Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C@@H:20]([OH:21])[C@@H:19]([CH2:22][OH:23])[O:18][C@@H:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C@@H:6]1[OH:24])[CH:2]=[CH2:3].N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].CO>CN(C)C=O>[CH2:1]([O:4][C@H:5]1[C@@H:20]([OH:21])[C@@H:19]([CH:22]([Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[OH:23])[O:18][C@@H:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C@@H:6]1[OH:24])[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCO[C@H]1[C@@H](O)[C@@H](CO)O[C@@H](OCCCCCC(=O)OC)[C@@H]1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CO
Product: C=CCO[C@H]1[C@@H](O)[C@@H](C(O)[Si](C)(C)C(C)(C)C)O[C@@H](OCCCCCC(=O)OC)[C@@H]1O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Compound 2 of Example 2 (10.85 g) was dissolved in dry dimethylformamide (DMF, 120 mL) containing imidazole (1.63 g) and 4 Å molecular sieves and cooled in an ice bath. To this, t-butyldimethylsilyl chloride (tBDMS chloride, 3.6 g) was added and stirred at this temperature for 10 min and then at room temperature 1 h. Another portion of imidazole (1.05 g) and tBDMS chloride (2.34 g) were added to the ice cold solution and stirred for 1 h. Methanol (1 mL) was added and the reaction mixture was evaporated to dryness. The residue was dissolved in CH2Cl2 and washed with water, 1M ice cold HCl and saturated NaHCO3 solution. The solution was dried over anhydrous magnesium sulfate, filtered and evaporated. 1H n.m.r. of the crude product (12.0 g of colorless solid) showed it to be essentially pure titled compound. [α]D25 -3.2±2° (c 1.03, CHCl3). 1H n.m.r.(CDCl3 +D2O<5 %) ∂: 5.95 (m, 1 H, --CH=C), 5.33 and 5.23 (m, 2 H, C=CH2), 4.24 (m, 3 H, H-1, J1,2 =Hz, O--CH2 --C=), 4.06 (d, H-4), 3.9-3.8 (m, 3 H, H-6a,b, OCH2 --C), 3.73 (dd, H-2), 3.67 (s, COOCH3), 3.52 (m, OCH2 --C), 3.44 (m, H-5), 3.35 (dd, H-3),2.32 (t, CH2COO), 1.65 and 1.40 (6 H, hydrogens of pentyl group), 0.89 (s, t-butyl group), 0.09 (d, CH3 --Si--CH3). 13C n.m.r. (CDCl3) ∂: 173.9, 134.8, 117.4, 103.2, 80.7, 75.0, 71.2, 71.0, 69.3, 66.3, 62.2, 51.3, 33.9, 29.2, 25.9, 25.6, 24.6, 18.3, -5.34, -5.39. Anal. Calcd for C22H2842O8Si: C, 57.14; H, 9.09. Found: C, 56.30; H 9.06.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22].Br[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[O:41][C:42]([CH3:54])=[C:43]([CH2:45][CH2:46][N:47]3[CH2:51][CH2:50][C@@H:49]([O:52][CH3:53])[CH2:48]3)[N:44]=2)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(#N)C>[CH3:53][O:52][C@@H:49]1[CH2:50][CH2:51][N:47]([CH2:46][CH2:45][C:43]2[N:44]=[C:40]([C:37]3[CH:38]=[CH:39][C:34]([C:27]4[CH:28]=[CH:29][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:25][CH:26]=4)=[CH:35][CH:36]=3)[O:41][C:42]=2[CH3:54])[CH2:48]1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CO[C@@H]1CCN(CCc2nc(-c3ccc(Br)cc3)oc2C)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CO[C@@H]1CCN(CCc2nc(-c3ccc(-c4ccc(S(C)(=O)=O)cc4)cc3)oc2C)C1
Yield: 56.7 %

