Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:12][CH2:13][CH2:14][CH3:15])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O)[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[CH2:1]([CH:3]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCCCC(CC)C(=O)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCC(CC)Cc1ccccc1

Procedure:
A solution of 313.9 grams of 2-ethylhexanoylbenzene in 500 mL of acetic acid with 11.4 grams of 10% palladium on carbon (as a catalyst) was stirred at 110° C. in an atmosphere of hydrogen at 414 kPa for 34 hours. The mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The filtrate was concentrated in vacuo to give 2-ethylhexylbenzene.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[C@H:14]([CH:19]([CH3:21])[CH3:20])[C:15]([O:17]C)=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Cl.C>O>[ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[C@H:14]([CH:19]([CH3:21])[CH3:20])[C:15]([OH:17])=[O:16])(=[O:11])=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)[C@@H](C(C)C)N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: O
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)O)C(C)C)cc1
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
Methyl 2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoate hydrochloride (7164 g, 16.7 mol) is added to a solution of water (27 L) and concentrated hydrochloric acid (9 L), and heated to 120° C. for 3 days. After cooling down to room temperature, charcoal (350 g) is added, stirring is continued for 45 minutes, the reaction is filtered, and the solvent is evaporated. The crude solid is re-dissolved in methanol (7.1 L) and ethyl acetate (73 L), and cooled to 3° C. for 2 hours. The precipitated product is collected by filtration to give 2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoic acid hydrochloride.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:15]=2)[CH:7]=1.[CH3:28]I>C(OCC)C>[CH3:3][O:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([O:26][CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:15]=2)[CH:7]=1
Reactant: CCCCCC(O)c1cccc(OCc2cccc(C(=O)OC)c2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCC(OC)c1cccc(OCc2cccc(C(=O)OC)c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of sodium hydride (0.5 g.) in ethyl ether at 0° C. was added methyl-3-[[3-(1-hydroxyhexyl)phenoxy]methyl]benzoate (1.7 g.) in ether. The mixture was allowed to warm to room temperature. Methyl iodide (0.6 ml) was added and the reaction was stirred at room temperature for three days. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl ether. The organic extract was washed with water, dried (MgSO4) and concentrated to an oil. The oil was purified by HPLC on silica gel using a 1:9 ratio of ethyl acetate/hexanes as an eluent.
Reaction SMILES: CC(C1C(OC)=C(C(C)(C)C)C=C(P(C2C=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=2)[C:18]2[CH:23]=[CH:22][C:21]3OCO[C:20]=3[C:19]=2[C:27]2C3OCOC=3C=[CH:29][C:28]=2P(C2C=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=2)C2C=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=2)C=1)(C)C.[F-].C([O:88][SiH](OCC)OCC)C.C(=O)C1C=CC=CC=1.C([Si](OC)(OC)OC)=C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O.CN(C=O)C>[C:19]1([CH:27]([OH:88])[CH:28]=[CH2:29])[CH:20]=[CH:21][CH:22]=[CH:23][CH:18]=1
Reactant: COc1c(C(C)(C)C)cc(P(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccc3c(c2-c2c(P(c4cc(C(C)(C)C)c(OC)c(C(C)(C)C)c4)c4cc(C(C)(C)C)c(OC)c(C(C)(C)C)c4)ccc4c2OCO4)OCO3)cc1C(C)(C)C
Reactant: CCO[SiH](OCC)OCC
Agent: C=C[Si](OC)(OC)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: O=Cc1ccccc1
Solvent: CN(C)C=O
Product: C=CC(O)c1ccccc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a DMF (0.3 mL) solution of Cu(O-Bu-t) (20 mg, 0.02 mmol) as synthesized according to the method described in the publication Inorg. Chim. Acta, 1981, 20, 2728, (R)-DTBM-SEGPHOS (35 mg, 0.03 mmol) and triethoxysilane fluoride (4.0 μL, 0.02 mmol), benzaldehyde (0.020 mL, 0.20 mmol) and vinyltrimethoxysilane (62 μL, 0.40 mmol) were added at room temperature under an argon atmosphere, the temperature was then raised to 40° C., and the mixture was stirred for 30 minutes. Thereafter, the reaction mixture was allowed to stand for cooling to room temperature, to which was then added tetrabutylammonium fluoride (TBAF) (1M/THF, 0.5 mL), and the mixture was stirred for 10 minutes. After adding water, the mixture was extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After drying, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (ethyl acetate/hexane: 1/9 to 1/4), thereby obtaining desired 1-phenyl-2-propen-1-ol as an (S)-form in a yield of 65% and an optical purity of 94% ee.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:19])[C:10]([CH3:18])=[C:11]([C:15](=[O:17])[CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[OH-].[Na+:21]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH3:19])[C:10]([CH3:18])=[C:11]([C:15](=[O:17])[CH:16]=2)[C:12]([O-:14])=[O:13])=[CH:6][CH:7]=1.[Na+:21]
Reactant: Cc1c(C(=O)O)c(=O)cc(-c2ccc(Br)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)[O-])c(=O)cc(-c2ccc(Br)cc2)n1C
Reaction time: 1 h
Yield: 89 %

