Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([CH:25]([CH3:27])[CH3:26])[C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)(C)(C)C.[CH3:29][NH2:30]>>[CH:25]([NH:7][C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:30][CH3:29])[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)([CH3:26])[CH3:27]
Reactant: CN
Reactant: CSc1nccc(-c2cnc3c(N(C(=O)OC(C)(C)C)C(C)C)nccn23)n1
Product: CNc1nccc(-c2cnc3c(NC(C)C)nccn23)n1

Procedure:
Isopropyl-[3-(2-methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine was prepared by a process analogous to that described in Example 12 starting from isopropyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (from Example 11 supra), and methylamine.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11](NC(C2C(Cl)=CC=CC=2Cl)=O)=[CH:10][CH:9]=1)[NH2:6].ClC1C=CC=C(C)C=1C(O)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6]
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1cccc(Cl)c1C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](N)Cc1ccccc1
Yield: 137.2 %

Procedure:
A solution of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester hydrochloride (1.23 g, 3.05 mmol), 2-chloro-6-methylbenzoic acid (0.50 g, 2.93 mmol), HBTU (1.16 g, 3.05 mmol) and DIPEA (1.33 mL, 7.6 mmol) in DMF (12 mL) was stirred 15 hr at room temperature. The mixture was diluted with ethyl acetate (250 mL) and was washed with 0.5 N HCl (2×80 mL), sat. sodium bicarbonate (2×80 mL) and brine (2×80 mL) and was dried (Na2SO4). The solution was filtered and concentrated to a yellow gum which was crystallized from ethyl acetate-hexane to give N-(2-chloro-6-methylbenzoyl)-4-[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester (0.75 g), suitable for use in the next step. The mother liquors were concentrated and purified by silica gel chromatography eluting with 1:1 ethyl acetate:hexane to give an additional 0.625 g.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[C:19]([CH:25]([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[C:20](OCC)=[O:21])=[CH:14][CH:13]=1>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[C:19]([CH:25]([CH:26]([CH3:27])[CH3:28])[CH:29]([CH3:31])[CH3:30])=[CH:20][OH:21])=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)C(C(C)C)C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(C)C(C(=CO)C(c1ccc(F)cc1)c1ccc(F)cc1)C(C)C
Reaction time: 5 h
Yield: 93.8 %

Procedure:
Diisobutylaluminum hydride (33 mL of 1M solution, 33 mmol) was added to a solution of ethyl 3,3-bis(4-fluorophenyl)-2-[2-methyl-1-(1-methylethyl)-propyl]propenoate (2.5 g, 6.5 mmole) in methylene chloride at -70° C. After stirring for 5 hours, the temperature had risen to -20° C. and the reaction was quenched with 2N hydrochloric acid. The organic layer was separated, dried with magnesium sulfate and concentrated in vacuo to give 2.1 g of the title compound as an oil. MS(CI): m/e =344 for M+ of C22H26F2O.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH:14](O)[CH3:15])=[C:9]([O:17][CH2:18][CH3:19])[C:8]=1[C:20]1[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[N:24][CH:25]=1)#[N:6]>C(Cl)Cl.CN(C)C=O>[Cl:3][CH:14]([C:10]1[C:9]([O:17][CH2:18][CH3:19])=[C:8]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[N:24][CH:25]=2)[C:7]([C:5]#[N:6])=[C:12]([CH3:13])[CH:11]=1)[CH3:15]
Reactant: CCOc1c(C(C)O)cc(C)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1c(C(C)Cl)cc(C)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Reaction time: 3 h
Yield: 91 %

Procedure:
Thionyl chloride (900 μL, 10 mmol) was added dropwise to a solution of 5-[2-cyano-6-ethoxy-5-(1-hydroxyethyl)-3-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (2.3 g, 6.5 mmol) in methylene chloride (100 mL) and N,N-dimethylformamide (100 μL) at room temperature. The reaction was stirred for 3 hrs, was diluted with methylene chloride (100 mL) and washed with water saturated NaHCO3. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give crude 5-[3-(1-chloroethyl)-6-cyano-2-ethoxy-5-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (2.2 g, 91%). LCMS calculated for C20H23ClN3O2(M+H)+: m/z=372.1; found: 372.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(C)ccc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.9 %