Procedure:
Prepare using the method of Example 103 with palladium (II) acetate (0.003 g, 0.014 mmol), anhydrous acetonitrile (4 mL), triphenylphosphine (0.014 g, 0.055 mmol), distilled water (1 mL), 4-(methanesulfonyl)benzeneboronic acid (0.22 g, 1.03 mmol), 2-(4-bromophenyl)-4-{2-[(3R)-3-methoxypyrrolidin-1-yl]ethyl}-5-methyl-1,3-oxazole (See Example 115) (0.25 g, 0.68 mmol) and potassium carbonate (0.28 g, 2.05 mmol) to give the title compound as a white solid (0.17 g): MS (m/e): 441(M+1).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=O)=[CH:23][CH:22]=5)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:31]1[CH2:34][CH:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CO.ClCCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:1]1([C:7]2[C:11]([C:12]([F:13])([F:14])[F:15])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH2:29][N:31]3[CH2:32][CH:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34]3)=[CH:23][CH:22]=5)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc2c(c1)CCc1c-2noc1-c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: CC(C)(C)OC(=O)C1CNC1
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc3c(c2)CCc2c-3noc2-c2onc(-c3ccccc3)c2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a stirred solution of 3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (7B, 2.1 g, 5.12 mmol), tert-butyl azetidine-3-carboxylate, AcOH (1.668 g, 7.68 mmol), and acetic acid (0.586 mL, 10.24 mmol) in anhydrous MeOH (10 mL) and anhydrous 1,2-dichloroethane (30 mL) was added titanium(IV) isopropoxide (3.05 mL, 10.24 mmol) dropwise at room temperature under nitrogen. The solution was stirred at room temperature for 1 hr before sodium triacetoxyborohydride (4.34 g, 20.47 mmol) was added in 10 portions over 3.5 hr. The mixture was stirred at room temperature for 2 hr. Saturated sodium bicarbonate (70 mL) was added slowly to make the mixture basic. After celite was added, the mixture was stirred at room temperature for 30 min and then filtered through a pad of celite. The aqueous filtrate was separated and extracted with dichloromethane (3×20 mL). The combined organic solutions were dried (sodium sulfate) and concentrated. Flash chromatography purification (120 g silica gel column, 25→70% ethyl acetate in hexanes) afforded tert-butyl 1-((3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylate (2.24 g, 4.06 mmol, 79% yield) as a yellow solid. The compound had an HPLC retention time=3.40 min (condition C); LC/MS M+1=552.1.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH2:19][CH2:20][O:21][Si](C(C)C)(C(C)C)C(C)C)[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:32][C:33]1[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=1[F:40])=[O:9])=C.[F-].C([NH3+])(C)(C)C>C1COCC1>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH2:19][CH2:20][OH:21])[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:32][C:33]1[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=1[F:40])=[O:9]
Reactant: C=COCCONC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1CCO[Si](C(C)C)(C(C)C)C(C)C
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(NOCCO)c1c(Nc2ccc(I)cc2F)c2cnccc2n1CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2-fluoro-4-iodo-phenylamino)-1-(2-triisopropylsilanyloxy-ethyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (2-vinyloxy-ethoxy)-amide (58 mg, 0.085 mmol) in THF (2 mL) was added a 1M solution of tert-butylammonium fluoride in THF (0.1 mL, 0.1 mmol). The reaction mixture was stirred at room temperature for 1 hour and passed through a 5 g SCX-2 cartridge eluting with MeOH then 2M solution of ammonia in MeOH. The appropriate fractions were combined and concentrated to give a residue that was purified by flash chromatography (Si-PPC, MeOH:DCM, gradient 0:100 to 30:70). The title compound was obtained as a yellow solid (16 mg, 38%). LCMS (method A): RT=5.13 min, M+H+=501. 1H NMR (CDOD) 3.70 (2H, m), 3.90 (2H, t, J=5.3 Hz), 3.94 (2H, m), 4.60 (2H, t, J=5.3 Hz), 6.42 (1H, t, J=8.9 Hz), 7.2 (1H, m), 7.43 (1H, dd, J=10.9, 1.9 Hz), 7.60 (1H, dd, J=6.2, 0.9 Hz), 8.26 (1H, d, J=6.2 Hz), 8.58 (1H, d, J=0.9 Hz).
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH2:15][CH3:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C>[CH2:15]([N:14]([C:17]1[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=1)[CH2:13][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:26][CH:25]=1)[CH3:16]
Reactant: CCN(Cc1ccc(OCc2ccccc2)cc1)c1ccc(C#N)cc1
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: CCN(Cc1ccc(O)cc1)c1ccc(C#N)cc1
Yield: 35.5 %

