Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH:20]3[CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH:20]3[CH2:22][CH2:21]3)(=[O:18])=[O:19])=[CH:13][CH:12]=2)[C:8]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(=O)(=O)C3CC3)cc2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
A solution of (R)-3-cyclopentyl-2-(4-cyclopropanesulfonyl-phenyl)-propionic acid (50 mg, 0.16 mmol) was dissolved in methylene chloride (5 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 93 μL, 0.19 mmol) which produced gas evolution and it was stirred at 0° C. for 10 min and it was then allowed to warm to 25° C. and stirred 25 min at 25° C. After this time, the reaction was concentrated in vacuo to ˜1 mL. In a separate flask, a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 36 mg, 0.23 mmol), 2,6-lutidine (34 μL, 0.31 mmol) and methylene chloride (5 mL) was cooled to 0° C. in an ice bath. To this solution was added the solution of the prepared acid chloride, diluted with another portion of methylene chloride (1 mL), dropwise. After addition was complete the reaction was then allowed to warm to 25° C. and stirred for 16 hours. After this time the reaction mixture quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and transferred to a separatory funnel where it was extracted with methylene chloride (3×10 mL). The organic layers were then washed with a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 55% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-2-(4-cyclopropanesulfonyl-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (42 mg, 59%) as a white foam: [α]30589=−12.0° (c=0.10, methylene chloride); ES-HRMS m/e calcd for C24H33N3O4S (M+H)+ 460.2265, observed 460.2264; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96-1.21 (m, 6H, 3×CH2), 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.35-1.81 (m, 8H, 4×CH2), 2.10 (m, 1H, CH), 2.81 (m, 1H, SCH), 3.86 (s, 2H, NCH2), 3.93 (m, 1H, ArCHCO), 4.65 (s, 1H, OH), 6.45 (d, J=2.1 Hz, 1H, Ar), 7.50 (d, J=2.1 Hz, 1H, Ar), 7.63 (d, J=8.2 Hz, 2H, Ar), 7.84 (d, J=8.2 Hz, 2H, Ar), 10.78 (s, 1H, NH).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:19])[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:8]([CH3:11])[C:9]=1Br)=[O:4].C(O)C.[NH2:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:19])[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:8]([CH3:11])[C:9]=1[C:30]1[CH:31]=[CH:32][C:27]([S:24](=[O:26])(=[O:25])[NH2:23])=[CH:28][CH:29]=1)=[O:4]
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1c(Br)c(C)c(-c2ccc(Cl)cc2)n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1c(-c2ccc(S(N)(=O)=O)cc2)c(C)c(-c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Yield: 69.5 %

Procedure:
To the solution of methyl-3-bromo-5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrole-2-carboxylate (compound 49β, 2.0 g, 5.84 mmol) in a mixture of toluene:ethanol (15:40 ml) was added 4-aminosulfonylbenzene boronic acid (1.41 g, 7.01 mmol) and potassium carbonate (2.42 g, 17.52 mmol) at 25° C. in a sealed tube and a nitrogen gas was bubbled through the resulting mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.349 g, 0.29 mmol) under nitrogen and reaction mixture was heated at about 95 to about 100° C. for 15 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with ethanol (100 ml) and ethyl acetate (50 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (1.7 g, 69.6%).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[C:10]([OH:16])[CH:9]=1)[CH2:6][CH3:7])[CH3:4].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>O1CCCC1>[CH2:3]([N:5]([C:8]1[CH:15]=[CH:14][C:11]2[CH:12]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[O:16][C:10]=2[CH:9]=1)[CH2:6][CH3:7])[CH3:4]
Reactant: COC(=O)CBr
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)c1ccc2cc(C(=O)OC)oc2c1
Temperature: 25 °C
Yield: 45.1 %