Procedure:
To a solution of 2-chloro-5-methylphenol (10.7 g, 75 mmol) in DMF (40 mL) was added potassium carbonate (26 g, 188 mmol) followed by neat methyl iodide (4.9 mL, 79 mmol). The reaction mixture was stirred at room temp for 6 hr, extracted with EtOAc, washed with water and brine, dried and concentrated in vacuo to give 4-chloro-3-methoxytoluene (10.8 g, 92%). 1H-NMR (DMSO-d6): δ 2.26 (s, 3H), 3.79 (s, 3H), 6.71-6.73 (dd, 1H), 6.94 (s, 1H), 7.22-7.24 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][CH:24]=1>>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([NH:1][C:2]2[S:3][C:4]([C:10]3[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=3[F:16])=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])=[CH:24][CH:25]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(=O)c1ccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)cc1

Procedure:
2-[(4-acetylphenyl)amino]-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide was prepared according to the general procedure in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.2 g, 0.640 mmol) and 1-(4-bromophenyl)ethanone (0.127 g, 0.640 mmol) as the starting materials.
Reaction SMILES: O.[N+:2]([C:5]1[CH:39]=[CH:38][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=4)=[CH:24][CH:23]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([O-])=O.[H][H]>[Pd].O1CCCC1>[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29]4[CH:30]=[CH:31][C:32]([NH2:35])=[CH:33][CH:34]=4)=[CH:24][CH:23]=3)=[CH:14][CH:15]=2)=[CH:38][CH:39]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(CCCCCCc3ccc(Cc4ccc([N+](=O)[O-])cc4)cc3)cc2)cc1
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Cc2ccc(CCCCCCc3ccc(Cc4ccc(N)cc4)cc3)cc2)cc1
Yield: 84.5 %

Procedure:
In a 1-liter three-necked flask equipped with a stirring device and a nitrogen substituting device, 3.5 g of a Pd-C catalyst (a 5% product, containing 55.9% of water) and a solution of 35.0 g of 1,6-bis(4-(4-nitrobenzyl)phenyl)hexane in 200 milliliters of tetrahydrofuran were introduced, and contacted with hydrogen gas at a normal pressure with stirring. After hydrogen absorption was stopped, the catalyst was filtered off and the solution was concentrated. Crystals were dissolved in chloroform, subjected to a column chromatography treatment with active alumina and silica gel, and thereafter the solution was reconcentrated to give a concentrate, which was then recrystallized from a mixed solvent of toluene and denatured ethanol, to obtain 26.1 g of 1,6-bis(4-(4-aminobenzyl)phenyl)hexane. Melting point was from 111.4° to 112.2° C.
Reaction SMILES: C1(N=[C:8]([OH:24])[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]([OH:13])=[S:12])C=CC=CC=1.[OH-:25].[Na+].Cl>>[C:18]1([C:17]2[CH:16]=[CH:15][CH:14]=[C:10]([C:11]([OH:13])=[S:12])[C:9]=2[C:8]([OH:24])=[O:25])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: [OH-]
Reactant: OC(=S)c1cccc(-c2ccccc2)c1C(O)=Nc1ccccc1
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1c(C(O)=S)cccc1-c1ccccc1
Temperature: 100 °C

Procedure:
99.4 g (0.3 mol) of 3-phenylthiophthalic acid N-phenylimide are suspended in 1,326 ml of a 20% sodium hydroxide solution and the suspension is heated at 100° C. for 30 minutes, with stirring. After cooling, the alkaline suspension is acidified with 672 ml of 37% hydrochloric acid, with stirring. After one hour the fine suspension is filtered with suction, the material on the suction filter is suspended, whilst till wet, in 882 ml of 37% hydrochloric acid and the suspension is refluxed for one hour. The reaction mixture is cooled, the resulting fine suspension is filtered with suction and the product is dried at 80° C./13,000 Pa. 69.4 g (85 of theory) of 3-phenylthiophthalic acid are obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=O)=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.[CH2:13]1CCN2C(=NCCC2)C[CH2:14]1.[Br-].C(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=C>C(#N)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:7]=1[CH:8]=[CH:13][CH2:14][O:10]2
Reactant: COc1ccc(F)c(C=O)c1O
Reactant: C1CCC2=NCCCN2CC1
Agent: C=C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Solvent: O
Product: COc1ccc(F)c2c1OCC=C2
Yield: 35.1 %