Procedure:
The procedure of Preparation Example 9 was repeated, except that 111 mg of 4-[N-(4-benzyloxybenzyl)-N-ethylamino]benzonitrile was used in place of 4-[N-(4-benzyloxybenzyl)-N-methylsulfonylamino]phenyl methanesulfonate, and 3 ml of ethyl acetate was used in place of dioxane. The resulting mixture was stirred for 4 hours under an atmospheric pressure of hydrogen. The reaction mixture was filtered to remove any insoluble matter, and the solvent was distilled off from the filtrate. The resulting crude product was purified by TLC (using a 1:1 mixture of ethyl acetate and hexane as the developing solvent) to obtain 29 mg of 4-[N-ethyl-N-(4-hydroxybenzyl)amino]benzonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+].C(OCC)C.O>CN(C)C=O>[N:20]([C@@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N+:21]=[N-:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N=[N+]=[N-]
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
(1S,2S)-1-(tert-Butoxycarbonylamino)-2-methane-sulfonyloxycyclohexane (475 mg) was dissolved in N,N-dimethylformamide (6 ml), sodium azide (156 mg) was added, and the mixture was stirred for 2 hours at 60° C. and then for 24 hours at 80° C. After diethyl ether was added to the reaction mixture to conduct water washing twice, the resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane) to obtain the title compound (184 mg) as a colorless solid.
Reaction SMILES: [CH:1]([C:4]([CH3:6])=[O:5])([CH3:3])[CH3:2].[F:7][C:8]([F:12])([F:11])[S:9]Cl>C(Cl)Cl>[CH3:2][C:1]([S:9][C:8]([F:12])([F:11])[F:7])([CH3:3])[C:4](=[O:5])[CH3:6]
Reactant: CC(=O)C(C)C
Reactant: FC(F)(F)SCl
Solvent: ClCCl
Product: CC(=O)C(C)(C)SC(F)(F)F
Reaction time: 8 h
Yield: 80.7 %

Procedure:
334 g of methyl isopropyl ketone in 1.2 liters of methylene chloride were initially introduced into a narrow stirred vessel equipped with a condenser. 220 g of trifluoromethane-sulphenyl chloride were introduced, at room temperature in the course of 4 hours, through an inlet tube extending to the bottom of the vessel. The reaction mixture was allowed to stand overnight. It was then distilled. 242 g (80.7% of theory) of crude 3-methyl-3-trifluoromethylthio-butan-2-one were obtained and purified by fractional distillation: boiling point: 60° C./50 mbar and refractive index nD20 =1.4030. ##STR12##
Reaction SMILES: [C:1]1([CH:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21](Cl)([Cl:23])[Cl:22].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Cl:22][C:21]1([Cl:23])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C(=C(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: ClC(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: ClC1(Cl)C(c2ccccc2)C1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 63.7 %

