Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:27])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.[CH3:28][O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:13]([O:12][C:11]([N:10]([CH2:9][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:35]2[CH:36]=[CH:37][C:32]([C:30]([O:29][CH3:28])=[O:31])=[CH:33][CH:34]=2)=[CH:22][CH:21]=1)=[O:17])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O)cc1)C[C@H](O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Oc2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.1 %

Procedure:
To a suspension of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4-hydroxyphenyl)ethyl]carbamate (550 mg), (4-methoxycarbonylphenyl)boronic acid (300 mg), triethylamine (1.0 ml) and powdered 4 Å molecular sieves (600 mg) in dichloromethane (8 ml) was added copper(II) acetate (255 mg), and the mixture was stirred at room temperature for 18 hours under ambient atmosphere. The resulting slurry was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give methyl 4-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]benzoate (185 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:5].[Br-:17].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[Br:17][CH:3]([CH:2]([CH3:16])[CH3:1])[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(C)CC(=O)c1cccc2ccccc12
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)C(Br)C(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-methyl-1-(naphth-1-yl)butan-1-one (20 g) in anhydrous tetrahydrofuran (150 ml) was added phenyltrimethylammonium tribromide (35.7 g). The resulting mixture was stirred overnight at ambient temperature then partitioned between petroleum ether and water. The organic layer was separated, washed with water, brine, dried with sodium sulphate, filtered and evaporated in vacuo to yield crude 2-bromo-3-methyl-1-(naphth-1-yl)butan-1-one. Sodium acetate (7.7 g) and anhydrous dimethylformamide (40 ml) were added and the resulting mixture was stirred at 100° C. for 6 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The aqueous layer was back-extracted once with ethyl acetate. The combined organic layers were washed with water, brine, dried with sodium sulphate, filtered and evaporated in vacuo. The title compound (8.4 g) was obtained following silica gel column chromatography of the residue in 50% dichloromethane in petroleum ether.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)[CH:27]=[C:28]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[Cl:39])[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[Cl:39])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)C=C(CBr)Oc1cccc(Cl)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.2 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.15 g, 0.062 mol) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (3.63 g, 0.282 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with 4-bromo-3-(2,3-dichloro-phenoxy)-but-2-enoic acid ethyl ester (2.0 g, 0.006 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification using flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (0.40 g, 17%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:42])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:30][C:31]1[CH:32]=[C:33]([CH2:37][C:38]([O:40]C)=[O:39])[CH:34]=[CH:35][CH:36]=1)[CH2:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29].[OH-].[Li+].O1CCCC1>O>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:42])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:30][C:31]1[CH:32]=[C:33]([CH2:37][C:38]([OH:40])=[O:39])[CH:34]=[CH:35][CH:36]=1)[CH2:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CCCN3CCCC3=O)Cc3cccc(CC(=O)OC)c3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CCCN3CCCC3=O)Cc3cccc(CC(=O)O)c3)c2n1

Procedure:
The compound obtained in Example 2-33 (50 mg) and lithium hydroxide (20 mg) were added to tetrahydrofuran (5 ml) and water (1 ml), and the same manner to Example 2-12 was conducted to give the titled compound as a white solid. Yield: 39 mg (80%); MS APCI+ve 568 (M+H).
Reaction SMILES: [ClH:1].C([N:9]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:10][C:11]([C:13]1[CH:22]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:16]([O:23][CH3:24])=[CH:15][CH:14]=1)=[O:12])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[ClH:1].[C:25]([NH:9][CH2:10][CH:11]([C:13]1[CH:22]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:16]([O:23][CH3:24])=[CH:15][CH:14]=1)[OH:12])([CH3:28])([CH3:27])[CH3:26]
Reactant: [H][H]
Reactant: COC(=O)c1cc(C(=O)CN(Cc2ccccc2)C(C)(C)C)ccc1OC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COC(=O)c1cc(C(O)CNC(C)(C)C)ccc1OC
Yield: 91.5 %

Procedure:
5-(N-Benzyl-N-tert.butylglycyl)-o-anisic acid, methyl ester, hydrochloride (4.05g) in ethanol (60 ml) was added to a pre-reduced suspension of 10% Pd/C (1.0g) in ethanol (15 ml) and hydrogenated until uptake ceased (hydrogen uptake was 441.cc). The catalyst was filtered off and the filtrate evaporated to dryness to afford 5-(2-tert.butylamino-1-hydroxyethyl)-o-anisic acid, methyl ester, hydrochloride as a white crystalline solid (2.9g) m.p. 189°-194° .
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](OS(C2C=CC(C)=CC=2)(=O)=O)=[C:4]([N+:23]([O-:25])=[O:24])[C:3]1=[O:26].[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C=O)C>[N:27]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:2]([CH3:1])[C:3](=[O:26])[C:4]=1[N+:23]([O-:25])=[O:24])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)Oc2c([N+](=O)[O-])c(=O)n(C)c3ccccc23)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c([N+](=O)[O-])c(N=[N+]=[N-])c2ccccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 92 %