Procedure:
2 g (0.0062 mol) of 6-(4-bromophenyl)-1,2-dimethyl-4-oxonicotinic acid is suspended in 50 ml of methanol and to it there is added 0.5 g (0.0062 mol) of 50% aqueous sodium hydroxide. The solution formed is allowed to stand at room temperature for 1 hr. and is concentrated in vacuo. The concentrate is washed with 50 ml of diethyl ether and dried to afford 1.9 g (89% yield) of product.
Reaction SMILES: [Na].[F:2][C:3]([F:7])([F:6])[CH2:4][OH:5].Cl[C:9]1[N:10]=[C:11]([CH3:19])[C:12]([C:15]([O:17]C)=[O:16])=[N:13][CH:14]=1.[OH-].[Na+]>>[CH3:19][C:11]1[C:12]([C:15]([OH:17])=[O:16])=[N:13][CH:14]=[C:9]([O:5][CH2:4][C:3]([F:7])([F:6])[F:2])[N:10]=1
Reactant: OCC(F)(F)F
Reactant: COC(=O)c1ncc(Cl)nc1C
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Product: Cc1nc(OCC(F)(F)F)cnc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
Sodium, which had been stored in mineral oil, was rinsed in hexane and cut into approximately 70-mg slivers. Those slivers of sodium (0.37 g, 16.08 mmol) were loaded into a 150-mL resealable vessel. The vessel was purged with argon, placed in a water bath, and 2,2,2-trifluoroethanol (31.2 mL, 429 mmol) was added. Bubbling ensued immediately. Bubbling had ceased and sodium had disappeared around 30 minutes. The mixture was stirred at room temperature for another 30 minutes. To this mixture was added methyl 5-chloro-3-methylpyrazine-2-carboxylate (1.00 g, 5.36 mmol). The vial was sealed and heated at 45° C. overnight. After addition of 1 M sodium hydroxide (5.90 mL, 5.90 mmol), the mixture was stirred at 45° C. overnight. The reaction mixture was concentrated to remove most of the trifluoroethanol. The residue was dissolved in the minimum amount of water (300 mL), and the aqueous phase was washed with diethyl ether (2×30 mL). The aqueous phase was acidified with 5 M HCl (5 mL). The aqueous phase was extracted with DCM until TLC (15% MeOH-DCM) showed product wasn't coming out any more. The organics were combined, dried over MgSO4 and concentrated to give 3-methyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid (1.28 g, 100% yield). 1H NMR (300 MHz, CDCl3) δ ppm 10.57 (br, 1H), 8.15 (s, 1H), 4.87 (qt, 2H, J=8.2), 2.93 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C@H:11]1[CH2:25][C@H:24]2[C@@H:14]([CH2:15][C:16]3[C:26]4[C:19](=[CH:20][CH:21]=[CH:22][C:23]2=4)[NH:18][CH:17]=3)[N:13]([CH2:27][CH2:28][CH3:29])[CH2:12]1>C(Cl)Cl.C(N(CC)CC)C>[C:1]([NH:10][C@H:11]1[CH2:25][C@H:24]2[C@@H:14]([CH2:15][C:16]3[C:26]4[C:19](=[CH:20][CH:21]=[CH:22][C:23]2=4)[NH:18][CH:17]=3)[N:13]([CH2:27][CH2:28][CH3:29])[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN1C[C@@H](N)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN1C[C@@H](NC(=O)c2ccccc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 20 °C
Reaction time: 17.5 h