Procedure:
Prepared in 64% yield from 3.2 g (12.5 mmol) of triphenylethylene (3.2 g; 12.5 mmol) and 0.25 g (1.1 mmol) benzyltriethylammonium chloride (TEBA) by dissolving in 50 g (419 mmol) CHCl3, stirring rapidly at room temperature, and treating with 27 mL of chilled 50% aqueous NaOH dropwise according to the method of Dehmlow, E. V., et al., S.S. Phase Transfer Catalysis, Verlag Chemie: Deerfield Beach 1980. After stirring 75 h, the resulting mixture was poured onto 150 mL H2O and extracted with CH2Cl2 (2×100 mL). The combined organic layers were washed with 100 mL H2O, dried (Na2SO4), filtered and concentrated. The resulting brown oil was dissolved in boiling petroleum ether, quickly filtered, and allowed to stand at room temperature, yielding 2.7 g (64%) of Compound 4a as a white powder, mp: 106°-107° C. (petroleum ether) (lit. 105°- 107° C.); NMR δ7.23 (m, 15H, ArH), 3.57 (s, 1H, cyclopropyl H); IR (CM-1) 3020, 3000, 1600, 1490, 1435, 860, 775 765, 750, 695; MS (m/z, % base) 342 (M+4), 3.2; 340 (M+2), 6.3; 338 (M+), 10.23; 303 (--Cl), 100; 267 (--Cl, --HCl), 80.7.
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.O=S(Cl)Cl.CCN(CC)CC.[C:24]([O:28][C:29](=[O:45])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][C:38]=2[CH3:44])[CH:31]=1)([CH3:27])([CH3:26])[CH3:25]>ClCCCl.CN(C=O)C>[C:24]([O:28][C:29](=[O:45])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]2[CH:42]=[CH:41][C:40]([NH:43][C:9]3[C:4]4[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=4[N:6]=[CH:7][N:8]=3)=[CH:39][C:38]=2[CH3:44])[CH:31]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1cc(N)ccc1Oc1cccc(C(=O)OC(C)(C)C)c1
Reactant: O=c1[nH]cnc2cnc(F)cc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1Oc1cccc(C(=O)OC(C)(C)C)c1
Yield: 80.8 %

Procedure:
A solution of 6-Fluoro-3H-pyrido[3,4-d]pyrimidin-4-one (0.5 g, 3.05 mmol), SOCl2 (3.63 g, 30.5 mmol), and DMF (0.2 mL) in DCE (20 mL) was heated to reflux for 12 h. The reaction was then concentrated and the resulting dark residue was dissolved in t-BuOH/DCE 1:1 (20 mL), NEt3 (0.34 g, 3.36 mmol) and 3-(4-Amino-2-methyl-phenoxy)-benzoic acid tert-butyl ester (0.91 g, 3.05 mmol) were added, the resulting solution was heated to reflux for 5 h. The reaction was concentrated, the residue was dissolved in EtOAc and washed 2× water then the organic layer was dried over Na2SO4. Purification by flash column chromatography (Hexane/Ethyl Acetate 4:6) gave the title compound as a yellow solid (1.1 g, 80%). LRMS: 447.3/391.2 (MH+). 1H NMR (DMSO-d6, 400 MHz): δ 10.03 (s, 1H), δ 8.90 (s, 1H), δ 8.65 (s, 1H), δ 8.23 (s, 1H), δ 7.803 (d, 1H), δ 7.73 (dd, J=6.23, 2.49, 1H), δ 7.58 (d, 1H) δ 7.45 (t, J=7.89, 1H), δ 7.31-7.32 (m, 1H), δ 7.14-7.16 (m, 1H), δ 7.027 (d, J=8.72, 1H), δ 2.16 (s, 3H), δ 1.48 (s, 9H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[C:21](=[O:23])[CH3:22])[C@H:16]2[C@H:7]1[C@:8]1([CH3:27])[C@@H:13]([CH2:14][CH2:15]2)[CH2:12][CH:11]=[CH:10][CH2:9]1)=[O:4].ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]([O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[C:21](=[O:23])[CH3:22])[C@H:16]2[C@H:7]1[C@:8]1([CH3:27])[C@@H:13]([CH2:14][CH2:15]2)[CH2:12][C@@H:11]2[O:36][C@@H:10]2[CH2:9]1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3[C@@H](OC(=O)CCl)C[C@]12C
Solvent: ClC(Cl)Cl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3[C@@H](OC(=O)CCl)C[C@]12C
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
11β-Chloroacetoxy-5α-pregn-2-en-20-one (1.25 g) in chloroform (50 ml) was treated with m-chloroperbenzoic acid (85%; 700 mg) and the solution was stirred at room temperature for 4 hours. Chloroform (50 ml) was added, and the solution was washed with potassium bicarbonate solution and with water; it was then dried over sodium sulphate and evaporated to a white foam which was triturated with ether to give title compound (1.05 g) as colourless prisms, m.p. 163°-169°, [α]D +107°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH:18]([OH:19])[CH2:17][N:16]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C([O-])(=O)C.[NH4+]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([N:16]2[CH2:15][CH:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:18]([OH:19])[CH2:17]2)=[O:28])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CN(C(=O)c3ccc(Cl)cc3)CC2O)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=C(c1ccc(Cl)cc1)N1CC(O)C(N2CCNCC2)C1
Yield: 99 %