Procedure:
A solution of toluene-4-sulfonic acid 1-methyl-3-nitro-2-oxo-1,2-dihydro-quinolin-4-yl ester (20.0 g, 53.42 mmol) in DMF (70 mL) was treated with a small excess of sodium azide (3.8 g, 59.0 mmol) and stirred at room temp for 17 h. The solvent was evaporated under reduced pressure. Then the reaction mixture was poured into 500 mL of ice water and the resulting precipitate was collected by suction filtration and dried in vacuo. The pure 4-azido-1-methyl-3-nitro-1H-quinolin-2-one was obtained (12.0 g, 92% yield). 1H-NMR (CDCl3): δ 8.16 (d, 1H, J=8.8 Hz), 7.75 (t, 1H, J=7.6 Hz), 7.42 (d, 1H, J=8.4 Hz), 7.36 (t, 1H, J=7.6 Hz), 3.79 (s, 3H). MS: calculated for C10H7N5O3+H 246.1; found: 246.2.
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:21]=[CH:20][C:19]=2[F:31])=[C:14]([F:32])[C:13]([CH3:33])=[CH:12][C:3]=1[O:4][CH2:5][C:6]([O:8]C(C)C)=[O:7].[Li+].[OH-]>C1COCC1>[F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:21]=[CH:20][C:19]=2[F:31])=[C:14]([F:32])[C:13]([CH3:33])=[CH:12][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: Cc1cc(OCC(=O)OC(C)C)c(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(OCC(=O)O)c(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
To a solution of isopropyl 2-[2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-5-methyl-phenoxy]acetate (194 mg, 0.42 mmol, 1.0 eq) in THF (10 mL) was added LiOH (2M aqueous solution, 5 mL, 5 mmol). The reaction mixture was stirred at room temperature overnight. The THF was removed under reduced pressure and the pH of the aqueous phase adjusted to pH 5 by addition of diluted HCl. The solid that formed was collected by filtration, washed with water and dried in vacuo to give the title compound as a white solid (61 mg, 91%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([OH:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br.Br[CH2:37][C:38]1[CH:47]=[C:46]2[C:41]([CH:42]=[CH:43][CH:44]=[N:45]2)=[CH:40][CH:39]=1.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:37][C:38]2[CH:47]=[C:46]3[C:41]([CH:42]=[CH:43][CH:44]=[N:45]3)=[CH:40][CH:39]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2O)cc1
Reactant: BrCc1ccc2cccnc2c1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3cccnc3c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.5 %

Procedure:
3.40 g (7.20 mmol) of (3R,4R)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butylester and 2.18 g (7.20 mmol) of 7-bromomethyl-quinoline hydrobromide (1:1) [J. Am. Chem. Soc. 77, 1054(1955)], were dissolved in 50 ml of absolute dimethylformamide under argon and then 0.83 g (19.0 mmol) of sodium hydride dispersion (55% in mineral oil) was added at room temperature in small portions. Subsequently, the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured onto ice-water, the product was extracted 3 times with ethyl acetate, the combined organic phases were washed twice with distilled water, then dried over magnesium sulphate, filtered and concentrated. The crude product (5.2 g, yellow oil) was chromatographed on silica gel with ethyl acetate/hexane 2:1 to yield 3.77 g (85.4% of theory) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(quinolin-7-yl-methoxy)-piperidine-1-carboxylic acid tert-butylester as a colourless oil; MS: 613 (M+H)+.
Reaction SMILES: C([Li])CCC.C1([SiH3])C=CC=CC=1.[CH3:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH:15]=1.[H][H]>C1COCC1>[CH3:13][CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: CC1=CCCc2ccccc21
Reactant: [H][H]
Agent: [Li]CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: CC1CCCc2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70.1 %

