Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].N1C=CN=C1.[C:14]([Si:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)Cl)([CH3:17])([CH3:16])[CH3:15]>N1C=CC=CC=1>[Si:18]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccc(O)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](Oc1ccc(O)cc1)(c1ccccc1)c1ccccc1
Yield: 55.1 %

Procedure:
To a solution of 8.26 g of hydroquinone and 6.3 g of imidazole in 80 mL of pyridine was added 20.6 g of t-butyldiphenylchlorosilane in 20 mL of pyridine. After 1.5 h the mixture was partitioned between water and ethyl acetate. The organic layer was washed twice with phosphate buffer (pH 2) and once each with phosphate buffer (pH 8) and brine before being filtered through N/N/S and concentrated in vacuo. Preparative liquid chromatography [silica; hexane/ethyl acetate (85:15)] afforded 14.4 g of 4-(t-butyldiphenylsilyloxy)phenol. The structure was confirmed by its NMR spectrum. To a solution of 46 mg of 1,1'-carbonyldiimidazole in 0.5 mL nitromethane was added 65 μL of methyl triflate followed by 100 mg of 4-(t-butyldiphenylsilyloxy)phenol in 1.4 mL of nitromethane. A total of 1.9 mL of this solution was added to a mixture of 100 mg of phorbol 12,13-bis[(2',4'-difluorophenyl)acetate] and approximately 10 mg of 4-dimethylaminopyridine in 500 μL of anhydrous tetrahydrofuran. After 4.5 h this mixture was partitioned between ethyl acetate and water. The organic layer was filtered through N/N/S, concentrated in vacuo and subjected to preparative liquid chromatography [silica; hexane/ethyl acetate (80:20)] to afford 142 mg of 20-O-[4'-(t-butyldiphenylsilyloxy)phenoxy]carbonylphorbol 12,13-bis[(2',4'-difluorophenyl)acetate]. A solution of this material in 1 mL tetrahydrofuran was treated with 160 μL of 1.0M tetrabutylammonium fluoride in tetrahydrofuran. After 14 min the mixture was partitioned between ethyl acetate and phosphate buffer (pH 8). The organic layer was filtered through N/N/S and concentrated in vacuo. After preparative liquid chromatography [silica, hexane/ethyl acetate (65:35)] 108 mg of 20-O-(4'-hydroxyphenoxy)carbonylphorbol 12,13-bis[(2',4'-difluorophenyl)acetate] was obtained. The structure was confirmed by NMR and mass spectral analysis.
Reaction SMILES: [O:1]=[C:2]([N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:3][O:4][C@@H:5]1[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[C@H:8]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[O:16])[C@@H:7]([C:29](OC)=[O:30])[CH2:6]1.[OH:38][NH2:39].C[O-].[Na+].Cl>CO>[OH:38][NH:39][C:29]([C@H:7]1[CH2:6][C@H:5]([O:4][CH2:3][C:2](=[O:1])[N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[C@@H:8]1[C:15]([N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:21][CH2:22]1)=[O:16])=[O:30]
Reactant: NO
Reactant: COC(=O)[C@H]1C[C@H](OCC(=O)N2CCCC2)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)N1C[C@@H](OCC(=O)N2CCCC2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
To the reaction mixture of dimethyl (2S,3S,5S)-5-(2-oxo-2-pyrrolidin-1-ylethoxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (64 mg, 0.00012 mol) in methanol (0.5018 mL, 0.01239 mol) was added 1.640 M of N-hydroxyamine in methanol solution (1.51 mL) made from the corresponding salt and sodium methoxide. After stirred at rt for 1 h, the mixture was acidified with 1N HCl. The resultant mixture was applied directly on RP-HPLC to afford the product as a TFA salt (14 mg, 18%). MS (ESI): (M+H)+=518.2.
Reaction SMILES: [C:1](=[O:33])([O:7][C:8]1[C:13](I)=[C:12]([CH3:15])[N:11]=[C:10]([CH3:16])[C:9]=1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[Cl-].[Li+].[CH2:36]([Sn](CCCC)(CCCC)C=C)[CH2:37]CC>O1CCOCC1.C(Cl)(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1](=[O:33])([O:7][C:8]1[C:13]([CH:36]=[CH2:37])=[C:12]([CH3:15])[N:11]=[C:10]([CH3:16])[C:9]=1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[O:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCCCCCCCCCCCCCCCc1c(C)nc(C)c(I)c1OC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: C=Cc1c(C)nc(C)c(CCCCCCCCCCCCCCCC)c1OC(=O)OC(C)(C)C
Yield: 4.6 %