Procedure:
The desired compound was prepared in a manner similar to that described in Example 137 from 4-[1-(4-Chloro-benzoyl)-4-hydroxy-pyrrolidin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester in 99% yield. 1H-NMR (300 MHz, D2O): δ 2.75 (1 H, m), 3.0 (1 H, m), 3.15 (4 H, m), 3.25 (3 H, m), 3.3-3.5 (2 H, m), 3.7 (1 H, m), 3.9 (1 H, m), 4.4 (1 H, m), 7.35 (4 H, dd). Retention Time (LC, method: ammonium acetate standard):0.89 min. MS (M+H+): 310.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH2:15]([O:17][C:18](=[O:21])[CH:19]=[CH2:20])[CH3:16]>C(O)C>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][CH2:20][N:11]1[CH2:12][CH2:13][C:14]2=[C:2]([CH3:1])[C:3]3[C:8]([CH:9]2[CH2:10]1)=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:16]1[CH:4]=[CH:3][CH:2]=[CH:14][CH:13]=1
Reactant: CC1=C2CCNCC2c2ccccc21
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CC1=C2CCN(CCC(=O)OCc3ccccc3)CC2c2ccccc21

Procedure:
A mixture of 12.5 g of 1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and 10 g acrylic acid ethyl ester are heated in 100 ml of ethanol for 3 hours at 80° C and then evaporated to dryness. The title compound is obtained as a colourless oil after distillation under a vacuum of 0.1 Torr.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([OH:9])[C:6](I)=[CH:5][N:4]=1.[C:11]1([CH2:17][C:18]#[CH:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N(CC)CC)C.CN1C(=O)CCC1.C(OCC)(=O)C.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:19]=[C:18]([CH2:17][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:9][C:7]=2[N:8]=1
Reactant: CSc1ncc(I)c(O)n1
Reactant: C#CCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CSc1ncc2cc(Cc3ccccc3)oc2n1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
A mixture of 2-methylthio-4-hydroxy-5-iodopyrimidine (2.65 g), 3-phenyl-1-propyne (1.49 mL), copper (I) iodide (90 mg) and bis(triphenylphosphine) Palladium (II) dichloride (Fluka, 160 mg) in 20 mL of triethylamine and NMP (7 mL) was stirred at 40° C. for 6 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (3×50 mL), concentrated and purified by column chromatography (5% EtOAc/hexanes) to give 0.57 g of a solid product. MP: 69–72.2° C. MS: 257.2 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16]([O:18][CH3:19])=[O:17])[C:6]2[C:7]([CH3:15])=[CH:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1)#[N:2].[N:20]([Si](C)(C)C)=[N+:21]=[N-:22].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>CCOC(C)=O.CC(O)=O>[CH:12]([N:9]1[C:10]2[CH:11]=[C:3]([C:1]3[NH:22][N:21]=[N:20][N:2]=3)[CH:4]=[C:5]([C:16]([O:18][CH3:19])=[O:17])[C:6]=2[C:7]([CH3:15])=[CH:8]1)([CH3:14])[CH3:13]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COC(=O)c1cc(C#N)cc2c1c(C)cn2C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(-c2nnn[nH]2)cc2c1c(C)cn2C(C)C
Temperature: 85 °C
Reaction time: 18 h
Yield: 47.9 %