Procedure:
1.4 ml benzoylchloride in 5 ml CH2Cl2 are added drop-wise with stirring at 5°-10° C. to a suspension of 3.0 g 8α-amino-6-n-propylergoline in 100 ml CH2Cl2 and 2.0 ml triethylamine. The obtained reaction mixture is stirred for 15 to 20 hours at 20° C. and then washed thoroughly 2× with 25 ml 2N NaOH and H2O. The organic phase is dried over MgSO4, filtered and evaporated. The residue (pale brown foam) is dissolved in ethanol, and crystallised as the hydrobromide by addition of equivalent amounts of HBr in acetic acid. M.P. on recrystallisation from C2H5OH/H2O (80:2)=290° with decomposition.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[C:26]([F:33])=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[F:31].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1.O>[F:33][C:26]1[C:27]([OH:32])=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[C:10]([CH3:11])[C:2]=1[CH3:1]
Reactant: Cc1cc(-c2ccccc2)cc(C(=O)O)c1C
Reactant: Nc1c(F)ccc(O)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(-c2ccccc2)cc(C(=O)Nc2c(F)ccc(O)c2F)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a solution of 2,3-dimethyl-5-phenyl-benzoic acid (315 mg, 1.4 mmol, 1.1 eq) in CH2Cl2 (10 mL) was added oxalyl chloride (530 mg, 4.2 mmol, 3.3 eq) at 0° C. The reaction was allowed to warm to room temperature and stirred for 1 h. The solvent and excess reagent were removed under reduced pressure and the residue that remained dissolved in THF (10 mL) and added dropwise to a mixture of 3-amino-2,4-difluoro-phenol (intermediate X(a)) (184 mg, 1.3 mmol, 1.0 eq) and NaHCO3 (532 mg, 6.3 mmol, 5.0 eq) in THF (8 mL) at 0° C. The reaction was stirred at room temperature for 2 h, water was added and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 20:1 to 10:1, then CH2Cl2:MeOH, 500:1 to 100:1) to give the title compound as a yellow solid (220 mg, 49%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8].CC1C=CC(S(O[CH2:23][CH2:24][CH2:25][S:26][C:27]2[CH:32]=[CH:31][C:30](/[C:33](/[C:40]3[CH:45]=[CH:44][C:43]([CH2:46][CH3:47])=[C:42]([O:48][CH3:49])[N:41]=3)=[CH:34]\[CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:29][C:28]=2[Cl:50])(=O)=O)=CC=1.O>C(#N)C>[Cl:50][C:28]1[CH:29]=[C:30](/[C:33](/[C:40]2[CH:45]=[CH:44][C:43]([CH2:46][CH3:47])=[C:42]([O:48][CH3:49])[N:41]=2)=[CH:34]\[CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:31]=[CH:32][C:27]=1[S:26][CH2:25][CH2:24][CH2:23][N:9]([CH2:10][CH3:11])[CH2:7][CH3:8]
Reactant: CCNCC
Reactant: CCc1ccc(/C(=C/C2CCCC2)c2ccc(SCCCOS(=O)(=O)c3ccc(C)cc3)c(Cl)c2)nc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCc1ccc(/C(=C/C2CCCC2)c2ccc(SCCCN(CC)CC)c(Cl)c2)nc1OC
Temperature: 90 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Potassium carbonate (290 mg) and diethylamine (219 mL) were sequentially added to a solution of 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridin-2-yl)ethenyl]phenyl}sulfanyl)propyl 4-methylbenzenesulfonate (120 mg) in acetonitrile (3 mL), and the mixture was stirred at 90° C. for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0→9:1) to give 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridin-2-yl)ethenyl]phenyl}sulfanyl)-N,N-diethylpropan-1-amine (110 mg, 80%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[C:18](I)[CH:19]=[CH:20][C:13]3=[N:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH2:31]([OH:34])[C:32]#[CH:33]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[C:18]([C:33]#[C:32][CH2:31][OH:34])[CH:19]=[CH:20][C:13]3=[N:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cn2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cn2c1=O
Temperature: 90 °C
Yield: 58 %