Procedure:
To a solution of 8 (85 mg, 0.864 mmol) in 1,4-dioxane (4 ml) were added lithium chloride (73.2 mg, 1.73 mmol), tetrakis(triphenylphosphine)palladium (99.8 mg, 10 mol %) and tributyl(vinyl)tin (0.327 ml, 1.12 mmol). The mixture was heated at reflux for 3 h then cooled and diluted with CHCl3. The mixture was washed with brine, dried over Na2SO4, filtered, and concentrated in under diminished pressure. The residue was purified by column chromatography on silica gel [AcOEt/MeOH (20:1)] to afford tert-butyl 3-hexadecyl-2,6-dimethyl-5-vinylpyridin-4-yl carbonate (10) (19 mg, 27%). 1H NMR (CDCl3) δ 0.02-0.03 (m, 3H), 1.20-1.27 (m, 28H), 1.46 (s, 9H), 2.45 (s, 3H), 2.48 (s, 3H), 2.54-2.56 (m, 2H), 5.55 (dd, 2H, J=17.6 Hz, 11.6 Hz) and 6.50 (dd, 1H, J=11.2 Hz, 11.2 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:10][OH:11])[C:5]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:36])(=[N:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:29])=[CH:24][CH:23]=1>>[CH2:34]([O:33][C:31]([N:30]=[S:28]([C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:2]2[N:7]=[C:6]([NH:8][C@H:9]([CH2:10][OH:11])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)=[CH:4][N:3]=2)=[CH:27][CH:26]=1)([CH3:36])=[O:29])=[O:32])[CH3:35]
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(N)cc1
Reactant: CC(C)C[C@@H](CO)Nc1nc(Cl)ncc1-c1ccsc1
Product: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3ccsc3)c(N[C@H](CO)CC(C)C)n2)cc1
Yield: 42 %

Procedure:
In the reaction (S)-2-(2-chloro-5-thiophen-3-yl-pyrimidine-4-ylamino)-4-methyl-pentan-1-ol (278 mg, 0.89 mmol) with (RS)—S-(4-amino-phenyl)-N-(ethoxycarbonyl)-S-methylsulfoximide (240 mg, 0.99 mmol) according to procedure 5b, the desired product is obtained in 42% yield (220 mg) after chromatographic purification (silica gel, dichloromethane/methanol (0%-10% methanol)).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]#[C:19][Si](C)(C)C)=[CH:13][CH:12]=2.C(OCC)(=O)C>CO>[Cl:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]#[CH:19])=[CH:13][CH:12]=2
Reactant: C[Si](C)(C)C#Cc1ccc2cnc(Cl)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1ccc2cnc(Cl)cc2c1
Reaction time: 1 h
Yield: 89.6 %

Procedure:
Potassium carbonate (9 mg, 0.0654 mmol) was added to a solution of 3-chloro-6-((trimethylsilyl)ethynyl)isoquinoline (Preparation 51, 170 mg, 0.654 mmol) in methanol (1 mL) and the reaction was stirred for 1 hour. Ethyl acetate (20 mL) was added and the organic solution was washed with water (20 mL), brine (20 mL), dried over sodium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 50% hexane in dichloromethane to afford the title compound as a white powder (110 mg, 90%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH2:26]([S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH3:28]>>[CH2:26]([S:29]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:31])=[O:30])[CH2:27][CH3:28]
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Product: CCCS(=O)(=O)NCCc1ccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.5 g (1.4 mmol) of material from Example 50 and 9.0 μL (0.11 mmol) 1-propanesulfonyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:31][C:32]([CH:35]5[CH2:39][CH2:38][CH2:37][N:36]5[C:40](=[O:53])[CH:41]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH2:42][CH2:43]C(F)(F)F)=[N:33][CH:34]=4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC(=O)C(NC(OC)=O)CC[O:60][CH2:61][C:62]([F:65])([F:64])[F:63]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:31][C:32]([CH:35]5[CH2:39][CH2:38][CH2:37][N:36]5[C:40](=[O:53])[CH:41]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH2:42][CH2:43][O:60][CH2:61][C:62]([F:65])([F:64])[F:63])=[N:33][CH:34]=4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)NC(CCOCC(F)(F)F)C(=O)OC
Reactant: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Product: COC(=O)NC(CCOCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Yield: 74 %