Procedure:
To a 250 mL three-necked, round-bottom flask equipped with a mechanical stirrer, reflux condenser, and Y-tube with a rubber septum and nitrogen inlet was added 1.8 gm (45 mmol) of 60% sodium hydride in mineral oil. After washing twice with 20 mL of hexanes, 150 mL of THF was added, followed by the rapid dropwise addition via transfer syringe of 3.86 gm (20 mmol) of 4-(N,N-diethylamino)-2-hydroxybenzaldehyde, dissolved in 50 mL of tetrahydrofuran (THF). The flask was placed in an 80° C. oil bath and stirred vigorously for 5 minutes, at which time 2.08 mL (20 mmol) of methyl bromoacetate was added in one portion. Sodium bromide precipitated from solution and vigorous stirring had to be maintained throughout. The suspension was refluxed for 80 minutes, allowed to cool to room temperature, and diluted with 75 mL of diethyl ether. The reaction was quenched by the slow dropwise addition of 50 mL of dilute aqueous ammonium chloride. The phases were separated and the aqueous phase extracted with 100 mL of diethyl ether (Et2O). The combined organic phases were washed with 20 mL 1N NaOH and 20 mL water. After drying (MgSO4), the solvent was removed by rotary evaporation and the residual oil purified by flash chromatography (CH2Cl2 ; SiO2, 11/2×15") to yield 2.23 gm (45.3%) of the product as a colorless oil. Field desorption mass spectrum: m/e 247 (M+). Anal. calcd. for C14H17NO3 : C, 68.0; H, 6.9; N, 5.7. Found: C, 67.9; H, 6.8; N, 5.8. 1H 270 NMR (CDCl3): δ 6.7 (m, 2H, ArHa,b), B 7.4 (m, 2H, ArHc,d).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[C:6]=1[N:13]1[C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=[CH:14]1)[CH3:4]>C(Cl)Cl>[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[C:6]=1[N:13]1[C:17]([C:18]([O-:20])=[O:19])=[CH:16][N:15]=[CH:14]1)[CH3:4].[CH3:1][NH3+:2]
Reactant: CCc1cccc(CC)c1-n1cncc1C(=O)O
Reactant: CN
Solvent: ClCCl
Product: CCc1cccc(CC)c1-n1cncc1C(=O)[O-]
Product: C[NH3+]
Yield: 93 %

Procedure:
5.7 pbw (0.073 mole) of a 40% aqueous solution of methylamine are added dropwise to 15 pbw (0.061 mole) of 1-(2,6-diethylphenyl)imidazole-5-carboxylic acid in 50 pbv of methylene chloride. After 2 hours the mixture is evaporated in vacuo, the residue isstirred with 100 pbv of diethyl ether and filtered off with suction. 15.7 pbw (93% of theory) of methylammonium 1-(2,6-diethylphenyl)imidazole-5-carboxylate, a colorless solid with a m.p. of 110°-113° C., are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([OH:16])=O)[O:11][N:10]=2)=[C:5]([F:17])[CH:4]=1)#[N:2].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH:31][CH:32]2[CH2:34][CH2:33]2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([N:31]([C:14]([C:12]2[O:11][N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[F:17])[CH:13]=2)=[O:16])[CH:32]2[CH2:33][CH2:34]2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: N#Cc1ccc(-c2cc(C(=O)O)on2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cc(-c3ccc(C#N)cc3F)no2)C2CC2)CC1

Procedure:
The title compound is prepared from 3-(4-cyano-2-fluoro-phenyl)-isoxazole-5-carboxylic acid and 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester following a procedure analogous to that described for Intermediate 6. LC (method 4): tR=1.27 min; Mass spectrum (ESI+): m/z=455 [M+H]+.
Reaction SMILES: C[NH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[C:6](Br)=[CH:5][CH:4]=1.[NH2:20][CH2:21][CH2:22][CH2:23][NH2:24].[C:25]1(C)C=CC=CC=1>>[CH3:25][NH:20][C:21]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[C:6]([CH2:5][CH2:4][CH2:3][NH2:2])=[C:23]([NH2:24])[CH:22]=1
Reactant: NCCCN
Reactant: Cc1ccccc1
Reactant: CNc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Product: CNc1cc(N)c(CCCN)c2c1C(=O)c1ccccc1C2=O

Procedure:
A solution of 4-methylamino-1-bromo anthraquinone in a solvent such as toluene is heated to reflux for several hours with an excess of 1,3-diamino propane. After the reaction mixture has been treated in a manner similar to that described in Example I, the 4-methylamino-1-(γ-aminopropyl)--amino anthraquinone is isolated and after being crystallized in toluene, melts at 142° C.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[CH:15]1([NH2:18])[CH2:17][CH2:16]1>C1COCC1>[CH:15]1([NH:18][S:11]([C:6]2[C:5]([S:2]([NH2:1])(=[O:4])=[O:3])=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:13])=[O:12])[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: NS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1S(=O)(=O)NC1CC1
Temperature: 25 °C