Procedure:
To a solution of N-(4-chlorobenzyl)-7-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide (Procedure 3, 500 mg), PdCl2(PPh3)2 (21 mg), and Et3N (0.73 mL) in anhydrous DMF (3 mL) is added propargyl alcohol (0.094 mL). The mixture is heated at 90° C. for 1 h, then allowed to cool to room temperature. The reaction mixture is placed under high vacuum to remove the DMF. The resulting solid is dissolved in CH2Cl2 and washed with water. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried (Na2SO4), filtered, and condensed to afford a solid. The crude solid is adsorbed onto silica and chromatographed (1% MeOH/CH2Cl2 (1 L), 1.5% MeOH/CH2Cl2 (1 L), and 2% MeOHICH2Cl2 (1.5 L)). Product-containing fractions are combined and concentrated to afford 243 mg (58%) of the title compound as a creme solid. Physical characteristics: m.p. 179-181° C.; 1H NMR (300 MHz, DMSO-d6) δ9.34, 9.07, 9.00, 8.10, 7.85, 7.36, 5.50, 4.54, 4.36; IR (drift) 3294, 1676, 1632, 1618, 1561, 1541, 1521, 1490, 1353, 1335, 1131, 1061, 1040, 842, 797 cm−1; MS (ESI+) m/z 368 (M+H)+; Anal. found: C, 61.96; H, 3.69; N, 11.44.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([PH4])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].[CH3:15][C:16]1[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:10]([O:9][C:7](=[O:8])[CH2:6]/[C:5](/[C:3]([O:2][CH3:1])=[O:4])=[CH:21]\[C:19]1[O:20][C:16]([CH3:15])=[CH:17][CH:18]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1ccc(C=O)o1
Reactant: COC(=O)C([PH4])CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)/C(=C/c1ccc(C)o1)CC(=O)OC(C)(C)C
Yield: 99.2 %

Procedure:
A solution of 1-methoxycarbonyl-2-t-butoxycarbonyl ethyl phosphorane (JCS Perkin II, 1975, p1030; 2.69 g, 6 mmol, 1.2 eq) and 5-methylfuran-2-al (0.5 ml, 5 mmol) in dry toluene (10 ml) was stirred at 80° C. for 48 hrs, and then evaporated to dryness. The residue was chromatographed (50 g Bondelut, eluting with hexane containing 10% v/v ethyl acetate) to yield the title compound as a brown oil (1.39 g, 100%). NMR: 1.38 (s, 9H), 2.33 (s, 3H), 3.62 (s, 2H), 3.71 (s, 3H), 6.31 (d, 1H), 6.85 (d, 1H), 7.42 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5][OH:6].C(=O)([O-])[O-].[K+].[K+].[CH:19]1(Br)[CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C)C=O>[CH:19]1([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[N+:10]([O-:12])=[O:11])[CH2:5][OH:6])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: BrC1CCCC1
Reactant: O=[N+]([O-])c1ccc(CO)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CO)cc1OC1CCCC1
Temperature: 50 °C

Procedure:
To a solution of 9.6 g (56.5 mmol) of 3-hydroxy-4-nitrobenzyl alcohol in 960 mL of dry N,N-dimethylformamide under a nitrogen atmosphere was added 11.7 g (83.6 mmol) of anhydrous potassium carbonate followed by 18.1 mL (169.0 mmol) of cyclopentyl bromide. The reaction mixture was warmed to 50° C. for 24 hours after which time the mixture was cooled to room temperature and concentrated to a dark brown residue under high vacuum. The residue was dissolved in 500 mL of chloroform, washed with two, 50 mL portions of saturated sodium chloride, dried over magnesium sulfate, and concentrated to dryness. Purification of the crude product with liquid chromatography over 200 g of silica gel and eluting with 10% methanol in chloroform provided the analytically pure 3-cyclopentoxy-4-nitrobenzyl alcohol upon drying in vacuo.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(OC([NH:52][C@@H:53]([CH:81]([CH3:83])[CH3:82])[C:54]([O:56][CH2:57][O:58][C:59](=[O:80])[C@@:60]([CH2:78][OH:79])([CH3:77])[CH2:61][C@H:62]([NH2:76])[CH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)=[CH:66][CH:65]=1)=[O:55])=O)C1C=CC=CC=1>CN(C=O)C>[NH2:52][C@@H:53]([CH:81]([CH3:83])[CH3:82])[C:54]([O:56][CH2:57][O:58][C:59](=[O:80])[C@@:60]([CH2:78][OH:79])([CH3:77])[CH2:61][C@H:62]([NH:76][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:63][C:64]1[CH:65]=[CH:66][C:67]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)=[CH:68][CH:69]=1)=[O:55]
Reactant: O=C(O)c1c[nH]nn1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@H](N)C(=O)OCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 29.8 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (18 mg, 156 μmol), DIPEA (81.6 μL, 468 μmol) and HATU (59.3 mg, 156 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid (S)-2-benzyloxycarbonylamino-3-methyl-butyryloxymethyl ester (90 mg, 160 μmol) dissolved in DMF (1 mL). The resulting mixture was stirred for 20 minutes and the solvent was evaporated. The remaining solid was dissolved in degassed 4.4% formic acid-methanol (5 mL) in a flask containing palladium black (˜100 mg) under nitrogen. The mixture was continuously stirred at room temperature. The mixture was filtered and washed with MeOH. The solvent was evaporated and the product purified by preparative HPLC to yield the title compound (25 mg; purity 95%). MS m/z [M+H]+ calc'd for C28H35N5O6, 538.26. found 538.4.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1[S:7][C:8]([CH3:11])=[CH:9][CH:10]=1.Cl[C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(Cl)Cl>[CH3:5][C:6]1[S:7][C:8]([CH3:11])=[CH:9][C:10]=1[C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1ccc(C)s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1cc(C)sc1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of AlCl3 (29.5 g, 221 mmol) in CH2Cl2 (150 mL) was added 2,5-dimethyl thiophene (6.2 g, 55 mmol) followed by ethyl 2-chloro-2-oxoacetate (15.1 g, 110 mmol). The resulting mixture was stirred at room temperature for 12 h at which time the reaction mixture was filtered, diluted carefully with H2O and extracted with EtOAc. Removal of volatiles afforded mostly pure crude material, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:23][C:24]2[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=2[C:26]([O:28]CC)=O)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:10]=2)=[N:6][CH:7]=1.[CH3:35][S:36][CH2:37][CH2:38][NH2:39]>>[F:1][C:2]1[C:3]([NH:23][C:24]2[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=2[C:26]([NH:39][CH2:38][CH2:37][S:36][CH3:35])=[O:28])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[CH:10]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2cccc(CCN3CCOCC3)c2)ncc1F
Reactant: CSCCN
Product: CSCCNC(=O)c1ccccc1Nc1nc(Nc2cccc(CCN3CCOCC3)c2)ncc1F