Procedure:
This compound was made in 74% yield by the same procedure as 2-[5-(4′-{2-[1-(5,5,5-Trifluoro-2-methoxycarbonylamino-pentanoyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester, using 2-Methoxycarbonylamino-4-(2,2,2-trifluoro-ethoxy)-butyric acid methyl ester as the starting material. LCMS-ESI+: calculated for C39H46F3N7O6: 765.35; observed [M+1]+: 766.12.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH:37]1[CH3:42])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([CH2:20][C:17]2[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:28])[CH3:1])[N:22]([CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=2)[CH2:38][CH:37]1[CH3:42])=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC1CNCCN1C(=O)OC(C)(C)C
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Product: CC1CN(Cc2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CCN1C(=O)OC(C)(C)C

Procedure:
Following General Procedure C, 7-Cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.298 g, 0.788 mmol) and 2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.316 g, 1.58 mmol) gave 4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-ylmethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester a yellowish oil (0.341 g, 77%) [following purification by SiO2 chromatography eluting with 2-6% MeOH/DCM].
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]([F:24])([F:23])[F:22])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12]/[C:13](=[N:16]/[H])/[NH:14][OH:15])[C:7]([CH2:18][CH2:19][CH3:20])=[CH:6]2)#[N:2].[C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=O)#[N:26].C(N(CC)C(C)C)(C)C>C(#N)C>[C:25]([C:27]1[CH:28]=[C:29]([C:30]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:21]([F:24])([F:23])[F:22])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH2:18][CH2:19][CH3:20])[N:16]=2)[CH:33]=[CH:34][CH:35]=1)#[N:26]
Reactant: [H]/N=C(/Cn1c(CCC)cc2c(C(F)(F)F)c(C#N)ccc21)NO
Reactant: N#Cc1cccc(C(=O)Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccc(C#N)c2)n1
Temperature: 150 °C
Yield: 58.9 %

Procedure:
To a solution of (1Z)-2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (3.0 mL) under N2, was added 3-cyanobenzoyl chloride (0.204 g, 1.23 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.079 g (59% yield) of pure product: MS (ES) m/z 435 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:13][N:14]=[C:15]=[S:16]>C(O)C>[CH3:13][NH:14][C:15]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:6][CH:7]=1)=[S:16]
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Reactant: CN=C=S
Solvent: CCO
Product: CNC(=S)Nc1ccc(-c2c[nH]cn2)cc1

Procedure:
A solution of 2.3 gm of 4-(4-aminophenyl)-1-H-imidazole and 1.15 gm of methyl isothiocyanate in 30 ml of ethanol was refluxed for thirty minutes and evaporated to dryness. The oily base so obtained was purified by conversion into the corresponding hydrochloride salt by bubbling gaseous hydrochloric acid in isopropanol. The desired thiourea was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1.I[C:30]1[CH:31]=[CH:32][C:33](=[O:37])[N:34]([CH3:36])[CH:35]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:30]2[CH:31]=[CH:32][C:33](=[O:37])[N:34]([CH3:36])[CH:35]=2)=[CH:25][CH:26]=1
Reactant: C#Cc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Reactant: Cn1cc(I)ccc1=O
Product: Cn1cc(C#Cc2ccc(Cc3cc([C@@]4(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)ccc1=O