Procedure:
A solution of 1.28 g of 2-(aminosulfonyl)benzenesulfonyl chloride in 12 ml of dry THF was cooled to -65° C. and a solution of 0.80 ml of cyclopropylamine in 12 ml of dry THF added dropwise. The resulting mixture was allowed to warm to room temperature, filtered, and the filtrate concentrated in vacuo. The solid residue was partitioned between water and ethyl acetate, the organic phase was separated, washed with water, dried (MgSO4), concentrated in vacuo, and the residue triturated with 1-chlorobutane to provide 1.15 g of N-cyclopropyl-1,2-benzenedisulfonamide as a white solid, m.p. 202°-203° C.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[C:42](O)(C(F)(F)F)=[O:43]>CN(C=O)C>[F:1][C:2]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:23][CH2:24][N:25]([CH:42]=[O:43])[CH2:26][CH2:27]3)=[CH:18][CH:17]=2)[CH:7]=1
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cc(F)ccc1F
Reactant: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cnc(Nc2ccc(C3CCN(C=O)CC3)cc2)cc1NCc1cc(F)ccc1F

Procedure:
Compound 4-(2,5-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 214) (70 mg, 0.15 mmol) was stirred in 4 mL DMF with DIEA (300 μL) at 120° C. in a sealed tube for two days. The mixture was acidified with 0.5 mL TFA and subjected to reverse phase preparative HPLC to isolate the title compound (46 mg). MS found for C25H25F2N5O2 as (M+H)+ 466.4. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.05 (1H, s), 7.97 (1H, s), 7.25 (2H, dt, J=8.8; 2.0 Hz), 7.08-6.98 (4H, m), 6.94 (1H, m), 5.74 (1H, s), 4.41 (2H, s), 4.38 (1H, m), 3.77 (1H, m), 3.17 (1H, m), 2.83 (1H, m), 2.72 (1H, m), 1.85 (2H, m), 1.53 (2H, m) ppm.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]([N:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][C:21]([CH:27]([NH2:29])[CH3:28])=[CH:22][CH:23]=2)[CH2:18]1)=[O:16].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:13][O:14][C:15]([N:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][C:21]([CH:27]([NH:29][C:8](=[O:10])[CH:7]=[CH:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=3)[CH3:28])=[CH:22][CH:23]=2)[CH2:18]1)=[O:16]
Reactant: COC(=O)N1CCc2ccc(C(C)N)cc2C1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCc2ccc(C(C)NC(=O)C=Cc3ccc(F)cc3)cc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-fluorocinnamic acid (1 mmol), (±)-7-(1-aminoethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid methyl ester, Preparation 10 (280 mg, 1.2 mmol), EDC hydrochloride (387 mg, 2 mmol), DMAP (122 mg, 1 mmol), and triethylamine (404 mg, 4 mmol) in CH2Cl2 (8 mL) was stirred at room temperature for 16 hours. The reaction mixture was directly subjected to purification by flash column chromatography on silica gel eluted with EtOAc/hexane (50%) to provide the title compound (295 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27].C[O:31]C1C=CC(C(N2C(=O)C(O)CC2)=O)=CC=1>>[C:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12]([N:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27])=[O:13])(=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N1CCCC1=O
Reactant: COc1ccc(C(=O)N2CCC(O)C2=O)cc1
Reactant: COc1ccc(C(=O)Cl)cc1OCc1ccccc1
Product: COc1ccc(C(=O)N2CCCC2=O)cc1OC(=O)c1ccccc1

Procedure:
By heating equimolar amounts of 3-benzyloxy-4-methoxybenzoyl chloride and 1-trimethylsilyl-2-pyrrolidinone in an oil-bath of 100° C. in analogy to the procedure described in paragraph (b) of Example 9 there is obtained 1-(3-benzoyloxy-4-methoxybenzoyl)-2-pyrrolidinone. After stirring in diethyl ether and recrystallisation from ethyl acetate/n-hexane (3:1), the substance melts at 90.5°-91° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:17]=[C:18]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:19]=[CH:20][CH:21]=1)([CH3:3])[CH3:2].[C:30]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][CH2:13][N:14]([CH2:15][C:16]1[CH:17]=[C:18]([C:22]([N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:23])[CH:19]=[CH:20][CH:21]=1)[CH3:30])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccccc1NCCNCc1cccc(C(=O)N2CCCCC2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)Oc1ccccc1NCCN(C)Cc1cccc(C(=O)N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 45.2 %

