Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH3:12][O:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1>C1COCC1>[OH:19][C:18]([C:17]1[CH:28]=[CH:29][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)(CC#N)c2ccc(OC)cc2)cc1
Temperature: -78 °C
Yield: 74.4 %

Procedure:
Acetonitrile (3.2 ml, 0.058 mol) was added dropwise to a solution of lithium diisopropylamide (1.5M in THF, 36.7 ml, 0.055 mol) stirred at -78° C. under argon. After 5 min. a solution of 4,4'-dimethoxybenzophenone (10.0 g, 0.048 mol) in dry THF (130 ml) was added slowly. The mixture was allowed to warm up to -35° C. and after 20 min. was quenched by the cautious dropwise addition of a solution of acetic acid (3.0 g) in water (6 ml). Brine (50 ml) was added, the organic layer separated washed with brine (50 ml) and the combined aqueous phases were extracted with DCM (2×50 ml). The combined organics were dried over anhydrous magnesium sulphate, filtered and concentrated. The residue was crystallised from ethyl acetate to give 3-hydroxy-3,3-di(4-methoxyphenyl)propanenitrile (10.12 g, 85%) as a white crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]([O:18]CC)=[O:17])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/c1cccc(C(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)c1cccc(/C=C/C(=O)O)c1
Reaction time: 2 h

Procedure:
To a stirred solution of ethyl (2E)-3-[3-(tert-butoxycarbonyl)phenyl]prop-2-enoate from the previous step (3.44 g, 12.4 mmol) in EtOH (30 mL), was added 1N NaOH (15 mL, 15 mmol) and the mixture was stirred for 2 hours. The reaction was concentrated under reduced pressure to ˜20 mL, acidified with 10% aqueous citric acid and extracted with 2×100 mL EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and the solvent removed under reduced pressure to give (2E)-3-[3-(tert-butoxycarbonyl)phenyl]prop-2-enoic acid as an oil which solidified on standing (3.1 g, 100%). HPLC RT=2.43 min, method B; 1H NMR, 400 MHz, CDCl3, 8.16, (s, 1H); 8.03 (d, J=8 Hz, 1H); 7.81, (d, J=16 Hz, 1H); 7.70, (d, J=8 Hz, 1H); 7.47 (t, J=8 Hz, 1H); 6.52 (d, J=16 Hz, 1H); 1.62 (s, 9H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:11]=[C:10]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)[CH:9]=[CH:8][N:7]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl.O>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][C:10]3[CH:9]=[CH:8][N:7]=[C:6]([CH2:5][OH:4])[N:11]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: CC(=O)OCc1nccc(Oc2ccc3[nH]ccc3c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: OCc1nccc(Oc2ccc3[nH]ccc3c2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4-(1H-indol-5-yloxy)pyrimidin-2-yl)methyl acetate (0.51 g, 1.8 mmol) in MeOH (18 mL) at 0° C. is added solid K2CO3 (0.6 g, 4.5 mmol). The reaction is stirred for 30 minutes at 0° C. and then warmed to room temperature and stirred for an additional 30 minutes. The reaction mixture is then diluted with DCM and water and the layers are separated. The aqueous layer is extracted 2 additional times with DCM. The organic layers are combined dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound. MS (ESI) m/z 242.1 (M+1).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:19]([C:20](O)=[O:21])=[C:18]3[C:13]([CH2:14][CH2:15][CH:16]([CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:25])[O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.[CH3:37][NH2:38]>C(Cl)Cl.C(#N)C>[C:29]([O:28][C:26](=[O:27])[N:24]([CH2:23][CH:16]1[CH2:15][CH2:14][C:13]2[C:18](=[C:19]([C:20](=[O:21])[NH:38][CH3:37])[C:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:8])=[O:9])=[CH:11][CH:12]=2)[O:17]1)[CH3:25])([CH3:31])([CH3:30])[CH3:32]
Reactant: CN(CC1CCc2ccc(S(=O)(=O)c3ccccc3)c(C(=O)O)c2O1)C(=O)OC(C)(C)C
Reactant: CN
Solvent: CC#N
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1c(S(=O)(=O)c2ccccc2)ccc2c1OC(CN(C)C(=O)OC(C)(C)C)CC2