Procedure:
6-Fluoro-2-hydroxy-3-methoxy-benzaldehyde (3.32 g, 19 mmol) was dissolved in acetonitrile (20 ml) and DBU (2.97 ml, 19 mmol) was added followed by vinyltriphenylphosphine bromide (7.2 g, 19 mmol). The reaction mixture was heated under reflux for 48 h, diluted with water and extracted with ether (3×50 ml). The organic phase was washed with water, 10% sodium hydroxide, water and brine and evaporated in vacuo. The residue was submitted to column chromatography (silica gel, EA:Hex, 1:20) yielding 1.2 g of 5-fluoro-8-methoxy-2H-chromene (34%).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]3=[N:21][N:20]=1)[CH:15]=[CH:14]2)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.[Cl-].[NH4+]>[CH3:28][C:26]1[CH:25]=[CH:24][N:23]2[C:19]([C:16]3[CH:15]=[CH:14][C:13]4[C:18](=[C:9]([OH:8])[CH:10]=[CH:11][CH:12]=4)[N:17]=3)=[N:20][N:21]=[C:22]2[CH:27]=1
Reactant: Cc1ccn2c(-c3ccc4cccc(O[Si](C)(C)C(C)(C)C)c4n3)nnc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccn2c(-c3ccc4cccc(O)c4n3)nnc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
To a solution of 8-(tert-butyldimethylsilyloxy)-2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline (5.00 g, 12.8 mmol) in tetrahydrofuran (100 mL) at 0° C. was added tetrabutylammonium fluoride (19.2 mL, 1 M in tetrahydrofuran, 19.2 mmol). The reaction was stirred for 6 hours at ambient temperature and then diluted with saturated aqueous ammonium chloride. The mixture was concentrated under reduced pressure, triturated with water, filtered and air-dried to provide 3.50 g (99%) of desired product as a white solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[CH:13][C:12]=1[NH:29][C:30](=[O:37])[CH2:31][CH:32]([CH3:36])[C:33](O)=[O:34]>CC(N(C)C)=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[CH:13][C:12]=1[N:29]1[C:30](=[O:37])[CH2:31][CH:32]([CH3:36])[C:33]1=[O:34]
Reactant: CC(CC(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC1CC(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.8 %

Procedure:
O-Benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate (1.09 g, 3.4 mmol) and diisopropylethylamine (0.98 g, 5.7 mmol) were added sequentially to a stirred solution of N-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-2-methylsuccinamic acid (1 g, 2.6 mmol) in dimethylacetamide (5 ml), the mixture was stirred at ambient temperature for 15 minutes, then it was poured onto water (50 ml) and allowed to stand at ambient temperature for 20 hours. The resulting solid was collected by filtration, washed with hexane (20 ml) and dried in vacuo to give 1-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-3-methylpyrrolidine-2,5-dione (0.654 g) as a beige solid, m.pt. 171–172° C.; 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 1.4 (d, 3H) (CH3), 2.6–2.7 (m, obscured by DMSO signal, 1H) (—CHMe-), 3.05–3.3 (m, 2H) (—CH2CHMe-), 4.5 (s, 2H) (ArCH2—), 7.3–7.55 (m, 2H) (2×ArH), 7.6–7.7 (m, 1H) (ArH), 7.9–8.2 (m, 3H) (3×ArH), 8.4 (d, 1H) (ArH), 12.8 (s, 1H) (CONH); m/z (M+H)+ 366, 98% purity.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]CO.[C:9](=[O:14])([O:12][CH3:13])[O:10][CH3:11].C[O-].[Na+]>>[C:9](=[O:14])([O:12][CH2:13][CH2:1][O:2][CH2:3][CH2:4][O:5][CH3:6])[O:10][CH3:11]
Reactant: COC(=O)OC
Reactant: COCCOCCO
Agent: C[O-]
Agent: [Na+]
Product: COCCOCCOC(=O)OC
Temperature: 84 °C
Yield: 90 %

