:14].CSC>C(Cl)Cl>[CH3:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:1])=[CH:8][C:7]=1[OH:14]
Reactant: O=O
Reactant: C=Cc1ccc(C(=O)OC)c(O)c1
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)c1ccc(C=O)cc1O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A steady stream of O2 (g) is passed through a cold (−78° C.) solution of 2-hydroxy-4-vinyl-benzoic acid methyl ester (3.28 g, 0.0184 mol) in CH2Cl2 (50 ml). After 5 minutes, O3 (g) is bubbled into the solution until the solution's color turns blue/gray. The solution is then purged with O2 (g) for 5 minutes, treated with DMS (4.05 ml, 0.0552 mol) and allowed to warm to room temperature overnight. All volatiles are removed in vacuo and the crude product is purified with silica gel column chromatography (0-100% ethyl acetate in hexanes gradient) to afford 4-formyl-2-hydroxy-benzoic acid methyl ester: ESMS m/z 181.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]([OH:13])[CH2:11][CH3:12])[CH2:9][C@H:4]2[O:3]1.N1C=CN=C1.[C:20]([Si:24](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:23])([CH3:22])[CH3:21].CCOC(C)=O>CN(C=O)C>[CH3:14][C:2]1([CH3:1])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]([O:13][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:11][CH3:12])[CH2:9][C@H:4]2[O:3]1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCC(O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Yield: 81.7 %

Procedure:
To a solution of 1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propan-1-ol (compound 1e, 2.02 g, 10 mmol) in DMF (30 mL) was added imidazole (6.5 g, 100 mmol) and tert-butylchlorodiphenylsilane (8.22 g, 30 mmol) with stirring. After being stirred at room temperature for 2 hours, the resulting solution was diluted by EtOAc (200 mL), washed with water, brine and dried over Na2SO4. The organic layer was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:10 EtOAc in petroleum ether) to afford 3.6 g of 1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propoxy-tert-butyl-diphenyl-silane (compound 3a).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CO.ClCCl>[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[C:14]1[O:10][C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[N:1]=1
Reactant: COc1ccc(O)c(N)c1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2oc(-c3ccc(Cl)cc3Cl)nc2c1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-4-methoxyphenol (1 g, 7.1 mmol), a compound of formula (d) in 20 mL MeOH was added 2,4-dichlorobenzaldehyde (1.2 g, 7.1 mmol), a compound of formula (e). The mixture was heated at 45° C. for 12 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in 50 mL dichloromethane. To the solution was added DDQ (1.7 g, 7.8 mmol), and the mixture was allowed to stir at room temperature for 30 minutes. The reaction mixture was then diluted with an additional 30 mL of dichloromethane and washed sequentially with saturated NaHCO3 (2×50 mL) and brine. The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure to yield 2-(2,4-dichlorophenyl)-5-methoxybenzoxazole, a compound of formula (f), which was purified using flash column chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.C1(P([N:24]=[N+:25]=[N-:26])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1COCC1>[N:24]([CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1cncc(Br)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1cncc(Br)c1
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of (5-bromo-pyridin-3-yl)-methanol 249 (1.4 g, 7.5 mmol, 1.00 equiv) and diphenylphosphoryl azide (2.4 mL, 9.0 mmol, 1.2 equiv) in THF (15 mL) at it was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.4 mL, 9.0 mmol, 1.2 equiv). The resulting solution was stirred overnight, concentrated and chromatographically purified (15% ethyl acetate in hexanes) to give 3-azidomethyl-5-bromo-pyridine 250 (1.49 g). LCMS (MH)+=212.9, rt=1.50 min.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:56])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([N:51]=[N+:52]=[N-:53])[CH:47]([O:54][CH3:55])[CH2:46]2)[CH:7]([CH3:57])[CH:6]=[CH:5][C:4]1=[O:58])[CH3:2].C(O)(=O)C.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:56])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([N:51]=[N+:52]=[N-:53])[CH:47]([O:54][CH3:55])[CH2:46]2)[CH:7]([CH3:57])[CH2:6][CH2:5][C:4]1=[O:58])[CH3:2]
Reactant: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 17-ethyl-20-fluoro-1-hydroxy-12-[2'-(4"-azido-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-14,18-diene-2, 3,10,16-tetraone (55 mg), tetrakistriphenylphosphine palladium (10 mg), and acetic acid (10 μl) in 3 ml of dry toluene is stirred for 5 min at room temperature under nitrogen atmosphere. To this yellow solution is added tributyltin hydride (30 μl) and stirred an additional 45 min at room temperature. The reaction mixture is subjected to column chromatography on silica gel (elute first with hexane and then with 50% ethyl acetate/hexane) to give the title compound.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[F:21][C:22]1[CH:35]=[CH:34][C:25]([O:26][C:27]2[O:31][C:30]([C:32]#[CH:33])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1.[CH:36](=[O:38])[CH3:37]>C1COCC1>[F:21][C:22]1[CH:35]=[CH:34][C:25]([O:26][C:27]2[O:31][C:30]([C:32]#[C:33][CH:36]([OH:38])[CH3:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1
Reactant: CC=O
Reactant: C#Cc1ccc(Oc2ccc(F)cc2)o1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)C#Cc1ccc(Oc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
Lithium diisopropylamide was generated by the addition of n-butyl lithium (14.2 mL, 35,4 mmol, 2.5M in hexanes) to a stirred -78° C. THF (100 mL) solution as of diisopropylamine (3.58 g, 35.4 mmol) followed by warming to -5° C. (ice/methanol) and stirring for 0.5 hours. To this stirred solution was added the 2-[5-(4-fluorophenoxy)-2-furyl]-ethyne (6.5 g, 32.2 mmol) prepared in step 3 as a THF solution via syringe. The reaction was stirred 0.5 hours and acetaldehyde (3.11 g, 70.8 mmol) was added via syringe, the ice bath was removed, and the reaction warmed to room temperature. Water was added and most of the THF removed in vacuo. The resulting mixture was partitioned between water and ethyl acetate. The combined ethyl acetate layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (30% ether/hexanes) to give 6.39 g (73%) of 4-[5-(4-fluorophenoxy)-2-furyl]-3-butyne-2-ol as a slightly yellow solid. mp(ether/hexanes) 56°-57.5° C. 1H NMR (300 MHz, CDCl3) δ 1.54 (d, 3H, J=7 Hz), 1.88 (d, 1H, J=6 Hz), 4.75 (m, 1H), 5.47 (d, 1H, J=4 Hz), 6.53 (d, 1H, J=4 Hz), 7.04 (m, 4H). MS (DCI/NH3) m/e 247 (M+H)+, 229.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C@H:5]([CH3:16])[CH2:4][N:3]1[C@H:17]([C:25]1[CH:37]=[CH:36][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1.[CH3:38]I>>[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C@H:5]([CH3:16])[CH2:4][N:3]1[C@H:17]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:36][CH:37]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:38])[CH:19]=1
Reactant: CI
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)N(Cc3ccccc3F)C[C@@H]2C)cc1
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(OC)c2)N2C[C@@H](C)N(Cc3ccccc3F)C[C@@H]2C)cc1

Procedure:
4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide was alkylated with methyl iodide by a procedure essentially identical to that of Example 29 to give 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide. Calc. for C32H40FN3O2.0.1 H2O: C, 73.99; H, 7.80; N, 8.09; F, 3.66. Found: C, 73.98; H, 7.86; N, 8.00; F, 3.77.