Procedure:
In a dry sealable Schlenk flask under an argon atmosphere 0.059 g (0.099 mmol) (S,S)-ethylene-1,2-bis(η5 -4,5,6,7-tetrahydro-1-indenyl)titanium (S)-1,1'- binaphth-2,2'-diolate was dissolved in THF (10 mL). The vessel was degassed by exposure to vacuum (2 x~10 sec), put under an atmosphere of hydrogen and subsequently cooled to 0° C. in an ice water bath. After equilibration, a solution of n-butyllithium (0.125 mL, 1.58M in hexanes, 0.196 mmol, 1.96 equiv) was added and the mixture was allowed to stir for 10 min. Phenylsilane (0.033 mL, 0.259 mmol, 2.6 equiv) and 0.273 g (1.87 mmol, 19 equiv) 1-methyl-3,4-dihydronaphthalene were then added. The flask was sealed and the solution moved into a dry box and transferred to a Parr® high pressure reaction vessel containing a magnetic stir bar. The pressure vessel was sealed and moved to a fume hood where it was charged to 2150 psig with hydrogen and placed in an oil bath at 65° C. The reaction mixture was allowed to stir for 184 h. The vessel was cooled to room temperature, vented and opened to air. The reaction mixture was worked up by partitioning between diethyl ether/hexane (1/4) and water and separating the layers. The organic extract was distilled at reduced pressure to yield 0.195 g (1.31 mmol, 70%) of 1-methyl-1,2,3,4-tetrahydronaphthalene with an ee of 70%, determined polarimetrically.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[NH:31]1[CH2:36][CH2:35][CH:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:31]5[CH2:32][CH2:33][CH:34]([NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[CH2:35][CH2:36]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:30])[F:29])[CH:3]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CS(=O)(=O)NC1CCNCC1
Product: CS(=O)(=O)NC1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
N-(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-methanesulfonamide was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and N-piperidin-4-yl-methanesulfonamide following General Procedure B.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[NH:20][N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][N:19]([C:25](=[O:26])[N:24]([CH3:28])[CH3:23])[N:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1cn[nH]c1-2
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C(=O)n1cc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of 0.33 g of 8-chloro-6-(2-chlorophenyl) 1H,4H-pyrazolo[4,3-d](2)benzazepine in 10 ml of methylene chloride, the mixture of 0.16 g of dimethylcarbamoyl chloride and 0.15 g of pyridine is added and the whole stirred for 2 hours at room temperature. The mixture is diluted with methylene chloride, washed with ice-cold aqueous sodium carbonate, dried and evaporated under reduced pressure. The residue is chromatographed on silica gel and eluted with benzene-methanol(95:5), to yield the 8-chloro-6-(2-chlorophenyl)-2-dimethylcarbamoyl-2H,4H-pyrazolo[4,3-d](2)benzazepine melting at 175°-176°.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35]([OH:37])=O)[CH:12]=[CH:13][CH:14]=1.[NH2:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:46][O:45][C:43](=[O:44])[C:42]1[CH:47]=[CH:48][C:39]([NH:38][C:35]([C@H:16]2[C@H:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Br:8])[CH:10]=3)[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:32])([CH3:34])[CH3:33])[NH:17]2)=[O:37])=[CH:40][CH:41]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Br)c2)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Br)c2)cc1
Yield: 36.6 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 66c (0.44 g, 0.74 mmol) was reacted with methyl 4-aminobenzoate (0.1 g, 1.32 mmol), HATU (0.3 g, 0.4 mmol) and iPr2NEt (0.32 mL, 1.8 mmol) in CH2Cl2 at room temperature to give rac-4-{[(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid methyl ester as a white solid (0.17 g, 37%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10](I)=[CH:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH:27]=1)[C:21](N(OC)C)=[O:22]>>[Br:15][C:16]1[CH:27]=[C:20]([C:21]([C:10]2[C:5]3[CH:4]=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]=2)=[O:22])[CH:19]=[N:18][CH:17]=1
Reactant: CON(C)C(=O)c1cncc(Br)c1
Reactant: CC(C)n1cc(I)c2cnc(Cl)nc21
Product: CC(C)n1cc(C(=O)c2cncc(Br)c2)c2cnc(Cl)nc21

Procedure:
The title compound was prepared according to the method described for Preparation 28 using 2-chloro-5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (Preparation 120) and 5-bromo-N-methoxy-N-methylnicotinamide to afford the title compound as a yellow solid in 41% yield, 1.2 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4]P(OCC)(OCC)=O.CC(C)([O-])C.[K+].[C:20]1([S:26]([N:29]2[C:37]3[C:32](=[C:33]([Br:38])[CH:34]=[CH:35][CH:36]=3)[CH:31]=[C:30]2[C:39](=O)[CH3:40])(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]=[C:39]([C:30]1[N:29]([S:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:27])=[O:28])[C:37]2[C:32]([CH:31]=1)=[C:33]([Br:38])[CH:34]=[CH:35][CH:36]=2)[CH3:40]
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: CC(=O)c1cc2c(Br)cccc2n1S(=O)(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C=C(C)c1cc2c(Br)cccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 769.1 %