Procedure:
To a stirred suspension of methyl 6-cyano-1-isopropyl-3-methyl-1H-indole-4-carboxylate (0.50 g, 1.951 mmol) in azidotrimethylsilane (1.0 mL, 7.53 mmol) in a small vial was added tetrabutylammonium fluoride trihydrate (300 mg, 0.951 mmol). The reaction was heated to 85° C. and stirred for 18 hr (attached a small reflux condensor). (The reaction became a semi-solid mass.) The reaction was taken up in EtOAc (75 mL), washed with 1 N HCl (75 mL) (stirred till dissolved). The organic phase was removed, dried (Na2SO4), filtered and concentrated under vacuum. Purification by silica gel chromatography (Analogix, SF40-80 g, 0 to 3% MeOH/CH2C12 with 0.1% HOAc) gave the product methyl 1-isopropyl-3-methyl-6-(1H-tetrazol-5-yl)-1H-indole-4-carboxylate (0.28 g, 0.935 mmol, 48.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J=1.3 Hz, 1H), 8.15 (d, J=1.5 Hz, 1H), 7.69 (s, 1H), 4.86 (quin, J=6.6 Hz, 1H), 3.94 (s, 3H), 2.33 (s, 3H), 1.50 (d, J=6.6 Hz, 6H). MS(ES)+m/e 300.3 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH2:9][NH:10][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:55]([O:57][C:58]([CH2:60][C:61](Cl)=[O:62])=[O:59])[CH3:56]>>[CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=2)[C:8]2[CH2:9][N:10]([C:61](=[O:62])[CH2:60][C:58]([O:57][CH2:55][CH3:56])=[O:59])[CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)CNC(C(=O)OC)C2
Reactant: CCOC(=O)CC(=O)Cl
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)CN(C(=O)CC(=O)OCC)C(C(=O)OC)C2

Procedure:
Methyl 2-n-butyl-3-{2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]-pyridine-6-carboxylate and ethoxycarbonylacetyl chloride are treated in the same manner as in Example 1-(2) to give methyl 2-n-butyl-5-ethoxycarbonylacetyl-3-{2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[C:14]([CH3:38])=[C:15]([N:19]([CH2:23][C:24]2[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:26]([CH3:37])[CH:25]=2)[CH2:20][CH2:21][CH3:22])[CH:16]=[CH:17][CH:18]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]([CH2:23][C:24]3[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([CH3:37])[CH:25]=3)[CH2:20][CH2:21][CH3:22])[C:14]=2[CH3:38])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C#N)cc2)c1C

Procedure:
Prepared from 4-cyanophenylboronic acid and ethyl (4-{[(3-bromo-2-methylphenyl)(propyl)amino]methyl}-2-methylphenoxy)acetate using the procedure described for Example 25 (Method A).
Reaction SMILES: [H-].[Na+].CC1C=CC(S(O[CH2:14][C@@H:15]2[O:17][CH2:16]2)(=O)=O)=CC=1.[F:18][C:19]1[CH:34]=[CH:33][C:22]2[C:23]([C:26]3[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=3)=[N:24][O:25][C:21]=2[CH:20]=1>CN(C)C=O.O>[F:18][C:19]1[CH:34]=[CH:33][C:22]2[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:14][C@H:15]4[CH2:16][O:17]4)[CH:27]=3)=[N:24][O:25][C:21]=2[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: Oc1cccc(-c2noc3cc(F)ccc23)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Yield: 75 %

Procedure:
The title compound is prepared from a mixture of sodium hydride in dimethylformamide, 3-(6-fluoro-benzo[d]isoxazol-3-yl)-phenol in dimethylformamide and (2R)-(−)-glycidyl tosylate in dimethylformamide essentially as described above except that the reaction mixture is diluted with water, extracted with ethyl acetate, washed with water (twice), dried (MgSO4), concentrated and purified by column (silica) chromatography eluting with a graded solvent mixtures of toluene to 1% ether in toluene to give the title compound as a white solid (9.29 g, 75% Yield). NMR and microanalysis (C, H, N) are consistent with the final, desired compound. Chiral HPLC, 16.92 minutes, [Chiralcel OD (250×4.6 mm), 98:2 heptane/ethanol @ 0.8 mL/min, UV @ 285 nm, 18.14] shows the title compound as 95.5% e.e. mp=84-85° C.