Procedure:
Ethyl 2-{[5-fluoro-2-({3-[2-(4-morpholinyl)ethyl]phenyl}amino)-4-pyrimidinyl]amino}benzoate (200 mg, 0.51 mmoles) and 2-(methylthio)ethylamine (2 mL) were heated at 120° C. for 48 h. The reaction mixture was concentrated to dryness under vacuum and the title compound was purified by flash chromatography on silica gel (ethyl acetate containing 0.1% triethylamine). MS: M(C26H31FN6O2S)=510.2, (M+H)+=511.
Reaction SMILES: [SH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]([CH3:13])=[N:4][N:3]=1.[CH3:14][O-].[Na+].CI>CO>[CH3:13][C:5]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]([S:1][CH3:14])=[N:3][N:4]=1
Reactant: C[O-]
Reactant: Cc1nnc(S)n1-c1ccccc1
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CSc1nnc(C)n1-c1ccccc1
Reaction time: 0.17 h

Procedure:
In 200 ml of methanol was suspended 19.1 g of 3-mercapto-5-methyl-4-phenyl-1,2,4-triazole and then 20 g of a 28% sodium methylate solution to the suspension. After 10 minutes, 15 g of methyl iodide was added dropwise to the mixture. After performing the reaction for 10 minutes, methanol was distilled off and the product was extracted with ethyl acetate to provide 5-methyl-3-methylthio-4-phenyl-1,2,4-triazole.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43](OC)=[O:44])=[N:8]1.O.[OH-].[Li+].[CH3:53][C:54]([CH3:58])([CH3:57])[CH2:55][NH2:56].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O1CCCC1.O>[CH3:53][C:54]([CH3:58])([CH3:57])[CH2:55][NH:56][C:43]([C:42]1[CH:47]=[CH:48][CH:49]=[C:40]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:20]=[CH:19][N:18]([C:21]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:17]=4)[CH:11]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=2)[CH:41]=1)=[O:44]
Reactant: CC(C)(C)CN
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)CNC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 60 °C
Reaction time: 67 h
Yield: 72.1 %

Procedure:
To a stirred solution of methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.431 g, 0.667 mmol) in a tetrahydrofuran/water mixture (2.70 mL/1.62 mL) was added lithium hydroxide monohydrate (0.0840 g, 2.00 mmol) and the mixture heated at 60° C. for 21 h. To this mixture was added tetrahydrofuran (2.16 mL), 2,2-dimethylpropyl amine (0.174 g, 2.00 mmol), 1-hydroxybenzotriazole hydrate (0.270 g, 2.00 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.384 g, 2.00 mmol). This reaction mixture was stirred for 67 h at ambient temperature. The mixture was extracted with ethyl acetate (2×). The combined organic extracts were washed with an aqueous saturated sodium bicarbonate solution, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography with 40–60% ethyl acetate/hexanes gave the title compound (0.337 g, 72% yield). ES-MS (m/z) 459 [M+1(−Tr)]+