Procedure:
Methyldiethylphosphonoacetate (366 mg, 0.97 mmol) was dissolved in DMF (8 mL) under nitrogen, cooled in an ice bath, and treated with potassium t-butoxide (434 mg, 3.87 mmol). The ice bath was removed and allowed to warm to room temperature over 30 min. 1-(1-Benzenesulfonyl-4-bromo-1H-indol-2-yl)ethanone (366 mg, 0.97 mmol) dissolved in DMF (4 mL) was added and the reaction heated at 50° C. for 1.5 h. The reaction was allowed to cool and poured into ethyl acetate/saturated ammonium chloride solution. The aqueous was washed with more ethyl acetate. Then the pH was lowered and the aqueous washed a third time with ethyl acetate. The organic portions were washed with brine, dried (MgSO4), filtered and evaporated to give 3.24 g brown oil. The material was purified by column chromatography using (5:1) hexane:ethyl acetate to give 207 mg (28%) of a crude foam. The material was used without further purification. MS [EI+] 434, 436 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[S:3]([N:6]1[C:10](SC2C=CC=CC=2)=[CH:9][N:8]=[C:7]1[Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])(=[O:5])=[O:4].CC(C[AlH]CC(C)C)C.CO.[C@H](O)(C([O-])=O)[C@@H](O)[C:39]([O-])=[O:40].[Na+].[K+]>CCOCC>[CH3:25][N:2]([CH3:1])[S:3]([N:6]1[C:10]([CH:39]=[O:40])=[CH:9][N:8]=[C:7]1[Si:18]([C:21]([CH3:23])([CH3:24])[CH3:22])([CH3:19])[CH3:20])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)n1c(Sc2ccccc2)cnc1[Si](C)(C)C(C)(C)C
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CN(C)S(=O)(=O)n1c(C=O)cnc1[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
A solution of cyclohexenone (1) (2.88 g, 30 mmol) in hexanes at −78° C. was treated with DIBAL (30 mL, 1.0 M in cyclohexane). After 25 m, MeOH (7 mL) was added and the mixture was warmed to rt. A saturated solution of Rochelle's salt was added followed by dilution with ether (100 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated under vacuum. The product was purified by chromatography on SiO2 with 20% EtOAc:Hx to give a clear colorless alcohol 2, 2.0 g (68%).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:16])[CH2:14][CH3:15]>>[CH2:13]([NH:16][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])[CH2:14][CH3:15]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCN
Product: CCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The product was made from D-glucose and n-propylamine comparable as in Example A.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[C:11]=2[F:19])[N:7]=[C:6]([C:20]([O:22]C)=[O:21])[C:5]=1/[CH:24]=[CH:25]/[Si:26]([O:33]CC)([O:30]CC)[O:27]CC.CO.Cl>O1CCCC1>[NH2:3][C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[C:11]=2[F:19])[N:7]=[C:6]([C:20]([OH:22])=[O:21])[C:5]=1/[CH:24]=[CH:25]/[Si:26]([OH:33])([OH:30])[OH:27]
Reactant: CCO[Si](/C=C/c1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC)(OCC)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(Cl)ccc(-c2nc(N)c(/C=C/[Si](O)(O)O)c(C(=O)O)n2)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.5 %

Procedure:
A 2M aqueous solution of sodium hydroxide (150 μL, 0.31 mmol, 1.05 equiv) was added to a stirred solution of (E)-methyl 6-amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-(2-(triethoxysilyl)vinyl)pyrimidine-4-carboxylate (145 mg, 0.29 mmol, 1.0 equiv) in 3:1 methanol:tetrahydrofuran (4.0 mL) at room temperature. The homogeneous yellow solution was stirred at room temperature for 20 h. The reaction mixture was adjusted to pH 4 using concentrated hydrochloric acid and concentrated under vacuum. The residue was slurried in water and vacuum filtered to provide the title compound as a tan powder (95 mg, 81% yield): mp 220-250° C. (decomposition); IR (thin film) 3323 (m), 3195 (m), 2944 (w), 1603 (s), 1534 (s) cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.56-7.76 (m, 1H), 6.59-7.52 (m, 4H), 3.93 (br s, 3H); ESIMS m/z 402 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].C1(C#C)C=CC=CC=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)C#N>C(#N)C1C=CC=CC=1>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][CH:22]=[C:23]([C:4]#[C:3][C:2]([CH3:6])([CH3:5])[CH3:1])[CH:24]=1
Reactant: C#CC(C)(C)C
Reactant: COc1cccc(C#N)c1
Solvent: C#Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: COc1cccc(C#CC(C)(C)C)c1
Reaction time: 16 h
Yield: 92.5 %

Procedure:
The procedure was identical to Example 1, with the exception that 3,3-dimethyl-1-butyne (0.488 ml; 0.329 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 3-methoxybenzonitrile (0.245 ml; 0.266 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 16 h at 65° C. showed the presence of 1.85 mmol (92% yield) of 1-methoxy-3-(3,3-dimethyl-1-butynyl)benzene and no remaining 3-methoxybenzonitrile in the reaction mixture.