Procedure:
A total of 144.2 grams (1.2 mol) of 2-(2-methoxyethoxy)ethanol, 400 grams (4.4 mol) of dimethyl carbonate and 3 grams (0.05 mol) of sodium methoxide were combined in a 1-liter 3-neck round bottom flask equipped with a 14 inch distillation column, distillation head, and magnetic stirbar. The system was evacuated and purged three times with nitrogen using a Firestone valve, and left under a constant nitrogen atmosphere. After a period of 1.5 hours at reflux (kettle temperature 84° C.), methanol (boiling point 64° C.) was slowly removed overhead to drive the equilbrium. A total of 49.8 grams of methanol was removed over a period of 3 hours, after which time the stopcock was closed and the reaction mixture was allowed to reflux overnight. The mixture was then cooled to room temperature, filtered and charged (429 grams) to a 500 milliliter round bottom flask equipped with a distillation head and magnetic stirbar. Excess dimethyl carbonate (boiling point 90° C.) was removed overhead. The flask was then cooled, put under vacuum (10-11 mm Hg , and methyl 2-(2-methoxyethoxy)ethyl carbonate removed overhead (boiling point 115°-125° C.). A total of 193 grams (ca. 90% yield) was obtained. Gas chromatography analysis of this material showed 97.74% purity (remainder was 2-(2-methoxyethoxy)ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si:23]([CH3:26])([CH3:25])[CH3:24])(=O)=O>C1(C)C=CC=CC=1>[CH3:24][Si:23]([N:1]([Si:23]([CH3:26])([CH3:25])[CH3:24])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)([CH3:26])[CH3:25]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: N#Cc1ccc(N)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N(c1ccc(C#N)cc1)[Si](C)(C)C
Yield: 95.2 %

Procedure:
About 5.09 g of 4-aminobenzonitrile, 10.03 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 22.02 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was heated to reflux for 40 hours to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding 4-[bis(trimethylsilyl)amino]benzonitrile (4-BTMSABZN) as a brown oil (10.77 g, 95% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 6.93 (doublet, 2H, aromatic protons), 6.43 (doublet, 2H, aromatic protons), −0.07 (singlet, 18H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]#[CH:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:16][O:11][C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][C:14]#[CH:15]
Reactant: C#CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: C#CC[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 3 h

Procedure:
The commercially available compound, 2-(R)-tert-butoxycarbonylaminopent-4-ynoic acid (0.321 g, 1.50 mmol) was dissolved in anhydrous DMF (5 mL). To the solution was added cesium carbonate (0.54 g, 1.65 mmol) in one portion. The mixture was stirred at room temperature for 45 min before methyl iodide (0.20 mL, 3.00 mmol) was added, and further stirred for three hours. The reaction was quenched with water (10 mL). The organics was extracted with dichloromethane (2×30 mL), washed with water (3×50 mL), and dried over anhydrous sodium sulfate. The solvent was completely removed under vacuum. The residue was further dried under high vacuum over night and used in the next reaction without further purification. The product 23 was obtained as a colorless viscous oil (0.326 g, 95% yield). 1H NMR (300 MHz, CDCl3): δ 1.48 (s, 9H), 2.08 (t, J=2.6 Hz, 1H), 2.75 (t, J=6.3 Hz, 2H), 3.78 (s, 3H), 4.46 (m, 1H), 5.32 (br s, 5H).
Reaction SMILES: Cl[CH:2](Cl)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:7]([Cl:17])[CH:6]=1)Cl.C[Li]>CCOCC>[Cl:17][C:7]1[CH:6]=[C:5]([C:3]#[CH:2])[CH:10]=[CH:9][C:8]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Clc1cc(C(Cl)C(Cl)Cl)ccc1C1CCCCC1
Agent: [Li]C
Solvent: CCOCC
Product: C#Cc1ccc(C2CCCCC2)c(Cl)c1

Procedure:
β.β,α,3-tetrachloro-4-cyclohexylphenylethane (55.8 g.; 0.17 moles) is dissolved in anhydrous ether (100 ml). The solution is cooled in an ice-bath with stirring under nitrogen. Methyl lithium (2.3 M in ether; 300 cc) is added dropwise and the mixture stirred in the icebath for 2.5 hours before destroying the excess methyl lithium with ice. The ethereal fraction is washed thoroughly with saline until the washings are neutral. Removal of solvent gives 3-chloro-4-cyclohexyl-1-ethynylbenzene (b.p. 82°-88°/0.15 m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)[CH:5]=[CH:6][CH:7]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[CH3:34])=[O:25])[CH2:18]1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]3[N:33]4[C:29]([S:30][CH:31]=[CH:32]4)=[N:28][C:27]=3[CH3:34])=[O:25])[CH2:18]2)=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of 5-(3-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: [CH:1](/[C:9]1[CH:18]=[C:17]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[ClH:25].CCOCC.[H][H]>CO.[Pd]>[ClH:25].[CH2:1]([C:9]1[CH:18]=[C:17]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: OCC(O)CNc1cc(/C=C/c2ccccc2)nc2ccccc12
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: OCC(O)CNc1cc(CCc2ccccc2)nc2ccccc12
Temperature: 25 °C
Yield: 29 %