Procedure:
To a solution of (3-{[2-(2-isopropoxy-phenylamino)-ethylamino]-methyl}-phenyl)-piperidin-1-yl-methanone (Example 1; 0.032 g, 0.081 mmol) in DMF (0.8 mL) was added K2CO3 (0.022 g, 0.16 mmol) and iodomethane (0.03 g, 0.2 mmol), and the resulting suspension was stirred at 25° C. for 45 min. The suspension was partitioned with EtOAc (20 mL) and H2O (20 mL), and the organic layer was washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (2% CH3OH/CH2Cl2) to provide a colorless oil (0.015 g, 47%). MS (ESI): mass calculated for C26H35N3O2, 409.27. m/z found, 410.5 [M+H]+, 432.4 [M+Na]+. 1H NMR (CDCl3, 400 MHz): 7.46 (d, J=7.6 Hz, 1H), 7.36-7.31 (m, 2H), 7.27-7.25 (m, 1H), 6.84 (dt, J=7.8, 1.3 Hz, 1H), 6.78 (dt, J=7.8, 1.3 Hz, 1H), 6.63 (dt, J=7.8, 1.6 Hz, 1H), 6.58 (dt, J=7.8, 1.6 Hz, 1H), 4.53 (hept, J=6.1 Hz, 1H), 3.70 (br s, 2H), 3.60 (br s, 2H), 3.31 (br s, 2H), 3.20 (t, J=6.1 Hz, 2H), 2.73 (t, J=6.1 Hz, 2H), 2.20 (s, 3H), 1.62-1.46 (m, 6H), 1.37 (d, J=6.1 Hz, 6H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=1>C1(C)C=CC=CC=1.CN(C=O)C>[OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=2)=[CH:14][CH:15]=1
Reactant: Oc1ccc(CCNC2CCCC2O)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc(CCN[C@@H]3CCC[C@H]3O)cc2)nc1
Yield: 18.2 %

Procedure:
Heat a mixture of 4-[2-(2-hydroxycyclopentylamino)ethyl]phenol (210.5 mg, 0.95 mmol), K2CO3 (395 mg, 2.85 mmol) and 6-chloronicotinamide (223.4 mg, 1.43 mmol) in 1:3 toluene/DMF (6 mL) at 165° C. for 2 hours, while removing H2O azeotropically with toluene. Remove DMF azeotropically with xylenes and take up the residue in H2O (50 mL) and 10% MeOH in CH2Cl2 (50 mL). Shake and separate the layers. Extract the aqueous layer with 10% MeOH in CH2Cl2 (2× 50 mL) and 10% MeOH in EtOAc (50 mL). Combine the organic layers, dry over MgSO4 and concentrate. Concentrate the aqueous layer, which still contains the product by TLC, to dryness and extract the product out with MeOH. Dry the solution with Na2SO4, filter and combine with the organic concentrate above. Concentrate, re-dissolve in MeOH and filter through a Na2SO4 pad. Concentrate and purify by flash chromatography, eluting with 10:15:75 2.0 M NH3 in MeOH/CH2CL2/EtOAc to afford the title compound (137.4 mg) along with the (cis)-isomer of the starting phenol (59.0 mg) recovered: MS ES+ 342.0 (M+H)+, HRMS calcd for C19H24N3O3 342.1818 (M+H)+, found 342.1812, time 0.34 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 5-95% over 19 min], tR=16.76 min, 100% purity; Anal. Calcd for C19H23N3O3.0.1CH2Cl2 0.1EtOAc: C, 65.29; H, 6.74; N, 11.71. Found: C, 65.35; H, 6.61; N, 11.98.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].S(Cl)([Cl:9])(=O)=O.[CH3:11][CH2:12][CH:13]([OH:16])[CH2:14][CH3:15].N1C=CC=CC=1>CCCCCC.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:11][CH2:12][CH:13]([O:16][C:2]([O:4][CH2:5][Cl:9])=[O:3])[CH2:14][CH3:15]
Reactant: COC(=O)Cl
Reactant: O=S(=O)(Cl)Cl
Reactant: CCC(O)CC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CCC(CC)OC(=O)OCCl
Yield: 55 %

