Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2([C:38](O)=[O:39])[CH2:37][CH2:36]2)=[O:34])=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:38]([C:35]5([C:33]([NH:32][C:29]6[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=6)=[O:34])[CH2:37][CH2:36]5)=[O:39])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.5 %

Procedure:
To a solution of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.460 mmol) in N,N-dimethylacetamide (3.0 mL) were added 1-[(4-fluorophenyl)carbamoyl]cyclopropanecarboxylic acid (154 mg, 0.689 mmol), HATU (262 mg, 0.689 mmol) and N,N-diisopropylethylamine (120 μL, 0.689 mmol), and the mixture was stirred at room temperature for 4 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=40/60→0/100), washed with hexane/ethyl acetate and collected by filtration to give the title compound (99 mg, 41%) as a white solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[C:18](=O)(O)[O-].[Na+].COS(OC)(=O)=O>CC(C)=O>[CH3:18][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][Br:1])=[CH:4][CH:5]=1
Reactant: BrCc1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: Cn1c(-c2ccc(CBr)cc2)nc2ccccc21
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 143.6 g (0.5 mole) of 2-(4-bromomethylphenyl)benzimidazole and 42.0 g (0.5 mole) of sodium bicarbonate in 85% aqueous acetone is added 66.0 g (0.5 mole) of dimethylsulfate dropwise. The mixture is stirred at 40° C. for about 3 hours until thin-layer chromatography indicates that the reaction is complete. The solvent is removed in vacuo, and the solid product is washed with water to eliminate sodium salts and purified by recrystallization from benzene.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[O:22])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][C:15]([N+:19]([O-])=O)=[CH:16][CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.[H][H]>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:19][C:15]1[CH:14]=[C:13]2[C:18]([C:10](/[CH:9]=[C:7]3\[O:8][C:4]4[C:3]([CH2:25][N:26]5[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:30][CH2:31]5)=[C:2]([OH:1])[CH:24]=[CH:23][C:5]=4[C:6]\3=[O:22])=[CH:11][NH:12]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4cc([N+](=O)[O-])ccc24)C3=O)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4cc(N)ccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.7 %

Procedure:
A solution of tert-butyl (Z)-4-({6-hydroxy-2-[(6-nitro-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.025 g, 0.048 mmol) obtained in Example A24, Step 2 in ethanol (2.0 mL) was added with Lindlar's catalyst (0.010 mg) under an argon atmosphere, and then the inside of the reaction vessel was replaced with hydrogen. The reaction mixture was stirred at room temperature for 5 hours, and then filtered through Celite, and the solvent was evaporated under reduced pressure to obtain tert-butyl (Z)-4-({2-[(6-amino-1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.023 g, 97%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[C:12](#[N:15])[CH:13]=[CH2:14].C([O-])(=O)C.[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(N(C)C)=O.[Pd]>[CH3:11][O:10][C:4]1[CH:3]=[C:2](/[CH:14]=[CH:13]/[C:12]#[N:15])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: C=CC#N
Reactant: COc1ccc(Br)cc1OC
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(=O)N(C)C
Product: COc1ccc(/C=C/C#N)cc1OC
Yield: 32.2 %

Procedure:
A mixture of 5 g of 4-bromo-1,2-dimethoxybenzene (3.31 mL, 23 mmoles), 3.2 g of acrylonitrile (3.9 mL, 60 mmoles, 2.6 eq.), 2.3 g of sodium acetate (27.6 mmoles, 1.2 eq.), 7.4 g of tetrabutylammonium bromide (23 mmoles, 1 eq.), 0.7 g of tri(o-tolyl)phosphine (2.3 mmoles, 0.1 eq.) and 4.9 g of palladium 5% on carbon (2.3 mmoles, 0.1 eq.) in 25 mL of DMAC is prepared. The black suspension is stirred at reflux for 12 hours. The reaction mixture is brought back to ambient temperature and filtered. The solid residue is rinsed twice with toluene. The filtrates are combined and evaporated under reduced pressure. The crude reaction product is purified on a silica column (eluant: methylcyclohexane:ethyl acetate 6:4) to yield 1.4 g of the expected product.