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 7-benzenesulfonyl-2-[(tert-butoxycarbonyl-methyl-amino)-methyl]-chroman-8-carboxylic acid (52 mg, 0.113 mmol) in DCM (10 mL) was added SOCl2 (25 μL, 0.339 mmol). The reaction was heated to reflux for 2 hours, then a solution of MeNH2 (40% in water, 0.5 mL) in acetonitrile (5 mL) was added and the mixture was allowed to stir for 1 hour. The reaction was concentrated in vacuo and the residue was purified via flash chromatography (DCM/MeOH, 98/2) to give (7-benzenesulfonyl-8-methylcarbamoyl-chroman-2-ylmethyl)-methyl-carbamic acid tert-butyl ester (52 mg, 98% yield) as clear oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH2:10][CH2:9]1)(=O)=O.[O:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30].CN(C)C(N(C)C)=N>O1CCCC1>[F:21][C:20]([F:23])([F:22])[C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:7][CH2:6][N:26]3[C:27](=[O:29])[CH2:28][O:24][C:25]3=[O:30])[CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)OCCC1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: O=C1COC(=O)N1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: O=C1COC(=O)N1CCC1CCN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
A solution of 2.3 g (6.545 mmol) of 2-{1-[3-(trifluoromethyl)phenyl]-4-piperidyl}ethyl methanesulfonate, prepared in step 3.2, 0.694 g (6.87 mmol) of 1,3-oxazolidine-2,4-dione (J. Med. Chem., 1991, 34, 1538–1544) and 1.5 g (13.09 mmol) of 1,1,3,3-tetramethylguanidine in 30 ml of tetrahydrofuran is refluxed for 12 hours under an inert atmosphere.
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Cl:17])[C:7](=[O:18])[C:6]=2[C:5]([NH:19][C:20](=[O:22])[CH3:21])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:25]I>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClC1C=CC=CC=1>[Br:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Cl:17])[C:7](=[O:18])[C:6]=2[C:5]([N:19]([CH3:25])[C:20](=[O:22])[CH3:21])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1ccc(Br)c2c1C(=O)c1cccc(Cl)c1C2=O
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: CC(=O)N(C)c1ccc(Br)c2c1C(=O)c1cccc(Cl)c1C2=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
To a mixture of 4-bromo-5-chloro-1-acetylaminoanthraquinone (purity 98%, 38.6 g), monochlorobenzene (460 g), tetra-n-butyl ammonium bromide (0.3 g) and 96% potassium hydroxide (12.0 g) was added methyl iodide (28.4 g) at 30° C. over 2 hours. A mixture was stirred at 30° C. for 30 minutes and 40° C. for 3 hours, successively. Then, the same after-treatment as in Example 3 was carried out to obtain 4-bromo-5-chloro-N-acetyl-1-methylaminoanthraquinone (39.3 g, purity 93.7%, yield 93.8%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:29])[O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18](CC2C=CC=CC=2)[CH2:17][CH2:16]3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl>[Pd].C(O)(C)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:29])[O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16]3)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(NC(=O)Oc2ccc3c(c2)CCN3Cc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: CC(C)c1ccc(NC(=O)Oc2ccc3c(c2)CCN3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of 1-benzylindolin-5-yl 4-isopropylphenylcarbamate (300 mg, 0.776 mmol) in a 2:1 solution (3.0 mL) of isopropylalcohol and 6 M HCl was added palladium 10% on carbon (30 mg) under nitrogen. After the vessel was purged with hydrogen, the reaction mixture was stirred under 1 atm of hydrogen at room temperature overnight. After the vessel was purged with nitrogen, the reaction mixture was filtered to remove palladium 10% on carbon. The filtrate was concentrated in vacuo. After the residue was diluted with ethyl acetate, the solution was washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=85/15 to 40/60) to obtain the title compound as a white solid (220 mg, 96%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29](B(O)O)[CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[C:20]([O:19][C:17]([NH:16][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:27]2[CH:26]=[C:25]([F:24])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])=[CH:3][CH:4]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reactant: COc1ccc(F)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a solution of (R)-ethyl 4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate, (3.12 g, 8.08 mmol), and 5-fluoro-2-methoxyphenylboronic acid (2.2 g, 12.93 mmol) in toluene (52 mL) and is added PdCl2(dppf)CH2Cl2 adduct (0.66 g, 0.81 mmol) and 2M aq. Na2CO3 (8.1 mL, 16.16 mmol). After stirring at 95° C. under nitrogen for 4 hours, the solution is cooled to ambient temperature and then quenched with ice water. The crude is diluted with ethyl acetate. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 50:50) to give (R)-ethyl 3-(tert-butoxycarbonylamino)-4-(5′-fluoro-2′-methoxybiphenyl-4-yl)butanoate (2.86 g). HPLC retention time=1.80 minutes (condition A); MS (m+1)=432.2; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (t, J=7.1 Hz, 3H) 1.45 (s, 9H) 2.45-2.65 (m, 2H) 2.83-2.94 (m, 1H) 2.94-3.09 (m, 1H) 3.80 (s, 3H) 4.20 (q, J=7.2 Hz, 2H) 4.24-4.33 (m, 1H) 5.11 (br. s., 1H) 6.90-6.96 (m, 1H) 7.00 (dd, J=7.8, 3.3 Hz, 1H) 7.06 (dd, J=9.2, 3.2 Hz, 1H) 7.27 (d, J=7.8 Hz, 2H) 7.49 (d, J=7.8 Hz, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].C(N(CC)CC)C.[C:19](Cl)([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:20]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:7][C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:20])[CH:8]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 20 h
Yield: 56.9 %

Procedure:
A solution of 10 g (58 mmol) 5-chloro-2-nitroaniline in 250 ml dry tetrahydrofuran was added 8.5 ml (62 mmol) dry triethylamine. A solution of 7.0 ml (62.7 mmol) ethoxalylchloride in 50 ml dry tetrahydrofuran was added dropwise Stirring was continued at 25° C. for 20 h. The reaction mixture was filtered and evaporated in vacuo. The residue was stirred with ethanol to give 9.0 g (57%) 4-chloro-2-ethoxalylamino-1-nitrobenzene. M.p. 105.1° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][C:5]1[N:6]([CH3:12])[C:7]([CH2:10][OH:11])=[N:8][N:9]=1.O.Cl.[C-]#[N:21].[Na+]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[F:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[C:3]=1[CH2:4][C:5]1[N:6]([CH3:12])[C:7]([C:10]([NH2:21])=[O:11])=[N:8][N:9]=1
Reactant: [C-]#N
Reactant: Cn1c(CO)nnc1Cc1c(F)cccc1F
Agent: [Mn+4]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1c(Cc2c(F)cccc2F)nnc1C(N)=O
Reaction time: 4 h

Procedure:
1.43 g (6 mmol) of 5-(2,6-difluorobenzyl)-3-hydroxymethyl-4-methyl-4H-1,2,4-triazole and 5.22 g (60 mmol) of manganese dioxide are heated under reflux in 40 ml of toluene for 3 hours using a water separator. The reaction mixture is then cooled and filtered over Hyflo, and the filtrate is concentrated by evaporation. The residue is added to 90 ml of isopropanol saturated with ammonia. At 0°, 1 47 g (30 mmol) of sodium cyanide and 10.44 g (120 mmol) of manganese dioxide are added. The reaction mixture is stirred for 4 hours at 0° and filtered over Hyflo. The filtrate is concentrated by evaporation. Recrystallisation of the residue from ethanol yields the pure 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide
Reaction SMILES: Cl[CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][NH:4][C:3]1=[O:10].S([O-])([O-])(=O)=[O:12].[NH4+].[NH4+]>O>[CH3:9][C:6]1([CH3:8])[CH2:5][NH:4][CH:2]([C:3]([OH:10])=[O:12])[CH2:7]1
Reactant: CC1(C)CNC(=O)C(Cl)C1
Reactant: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Product: CC1(C)CNC(C(=O)O)C1
Temperature: 150 °C

Procedure:
A suspension of 20.4 g (0.13 mol) of 3-chloro-5,5-dimethyl-2-piperidone and 45.2 g (0.14 mol) of Ba(OH)3-8H2O in 252 mL of water was heated in a Parr apparatus at 150° C. for 6 h. Then, 18.6 g (0.14 mol) of ammonium sulphate were added. The precipitate was filtered off, and the solution was concentrated under reduced pressure to dryness. Crude 4,4-dimethylpyrrolidine-2-carboxylic acid was obtained as a white solid (37.5 g). (J. Med. Chem., 20, 1176 (1977), EP 0 447 704 A1, page 17)
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].Cl.[C:8]1([CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][NH2:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.Cl>N1C=CC=CC=1>[C:8]1([CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][NH:20][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:6])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C(CN)c1cccc2ccccc12