Procedure:
(E)-(RS)-3-(2-Styryl-quinolin-4-ylamino)-propane-1,2-diol (0.23 g, 0.718 mmol) was dissolved in MeOH (25 ml) and acidified with HCl/Et2O. The reaction mixture was refluxed for 2 hours in the presence of 10% Pd/C (0.02 g) under an atmospheric pressure of hydrogen. The mixture was cooled to room temperature, the catalyst was filtered, and the filtrate was concentrated. Addition of EtOH provided (RS)-3-(2-phenethyl-quinolin-4-ylamino)-propane-1,2-diol hydrochloride (0.075 g, 29%) as a light yellow solid, m. p. 143-145° C., MS: m/e=323.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].F[C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=1)=[N:11][CH:12]=[N:13]2>>[NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][O:4][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=1)=[N:11][CH:12]=[N:13]2
Reactant: CC(C)(N)CO
Reactant: Cc1cc(Nc2ncnc3cccc(F)c23)ccc1O
Product: Cc1cc(Nc2ncnc3cccc(OCC(C)(C)N)c23)ccc1O
Yield: 78 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using 2-amino-2-methylpropan-1-ol and 4-[(5-fluoroquinazolin-4-yl)amino]-2-methylphenol (obtained as described in Example 3, preparation of starting materials) to give 4-{[5-(2-amino-2-methylpropoxy)quinazolin-4-yl]amino}-2-methylphenol as a white solid in 78% yield; NMR spectrum (DMSO-d6) 1.34 (s, 6H), 4.23 (s, 2H), 6.97 (d, 1H), 7.18 (d, 1H), 7.35 (d, 1H), 7.52 (dd, 1H), 7.73 (t, 1H), 7.96 (d, 1H), 8.46 (s, 1H), 10.50 (s, 1H); Mass spectrum MH+ 360.
Reaction SMILES: [CH2:1]([C@@H:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2].[H-].[Na+].[CH2:20](I)[CH3:21].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C@@H:3]1[C:8](=[O:9])[N:7]([CH2:20][CH3:21])[C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2]
Reactant: CC[C@H]1Oc2cc(C(=O)OC)ccc2NC1=O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC[C@H]1Oc2cc(C(=O)OC)ccc2N(CC)C1=O
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a solution of (R)-2-ethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine [prepared in Preparation 15(2)] (2.00 g) in dimethylformamide (20 ml) were added 60% sodium hydride (in oil) (0.35 g) and ethyl iodide (1.46 g) and the mixture was stirred at room temperature for two and a half hours. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:4 (v/v)] to give (R)-2,4-diethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine(2.0g).
Reaction SMILES: C[C:2]1([C:25]([O-:27])=[O:26])[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]1=[C:4]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14][CH:5]1[N:6]2[CH3:13].[OH-].[Na+]>CO>[C:21]([O:20][C:18]([N:16]1[CH2:15][CH2:14][C:5]2[N:6]([CH3:13])[C:7]3[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:2]([C:25]([OH:27])=[O:26])[C:3]=3[C:4]=2[CH2:17]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC1=C2C(=C3CN(C(=O)OC(C)(C)C)CCC3N2C)C(C)(C(=O)[O-])C=C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)O)c2c3c(n(C)c12)CCN(C(=O)OC(C)(C)C)C3

Procedure:
To a solution of 2-tert-butyl 9-methyl-6-methoxy-5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2,9-dicarboxylate (from step 3) (0.0026 mol) in methanol (20 ml) was added 1N NaOH (0.010 mol) solution and refluxed for overnight. Reaction was then concentrated under vacuum diluted with small amount of water and then washed with ethyl acetate (10×2 ml). Aqueous layer was neutralized with 1N HCl solution up to pH 2. Solid which was precipitated out was filtered washed well with water and dried.