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[C:13]([C:18]1[N:22]2[CH:23]=[C:24]([CH3:37])[CH:25]=[C:26]([O:27][CH2:28][C:29]3[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:36])[C:21]2=[N:20][C:19]=1[CH3:38])(OCC)=[O:14]>C1(C)C=CC=CC=1>[CH3:38][C:19]1[N:20]=[C:21]2[C:26]([O:27][CH2:28][C:29]3[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:36])=[CH:25][C:24]([CH3:37])=[CH:23][N:22]2[C:18]=1[CH2:13][OH:14]
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(C)cccc3C)cc(C)cn12
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(OCc2c(C)cccc2C)c2nc(C)c(CO)n2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
A mixture of vitride (3 ml, 10.2 mmol) in toluene (3 ml) was added dropwise to nitrogene-purged solution of 3-carboethoxy-2,6-dimethyl-8-(2,6-dimethylbenzyloxy)imidazo[1,2-a]pyridine (0.68 g, 1.93 mmol) in toluene (15 ml). The ice-bath was removed and the reaction mixture was stirred at room temp. For 2 h and 15 min. The reaction mixture was cooled to 0° C. and quenched by addition of water (6 ml). Methylene chloride/methanol was added and the reaction mixture was filtered. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel, using methylene chloride:methanol (100:5) as eluent to give 0.35 g (58%) of the title compound.
Reaction SMILES: [Br:1]Br.[CH2:3]([CH:5]1[CH2:16][C:15]2[C:7](=[CH:8][C:9]3[O:13][CH2:12][O:11][C:10]=3[CH:14]=2)[C:6]1=[O:17])C.CC([O-])=O.[Na+]>C(Cl)Cl.O>[Br:1][C:14]1[C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=[C:7]2[C:15]=1[CH2:16][CH:5]([CH3:3])[C:6]2=[O:17]
Reactant: BrBr
Reactant: CCC1Cc2cc3c(cc2C1=O)OCO3
Agent: CC(=O)O[Na]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC1Cc2c(cc3c(c2Br)OCO3)C1=O
Reaction time: 24 h
Yield: 58 %

Procedure:
Br2 (11.42 ml, 221.44 mmol) was added dropwise at 0° C. into well stirred mixture of 6-ethyl-6,7-dihydro-5H-indeno[5,6-d][1,3]dioxol-5-one (40.01 g, 210.37 mmol) solution in CH2Cl2 (93 ml) and NaOAc (35.32 g, 430 6 mmol) solution in water (62 ml). After 20 h of stirring at room temperature, 11.5 g of AcONa and 3.42 ml of Br2 (30% of starting amount) were added. This procedure was repeated after 24 h, the resulting mixture was stirred for additional 48 h. The resulting mixture was diluted by CH2Cl2 (200 ml), the organic layer was separated, washed with water (350 ml), dried over MgSO4 and evaporated. The residue was recrystallized from hexane-benzene (3:1) yielding 32.83 g (58%) of white-yellow solid.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][CH:13]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:10])[CH2:5][CH2:4][CH:3]2[CH2:6][NH:7][CH2:8][CH:2]12.Cl[C:27]1[C:36]2[C:31](=[N:32][CH:33]=[CH:34][N:35]=2)[CH:30]=[C:29]([Cl:37])[N:28]=1>O1CCOCC1>[Cl:37][C:29]1[N:28]=[C:27]([N:7]2[CH2:6][CH:3]3[CH:2]([N:1]([C:9]([O:11][CH2:12][CH:13]4[C:25]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[C:19]5[C:14]4=[CH:15][CH:16]=[CH:17][CH:18]=5)=[O:10])[CH2:5][CH2:4]3)[CH2:8]2)[C:36]2[C:31](=[N:32][CH:33]=[CH:34][N:35]=2)[CH:30]=1
Reactant: Clc1cc2nccnc2c(Cl)n1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC2CNCC21
Solvent: C1COCCO1
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC2CN(c3nc(Cl)cc4nccnc34)CC21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The mixture of (9H-fluoren-9-yl)methyl hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate (100 mg, 0.5 mmol) and 5,7-dichloropyrido[4,3-b]pyrazine (600 mg, 1.8 mmol) in dioxane was stirred at 0° C. for 30 minutes and then at room temperature for 4 hours. The mixture was concentrated, and the residue was purified by chromatography to give the title compound. MS (m/z): 498 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[C:23](O)=[O:24].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:23]([C:14]3[CH:15]=[N:16][C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:13]=3)=[O:24])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1cnc2ccccc2n1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cnc2ccccc2n1