Procedure:
A mixture of methyl chloroformate (25.0 g), sulfuryl chloride (35.7 g) and α,α'-azobis(isobutyronitrile) (100 mg) is refluxed for 8 hours. After cooling, the reaction mixture is diluted with hexane (150 ml) and 3-pentanol (24.0 g) is added thereto. Pyridine (42.0 g) is added dropwise to the mixture for 20 minutes under ice-cooling and stirring. After the mixture is stirred at room temperature overnight, hexane (200 ml) is added thereto. The reaction mixture is washed with water, dried, filtered and evaporated to remove the solvent. The residue is distilled under reduced pressure to give 3-pentyloxycarbonyloxymethyl chloride (26.3 g).
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@H]2C3C(=CC=CC=3)C[C@@H]2OC)=NC=1CC.[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[C:39]1[C:40]([C:58]([O:60][CH3:61])=[O:59])=[N:41][C:42]([NH:47][C@@H:48]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:50][C@@H:49]2[OH:57])=[C:43]([O:45][CH3:46])[N:44]=1>>[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[C:39]1[C:40]([C:58]([O:60][CH3:61])=[O:59])=[N:41][C:42]([NH:47][C@@H:48]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:50][C@@H:49]2[O:57][CH2:2][CH3:3])=[C:43]([O:45][CH3:46])[N:44]=1
Reactant: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(OC)nc1-c1ccc(Cl)cc1Cl
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1OC
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C(=O)OC)c(-c2ccc(Cl)cc2Cl)nc1OC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine but substituting methyl 3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-5-methoxypyrazine-2-carboxylate and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 1.13–0.20, 3.15, 3.55–3.58, 3.66–3.70, 3.76, 4.02, 4.41, 5.75–5.79, 6.16, 7.25–7.34, 7.48, 7.59–7.61; MS (ESI+) for C24H23Cl2N3O4 m/z 488 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([N:20](CC)CC)[CH3:19].ClCC#N>CC(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([O:14][CH2:19][C:18]#[N:20])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Reactant: CCN(CC)CC
Agent: N#CCCl
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)OCC#N)c1
Yield: 94.5 %

Procedure:
A mixture of 3-(t-butyloxycarbonylamino)benzoic acid (20 g), triethylamine (12.8 g), chloroacetonitrile (9.4 g) and acetone (150 ml) is refluxed for 4 hours. After acetone is distilled off under reduced pressure, the residue is dissolved in ethyl acetate (200 ml), and the solution is washed with water, and ethyl acetate is distilled off under reduced pressure. The residue is recrystallized from 80% aqueous acetonitrile solution to give the title compound (22 g, 99%) as white short needles.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]#[C:12][C:13]([CH3:16])([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[N:6]2[CH2:17][CH3:18].N1C2C(=CC=CC=2)C=CC=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[N:10]=[C:9](/[CH:11]=[CH:12]\[C:13]([CH3:16])([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[N:6]2[CH2:17][CH3:18]
Reactant: [H][H]
Reactant: CCn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC(C)(C)O)nc21
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: CCn1c(-c2cccc(F)c2)nc2c(N)nc(/C=C\C(C)(C)O)nc21

Procedure:
To a solution of 200 mg of 4-[6-amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-3-butyn-2-ol in 20 ml of methanol were added 5 μl of quinoline and 20 mg of 10% palladium/barium carbonate and the mixture was stirred in a hydrogen atmosphere at room temperature for 10 minutes. The palladium/barium carbonate was filtered off and the filtrate was concentrated and then the resulting residue was subjected to a silica gel column chromatography (15 g of silica gel; dichloromethane-dichloromethane/methanol=60:1-40:1) to give (Z)-4-[6-amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-3-buten-2-ol. This was dissolved in methanol and five drops of 5N hydrochloric acid were added thereto followed by concentrating. Ethyl acetate and ether were added to the resulting residue and the crystals were collected by filtration and washed with ether to give 851 mg of the product. The yield was 26%.