Procedure:
The compound was obtained starting from 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene and 5-iodo-1-methyl-1H-pyridin-2-one.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:43])=[N:14][C:15]([CH3:42])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:43])=[N:14][C:15]([CH3:42])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCCc3ccc(F)cc3)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Yield: 93.3 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.009 g, 0.015 mmol) and LiOH (3.65 mg, 0.152 mmol) in 9:1 EtOH/H2O (1 mL) was refluxed for 3 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid (0.0081 g, 0.014 mmol, 94% yield) as white solid. Alternatively, to a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.302 g, 0.5 mmol) in ethanol (5 mL) and water (0.500 mL) was added KOH (0.281 g, 5.00 mmol). The solution was heated at 75° C. for 8 h. The solvent in the mixture was evaporated. The remaining residue was treated with water (5 mL), and acidified with 1 N HCl (5.1 mL) to pH˜2. The resulting mixture was stirred for 1 h. The solid was collected on a filter, washed with water, dried under vacuum to give (0.281 g, 100%) as beige solid. 1H NMR (500 MHz, CDCl3) δ 7.27-7.32 (m, 2H), 7.12-7.18 (m, 1H), 7.01-7.09 (m, 3H), 6.95-7.00 (m, 2H), 5.95 (br. s., 1H), 4.16-4.29 (m, 2H), 3.61 (br. s., 1H), 3.13 (t, J=6.9 Hz, 2H), 2.77-3.02 (m, 1H), 2.66 (s, 3H), 2.22 (s, 3H), 1.99-2.37 (m, 2H), 1.25 (s, 9H), 1.07-1.40 (m, 4H), 0.88 (br.s., 3H), 0.68 (br. s., 3H). LCMS (M+H)=563.3.
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:17][CH2:18][CH2:19][Cl:20]>>[Cl:20][CH2:19][CH2:18][CH2:17][CH:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:8]
Reactant: ClCCCBr
Reactant: O=C(Cc1ccccc1)c1ccccc1
Product: O=C(c1ccccc1)C(CCCCl)c1ccccc1
Reaction time: 0.25 h

Procedure:
The compound is prepared from 19.6 g of desoxybenzoin, which is alkylated with 15.8 g of 3-bromo-1-chloropropane according to the procedure described in Example 17, method 1, except that the reaction time is only 15 min at room temperature. The product is recrystallized from methanol. The yield is 16.6 g (61%) of a product having m.p. 72°-4° C.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:6]([CH:18]=[CH2:19])[CH:5]=1)([O-])=O.[H][H]>C(O)C.O=[Pt]=O>[CH2:18]([C:6]1[CH:5]=[C:4]([CH:17]=[CH:16][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[NH2:1])[CH3:19]
Reactant: [H][H]
Reactant: C=Cc1cc([N+](=O)[O-])ccc1OCc1ccccn1
Agent: O=[Pt]=O
Solvent: CCO
Product: CCc1cc(N)ccc1OCc1ccccn1
Yield: 82.9 %

Procedure:
A mixture of 2-[(4-nitro-2-vinylphenoxy)methyl]pyridine (1.06 g, 4.16 mmol) and PtO2 (123 mg) in ethanol (100 ml) was stirred under an atmosphere of hydrogen until completion of the reaction (the reaction being complete when 4 mole equivalents of hydrogen have been reacted). After filtration on celite, the solvent was evaporated and the residue purified on silica gel (2% methanol/CH2Cl2) to give 3-ethyl-4-(pyridin-2-ylmethoxy)aniline (787 mg, 83%); NMR Spectrum: 1.12 (t, 3H), 2.53 (q, 2H), 4.56 (br s, 2H), 5.01 (s, 2H), 6.33 (dd, 1H), 6.43 (d, 1H), 6.69 (d, 1H), 7.32 (dd, 1H), 7.5 (d, 1H), 7.84 (t, 1H), 8.55 (d, 1H); Mass Spectrum: 229 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[SH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14]>C(O)C>[C:13]([C:12]1[CH:11]=[C:10]([S:9][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:18]=[CH:17][CH:16]=1)([OH:15])=[O:14]
Reactant: Clc1ccnc(Cl)n1
Reactant: O=C(O)c1cccc(S)c1
Solvent: CCO
Product: O=C(O)c1cccc(Sc2ccnc(Cl)n2)c1

Procedure:
4-(3-Carboxyphenylsulphanyl)-2-chloropyrimidine was prepared by heating a solution of 2,4-dichloropyrimidine (2.97 g, 19.9 mmol) and 3-mercaptobenzoic acid (3.07 g, 19.9 mmol) in ethanol (50 ml) at reflux for 1 h. On cooling to 0°, the resulting precipitate was collected and dried to give the desired material (3.38 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=3)[N:16]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC1C=CC(N2C3C(=CC([C:48]4N[N:51]=[N:50][N:49]=4)=CC=3)C(C3CCN(C(OC(C)(C)C)=O)CC3)=C2)=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]4[N:51]=[N:50][N:49]([CH3:48])[N:24]=4)[CH:21]=3)[N:16]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cn(-c3ccc(F)cc3)c3ccc(C#N)cc23)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cn(-c3ccc(F)cc3)c3ccc(-c4nnn[nH]4)cc23)CC1
Product: Cn1nnc(-c2ccc3c(c2)c(C2CCN(C(=O)OC(C)(C)C)CC2)cn3-c2ccc(F)cc2)n1