Reaction time: 15 h
Yield: 89.3 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.160 g, 0.696 mmol, Example 1, Step H), quinoxaline-2-carboxylic acid (0.254 g, 1.46 mmol), BOP-Cl (0.372 g, 1.46 mmol), and triethylamine (0.352 g, 3.48 mmol) were placed in DCM (5 mL) at room temperature and stirred for 15 hours. 3M aqueous LiOH (3 mL) was then added, and the reaction was stirred for 10 minutes. Water (10 mL) and DCM (10 mL) were then added, and the reaction was filtered. The resulting solid was slurried with 10:1 DCM:MeOH and filtered to give solid N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)quinoxaline-2-carboxamide (0.240 g, 89% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[S:15](=[O:17])(=[O:16])[N:14]([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:13](=[O:24])[CH2:12]2)=[C:7]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=1.[C:37](Cl)(=[O:39])[CH3:38]>N1C=CC=CC=1.CCOC(C)=O>[CH2:26]([O:25][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[N:11]1[CH2:12][C:13](=[O:24])[N:14]([CH2:18][CH2:19][Si:20]([CH3:21])([CH3:22])[CH3:23])[S:15]1(=[O:16])=[O:17])[CH2:4][C:3]1[CH:33]=[CH:34][CH:35]=[CH:36][C:2]=1[NH:1][C:37](=[O:39])[CH3:38])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(Cc3ccccc3N)cc2OCc2ccccc2)S1(=O)=O
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccccc1Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-[4-(2-aminobenzyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (Example 4, Step A) (250 mg, 0.478 mmol) in pyridine (1.5 mL) is added acetylchloride (41 mg, 0.525 mmol). The mixture is stirred at ambient temperature for 30 min., then diluted with EtOAc and washed with 0.5N HCl, saturated NaHCO3 and brine. It is then dried over Na2SO4/MgSO4, filtered and concentrated to afford N-(2-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-benzyl}-phenyl)-acetamide as a gum: MS (M+H)+=566.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[F:31][C:32]1[CH:33]=[C:34]([CH:41]=[CH:42][C:43]=1F)[C:35]([N:37]1[CH2:40][CH2:39][CH2:38]1)=[O:36].[H-].[Na+].Cl>CS(C)=O>[N:37]1([C:35]([C:34]2[CH:41]=[CH:42][C:43]([O:1][C:2]3[CH:3]=[C:4]([C:14]4[NH:15][C:16]([C:19]5[S:20][CH:21]=[CH:22][N:23]=5)=[CH:17][CH:18]=4)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=3)=[C:32]([F:31])[CH:33]=2)=[O:36])[CH2:40][CH2:39][CH2:38]1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Reactant: O=C(c1ccc(F)c(F)c1)N1CCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 65.3 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (70 mg, 0.163 mmol) synthesized in Example (38d) and 1-(3,4-difluorobenzoyl)azetidine (68 mg, 0.345 mmol) synthesized in Example (41a) were dissolved in dimethyl sulfoxide (3.0 mL), and sodium hydride (60%, 25 mg, 0.63 mmol) was added, followed by stirring at 100° C. for 5 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, 2N hydrochloric acid (30 mL) was added, and extraction was carried out with diethyl ether (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-80%) to afford the desired compound (54 mg, yield 65%) as a yellow solid.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13]([CH:15]1[CH2:19][C:18](=[O:20])[N:17]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[CH2:16]1)=[O:14].I[CH2:30][CH3:31].[NH4+].[Cl-]>C1COCC1>[CH3:11][O:12][C:13]([C:15]1([CH2:30][CH3:31])[CH2:19][C:18](=[O:20])[N:17]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[CH2:16]1)=[O:14]