Reactant: CCCN=C=O
Agent: Cl
Solvent: c1ccncc1
Product: CCCNC(=O)NCC(C(=O)OC)c1cccc2ccccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
0.011 mol of propyl isocyanate is added dropwise and with magnetic stirring to a suspension of 0.01 mol of 2-(1-naphthyl)-2-(methoxycarbonyl)ethylamine hydrochloride, obtained in stage B of Example 11, in 5 cm3 of pyridine. The reaction medium is stirred for 1 hour at a temperature of 80° C. and then poured into ice-cold water. The mixture is acidified with 1N hydrochloric acid solution. The precipitate formed is drained, washed with water, dried and then recrystallized in a toluene/cyclohexane mixture.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12](Br)[N:13]=2)[NH:8][C:7]=1[CH3:16])=[O:5])[CH3:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:21]3[CH:22]=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=3)[N:13]=2)[NH:8][C:7]=1[CH3:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH]c2ncc(Br)nc12
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)[nH]c2ncc(-c3cc(OC)c(OC)c(OC)c3)nc12
Temperature: 100 °C
Yield: 22.4 %

Procedure:
To a flask charged with 2-Bromo-6-methyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ethyl ester (360 mg, 1.26 mmol), 3,4,5-trimethoxyphenylboronic acid (320 mg, 1.51 mMol), Pd(dppf)Cl2 (31 mg, 0.038 mmol) was added K2CO3 (520 mg, 3.75 mmol). The mixture was heated to 100° C. overnight. The reaction mixture was cooled, diluted with EtOAc and filtered over celite. The solution was washed with water and brine, dried over Na2SO4, filtered, and concentrated. Flash chromatography afforded 105 mg of 6-Methyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@H:8]([CH2:10][N:11]([CH3:15])[CH2:12][C:13]#[CH:14])[OH:9])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(OCC)(=O)C.O>[CH3:15][N:11]([CH2:10][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:3]=1)[OH:9])[CH2:12][C:13]#[CH:14]
Reactant: C#CCN(C)C[C@H](O)c1cccc(O)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CCOC(C)=O
Product: C#CCN(C)CC(O)c1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
A mixture of 8.2 g (0.04 mol) of (R)-3-hydroxy-α-[[methyl-(2-propynyl)amino]methyl]benzene methanol, 7.1 g (0.04 mol) of 2-(chloromethyl)quinoline, 13.5 g (0.04 mol) of cesium carbonate, 0.5 g of potassium iodide, and 500 ml of tetahydrofuran is heated for 10 hours with stirring. The mixture is poured into water and ethyl acetate. The ethyl acetate is separated and washed with dilute aqueous sodium chloride solution. The ethyl acetate is dried over anhydrous magnesium sulfate, filtered and evaporated. The residue is chromatographed on silica gel with methylene chloride/isopropanol as eluent. Fractions 11-17 are combined, the solvent is evaporated and the residue, a viscous oil (2.1 g) is dried in vacuo.
Reaction SMILES: [CH3:1][C:2]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[C:14]([C:30]([F:33])([F:32])[F:31])=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([C@:23]2([CH3:29])[CH2:27][O:26]C(=O)[NH:24]2)[CH:17]=[CH:16]3)[CH2:8][CH2:7]1)([CH3:5])[CH2:3][CH3:4].O.C(O)C>[OH-].[Li+]>[NH2:24][C@@:23]([C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][C@H:9]3[CH2:8][CH2:7][C@H:6]([C:2]([CH3:1])([CH3:5])[CH2:3][CH3:4])[CH2:11][CH2:10]3)[C:14]=2[C:30]([F:32])([F:33])[F:31])[CH:19]=1)([CH3:29])[CH2:27][OH:26]
Reactant: CCC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2C(F)(F)F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2C(F)(F)F)CC1
Temperature: 80 °C

Procedure:
A mixture of (R)-4-{6-[trans-4-(1,1-dimethyl-propyl)-cyclohexyloxy]-5-trifluoromethyl-naphthalen-2-yl}-4-methyl-oxazolidin-2-one (33.00 mg, 0.07119 mmol) in 4.2 M lithium hydroxide in a mixture solvent of water (0.9 mL) and ethanol (0.9 mL) was heated at 80° C. overnight. The solution was concentrated and the residue was partitioned between methylene chloride (4 mL) and water (2 mL). The organic phase was washed with water, dried over MgSO4, filtered and concentrated to give 28 mg of white precipitate, (R)-2-amino-2-{6-[trans-4-(1,1-dimethyl-propyl)-cyclohexyloxy]-5-trifluoromethyl-naphthalen-2-yl}-propan-1-ol (90% yield). MS: m/z=421.30 M−16. 