Procedure:
Following the procedure in Example 8, the cyanoderivative 12a was converted to the corresponding 5-[1-(4-fluorophenyl)-3-(1-t-butyloxycarbonyl-4-piperidinyl)-5-(5-tetra-zolyl)-1H-indole which was methylated according to the procedure in Example 9 to give the title compound 13a.
Reaction SMILES: CN(C)C=O.Br[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:21]([CH2:22][CH2:23][CH3:24])=[C:20]2[C:15]([C:16]([C:26]([F:29])([F:28])[F:27])=[CH:17][C:18](=[O:25])[O:19]2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[O:36]1[CH2:41][CH2:40][O:39][C:38]2[CH:42]=[C:43]([C:46]3([CH3:53])[NH:50][C:49](=[O:51])[NH:48][C:47]3=[O:52])[CH:44]=[CH:45][C:37]1=2>O>[O:36]1[CH2:41][CH2:40][O:39][C:38]2[CH:42]=[C:43]([C:46]3([CH3:53])[NH:50][C:49](=[O:51])[N:48]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]4[C:21]([CH2:22][CH2:23][CH3:24])=[C:20]5[C:15]([C:16]([C:26]([F:29])([F:28])[F:27])=[CH:17][C:18](=[O:25])[O:19]5)=[CH:14][CH:13]=4)[C:47]3=[O:52])[CH:44]=[CH:45][C:37]1=2
Reactant: CC1(c2ccc3c(c2)OCCO3)NC(=O)NC1=O
Reactant: CCCc1c(OCCCCBr)ccc2c(C(F)(F)F)cc(=O)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCN2C(=O)NC(C)(c3ccc4c(c3)OCCO4)C2=O)ccc2c(C(F)(F)F)cc(=O)oc12
Reaction time: 8 h
Yield: 94.6 %

Procedure:
An N,N-dimethylformamide (2 mL) solution of 7-(4-bromobutoxy)-8-propyl-4-(trifluoromethyl)-2H-chromen-2-one (30 mg, 0.074 mmol) was added with potassium carbonate (20.4 mg, 0.148 mmol) and 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylimidazolidine-2,4-dione (27.4 mg, 0.111 mmol) and then stirred overnight. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated under vacuum. The obtained residue was purified using thin-layer silica-gel chromatography (hexane:ethyl acetate=5:2), and the title compound (40.2 mg, 95%) was obtained as colorless oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[CH2:9]([O:11][C:12](=[O:18])[C:13](OCC)=[O:14])[CH3:10].CC[O-].[Na+]>>[CH2:9]([O:11][C:12](=[O:18])[C:13](=[O:14])[CH2:6][C:5](=[O:7])[CH2:4][CH2:3][CH:2]([CH3:8])[CH3:1])[CH3:10]
Reactant: CC(=O)CCC(C)C
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)CC(=O)CCC(C)C
Temperature: 25 °C
Yield: 70.4 %

Procedure:
5-methyl-2-hexanone (5.0084 g, 43.9 mmol) and diethyloxalate (5.95 mL, 43.8 mmol) were mixed together, and then added to a solution of NaOEt (˜3 M, 14.6 mL) stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred overnight. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, and concentrated to yield crude 46. The crude material was purified with 1:1 Hexanes: CH2Cl2 to obtain 6.6035 g (70.3%) of 46. 1H (CDCl3, 400 MHz): δ 6.28 (1H, s), 4.25 (2H, q, J=7.0 Hz), 2.40 (2H, t, 7.6 Hz), 1.54-1.41 (3H, m), 1.27 (3H, t, J=7.3 Hz), 0.82 (6H, d, J=6.3 Hz) ppm. 13C (CDCl3, 100 MHz): δ 203.40, 166.27, 161.85, 101.37, 62.15, 38.74, 33.39, 27.46, 21.99, 13.77 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 21.99, 13.77; CH2 carbons: 62.15, 38.74, 33.39; CH carbons: 101.37, 27.46 ppm. HPLC: 11.038min.