Reactant: CCI
Reactant: COC(=O)C1CC(=O)N(c2c(C)cccc2C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1(C(=O)OC)CC(=O)N(c2c(C)cccc2C)C1
Temperature: -50 °C
Reaction time: 0.08 h
Yield: 59.2 %

Procedure:
LHMDS (1 M solution in THF, 24.3 mL, 24.3 mmol) was added slowly to a cooled (−50° C.) solution of 1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (5 g, 20.24 mmol) in THF (25 mL). The solution was stirred at −50° C. for 5 min then warmed to 0° C. and stirred further for 5 min. After cooling back to −50° C., iodoethane (3.27 mL, 40.48 mmol) was added and the resulting reaction mixture was warmed to room temperature and stirred for 2 h. Saturated aqueous NH4Cl solution (50 mL) was added, and the solution was extracted with EtOAc (3×100 mL). The combined organic layer were washed with water (100 mL), brine (100 mL), dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (SiO2, 20→50% EtOAc/hexanes) to give 1-(2,6-dimethylphenyl)-3-ethyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (3.3 g, 59% yield). LC-MS: Rt (retention time): 2.21 min, MS: (ES) m/z 276.1 (M+H+).
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[O:18])[CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].O[Li].O.C(O)(=O)C>C1COCC1.O>[CH2:1]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:18])[CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ccnc(C(=O)NCCCCC(=O)OCC)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCc1ccnc(C(=O)NCCCCC(=O)O)c1
Yield: 95.5 %

Procedure:
A solution of 0.20 g (0.52 mmol) of 5-[[(4-decyl-2-pyridinyl)carbonyl]amino]pentanoic acid, ethyl ester prepared in Example 7, 0.05 g (1 mmol, 2 eq) of LiOH·H2O in 4 ml of THF and 1 ml of H2O was stirred at room temperature for 21 hours, then 1.5 eq of glacial acetic acid was added. The resulting solution was poured into H2O and extracted with Et2O. The organic layers were combined, poured into H2O and extracted with Et2O. The organic layers were combined, dried (Na2SO4) and concentrated in vacuo. Hexanes were added to the residue and the flask was cooled. The resulting white solid was collected, yielding 180 mg (97%) of title compound: m.p. 54°-56° C.
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[CH2:23][CH2:22][C@@:13]34[C:14]5[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=5[CH2:20][C@@H:7]2[C@:8]3([OH:24])[CH2:9][CH2:10][CH2:11][CH2:12]4)[CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].Cl[CH2:29][O:30][CH2:31]Cl>C1C=CC=CC=1>[CH:1]1([CH2:5][N:6]2[CH2:23][CH2:22][C@@:13]34[C:14]5[CH:15]=[C:16]([O:21][CH2:29][O:30][CH3:31])[CH:17]=[CH:18][C:19]=5[CH2:20][C@@H:7]2[C@:8]3([OH:24])[CH2:9][CH2:10][CH2:11][CH2:12]4)[CH2:4][CH2:3][CH2:2]1
Reactant: ClCOCCl
Reactant: Oc1ccc2c(c1)[C@@]13CCCC[C@@]1(O)[C@@H](C2)N(CC1CCC1)CC3
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COCOc1ccc2c(c1)[C@@]13CCCC[C@@]1(O)[C@@H](C2)N(CC1CCC1)CC3

Procedure:
One mole of compound XXVII was placed in 3 liters of benzene. One mole of sodium methoxide was added, followed by the slow addition of 1 mole of chloromethyl ether with stirring. The solution was heated to reflux to yield the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](OC)=[O:10])=[N:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][OH:10])=[N:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(N)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ccc(CCO)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