1H NMR (400 MHz, CDCl3) δ ppm 0.74-0.89 (m, 10H), 1.04-1.22 (m, 2H), 1.22-1.35 (m, 2H), 1.43-1.61 (m, 5H), 1.82 (d, J=11.29 Hz, 2H), 2.18 (d, J=12.80 Hz, 2H), 2.35 (s, 3H), 3.63-3.82 (m, 2H), 4.23-4.36 (m, 1H), 7.28 (d, 1H), 7.61 (dd, J=9.16, 1.88 Hz, 1H), 7.82-7.95 (m, 2H), 8.19 (d, J=7.78 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)[CH3:2].[H-].[Na+].CS(O[CH2:20][CH2:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH3:31])=[C:23]1[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)(=O)=O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:20][CH2:21][N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([CH3:31])=[C:23]2[C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[CH:7][CH:6]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)c1ccc(S)cc1
Reactant: Cc1c(-c2cccnc2)n(CCOS(C)(=O)=O)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(SCCn2c(-c3cccnc3)c(C)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5.9 g of p-mercaptobenzoic acid ethyl ester (prepared according to the procedure found in J. Chem. Soc., 1963, 1947-1954) in 30 ml of dimethylformamide is added dropwise to a slurry of 1.55 g of 50% sodium hydride (dispersion in mineral oil in 30 ml of dimethylformamide. This mixture is stirred at room temperature for 0.5 hour under nitrogen atmosphere. This solution is added dropwise to a solution of 9.78 g of 1-(2-methylsulfonyloxyethyl)-2-(3-pyridyl)-3-methylindole in 60 ml of dimethylformamide at -10°. This mixture is stirred at room temperature overnight and poured into 1 liter of ice-water. This is extracted several times with ether (ca 1 liter total). The ether extract is washed with water (3×200 ml), dried over MgSO4 and evaporated in vacuo yielding 1-[2-(4-ethoxycarbonylphenylthio)ethyl]-2-(3-pyridyl)-3-methylindole as an oil; NMR (CDCl3) confirms the structure.
Reaction SMILES: O.O.[CH2:3]([O:10][C:11]([NH:13][C@H:14]([C:23]([OH:25])=O)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([O:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28][CH2:27]1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.ON1C(=O)CCC1=O>[CH2:3]([O:10][C:11]([NH:13][C@H:14]([C:23]([N:26]1[CH2:27][CH2:28][CH:29]([O:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:31]1)=[O:25])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@H](Cc2ccc(O)cc2)NC(=O)OCc2ccccc2)CC1
Yield: 85.2 %

Procedure:
10.2 g (30 mmol) of N-(benzyloxycarbonyl)-L-tyrosine dihydrate, 6.48 g (30 mmol) of t-butyl (4-piperidinyloxy)acetate and 0.17 g (1.5 mmol) of N-hydroxysuccinimide were dissolved in 200 ml of ethyl acetate while stirring under argon. 6.5 g (31.5 mmol) of dicyclohexylcarbodiimide dissolved in 33 ml of ethyl acetate were added dropwise to the yellowish solution within 19 minutes. A suspension formed slowly and this was stirred at 22° for 22 hours. The precipitated dicyclohexylurea was filtered off and the filtrate was extracted with 1N hydrochloric acid, water and sodium chloride solution. The organic phase was dried over sodium sulphate and, after removing the drying agent, evaporated. 13.1 g of t-butyl [[1-[N-[(benzyloxy)carbonyl]-L-tyrosyl]-4-piperidinyl]oxy]acetate were obtained as a white, hard foam, the microanalysis of which corresponded to that of authentic material.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH2:10][OH:11])=[CH:8][N:7]=[C:6]([S:12][CH3:13])[N:5]=1)[CH3:2]>C(Cl)(Cl)Cl.[O-2].[Mn+2]>[CH2:1]([NH:3][C:4]1[C:9]([CH:10]=[O:11])=[CH:8][N:7]=[C:6]([S:12][CH3:13])[N:5]=1)[CH3:2]
Reactant: CCNc1nc(SC)ncc1CO
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCNc1nc(SC)ncc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To 4-ethylamino-2-methylthio-5-pyrimidinemethanol (6.44 g, 32.4 mmol) in 600 mL of chloroform was added manganese oxide (21.0 g, 241 mmol) over 3 minutes. The suspension was stirred at room temperature for 2 hours, and an additional 5.5 g of manganese oxide was added. Stirring was continued for 4.5 hours. The mixture was then filtered through celite washing with chloroform. The filtrate was concentrated in vacuo to give 6.25 g (97%) of 4-ethylamino-2-methylthio-5-formylpyrimidine; mp 58°-61° C.