To a solution of methyl 2-(5-aminopyridin-2-yl)acetate (0.250 g, 1.5 mmol) in THF (20 mL) at 0° C. was added lithium aluminum hydride (1.0 M, 3.75 mL, 3.75 mmol). The mixture was warmed to rt and stirred for 2 h. After this time, the reaction was quenched with water and NaOH (2 M), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/methanol) to afford the title compound (0.046 g, 22%) as an orange oil. MW=138.17. 1H NMR (CDCl3, 500 MHz) δ 8.01-7.97 (m, 1H), 6.97-6.92 (m, 2H), 3.96 (t, J=5.5 Hz, 2H), 3.60 (s, 2H), 2.89 (t, J=5.5 Hz, 2H); APCI MS m/z 139 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([Si](C(C)C)(C(C)C)C(C)C)[CH:14]=[C:13]3[CH2:29][C@H:30]2[CH2:34][CH2:33][CH2:32][N:31]2[CH3:35])=[CH:7][CH:6]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[O:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[CH2:29][C@H:30]2[CH2:34][CH2:33][CH2:32][N:31]2[CH3:35])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)c(C[C@H]2CCCN2C)cn3[Si](C(C)C)(C(C)C)C(C)C)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc3[nH]cc(C[C@H]4CCCN4C)c3c2)o1

Procedure:
5-(5-Methoxycarbonyl-2-furyl)-3-(1-methylpyrrolidin-2(R)-ylmethyl)-1-triisopropylsilylindole (see Preparation 62) was reacted with tetra-n-butylammonium fluoride in tetrahydrofuran, using a procedure similar to that described in Example 62. This gave the title compound as a foam. Found: C,70.74; H,6.52; N,8.47. C20H22N2O3 requires: C,70.98; H,6.52; N,8.28%.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:23][C:24]([F:36])([F:35])[C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.Cl>CN(C)C1C=CN=CC=1.C(OCC)C.ClCCl>[F:36][C:24]([F:23])([F:35])[C:25]1[CH:26]=[CH:27][C:28]([S:31]([O:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][N:13]=3)[CH2:4][CH2:3]2)(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1ccc(N2CCC(O)CC2)nc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: N#Cc1ccc(N2CCC(OS(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a dichloromethane (50 mL) solution of 6-(4-hydroxypiperidin-1-yl)pyridine-3-carbonitrile (3.19 g, 15.7 mmol) and triethylamine (9.0 mL, 65 mmol) was added 4-(trifluoromethyl)benzenesulfonyl chloride (4.31 g, 17.6 mmol). 4-(Dimethylamino)pyridine (0.19 g, 1.6 mmol) was then added, and the reaction mixture was stirred at room temperature for 2 hours. Diethyl ether (100 mL) was added, followed by 1.0 M hydrochloric acid (70 ml, 70.0 mmol). The organic layer was separated and washed with 1.0 M hydrochloric acid (2×50 mL), saturated brine, dried (magnesium sulfate) to afford the title compound as a solid. This crude product was used in the subsequent step without further purification. 1H NMR (500 MHz, CDCl3) δ 8.39 (d, J=2.3 Hz, 1H), 8.08 (d, J=8.3 Hz, 2H), 7.85 (d, J=8.2 Hz, 2H), 7.61 (dd, J=9.0, 2.4 Hz, 1H), 6.61 (d, J=9.1 Hz, 1H), 4.94-4.88 (m, 1H), 3.87 (ddd, J=13.7, 7.9, 3.8 Hz, 2H), 3.62 (ddd, J=13.8, 7.3, 3.9 Hz, 2H), 1.97-1.90 (m, 2H), 1.89-1.81 (m, 2H); LC-MS: m/z 412.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[F:16][C:14]([F:15])([F:17])[C:12]1[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=2)[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-c3cccc(Br)c3)n2)cc1
Product: Nc1ccc(-c2cccc(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (example E.20) (0.525 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.286 g, 1.3 mmol) according to the general procedure VI. Obtained as a white solid (0.10 g, 22%). MS (ISP) 460.2 [(M+H)+]; mp 170-172° C.